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Genotoxic and cytotoxic effects of manganese chloride in
Available online at www.sciencedirect.com Toxicology in Vitro 22 (2008) 1032–1037 www.elsevier.com/locate/toxinvit Genotoxic and cytotoxic eﬀects of manganese chloride in cultured human lymphocytes treated in diﬀerent phases of cell cycle P.D.L. Lima a, M.C. Vasconcellos b, M.O. Bahia a, R.C. Montenegro b, C.O. Pessoa b, L.V. Costa-Lotufo b, M.O. Moraes b, R.R. Burbano a,*a ´ ´ ´ Human Cytogenetics Laboratory, Institute of Biological Sciences, Federal University of Para, Av. Augusto Correa, 01, CEP 66075-110 Belem, Para, Brazil b ´ Department of Physiology and Pharmacology, School of Medicine, Federal University of Ceara, Rua Coronel Nunes de Mello, 1127, Rodolfo Teoﬁlo, ´ ´ P.O. Box 3157, CEP 60431-970 Fortaleza, Ceara, Brazil Received 2 September 2007; accepted 20 December 2007 Available online 31 December 2007Abstract Manganese (Mn) has a natural occurrence and is necessary during the initial periods of the development. However, in high concen-trations, Mn can be related to neurodegenerative disorders. The aim of the present study was to evaluate the mutagenic potential of man-ganese chloride (MnCl2 Á 4H2O). Comet assay and chromosome aberrations analysis were applied to determine the DNA-damaging andclastogenic eﬀects of MnCl2 Á 4H2O. Cultured human lymphocytes were treated with 15, 20 and 25 lM manganese chloride during theG1, G1/S, S (pulses of 1 and 6 h), and G2 phases of the cell cycle. All tested concentrations were cytotoxic and reduced signiﬁcantly themitotic index in G1, G1/S and S (1 and 6 h) treatments, while in G2 treatment only the higher concentrations (20 and 25 lM) showedcytotoxic eﬀects. Clastogenicity and DNA damage were found only in treatments with the highest concentration (25 lM). Chromosomeaberrations were found exclusively in the G2 phase of the cell cycle. The absence of polyploidy in mitosis, suggests that manganese doesnot aﬀect the formation of the mitotic spindle with the concentrations tested. The genotoxicity found in G2 phase and in the comet assaycan be related to the short time of treatment in both cases.Ó 2007 Elsevier Ltd. All rights reserved.Keywords: Manganese chloride; Chromosome aberration; Comet assay1. Introduction deﬁciency can aﬀect agriculture worldwide (Gerber et al., 2002). In animals, Mn acts in physiological processes such Manganese (Mn) is the 5th most abundant metal and as the regulation of reproduction, formation of connectivethe 12th most abundant element of the terrestrial crust, tissues and bone marrow, lipid and carbohydrate metabo-where its minerals (especially oxides, silicates and carbon- lism and in the maintenance of the brain (Keen et al., 1999;ates) are widely distributed. Mn is an essential nutrient that Pittman, 2005). This metal is also an important co-factorplays a role in plant and animal physiological processes. In for numerous enzymes involved in the biosynthesis ofplants, it participates in the respiratory process, where its DNA and neurotransmitters and in transduction signals (Roth and Garrick, 2003; Pittman, 2005). Abbreviations: Mn, manganese; MnCl2 Á 4H2O, manganese chloride te-trahydrate; MnCl2, manganese chloride; MnSO4, manganese sulfate; In one way, Mn has a natural occurrence, where the ero-KMnO4, potassium permanganate; CA, chromosomal aberration; COL, sion of soil is one of its most important natural sources. Incolchicine; DOX, doxorubicin; EMS, ethylmethanesulfonate; End, endo- another way, Mn can be found as a result of contaminationreduplication; FBS, fetal bovine serum; HAR, harvest; MI, mitotic index; in the ground, sediments and/or water by aerosols, insecti-PHA, phytohaemaglutinin; Polyp, polyploid cells. cides and fertilizers (Gerber et al., 2002). Despite the fact * Corresponding author. Tel.: +55 091 3183 1102/8802 7972; fax: +55091 3183 1601. that the absorption of the Mn is only 3–5%, food is the pri- E-mail address: firstname.lastname@example.org (R.R. Burbano). mary sources of the metal ingested by human beings and0887-2333/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.doi:10.1016/j.tiv.2007.12.011
P.D.L. Lima et al. / Toxicology in Vitro 22 (2008) 1032–1037 1033animals. Other sources of Mn exposure is related to work Doxorubicin hydrochloride (Adriamycin, CAS no.conditions, where Mn particles can be inhaled or absorbed 25316-40-9) and ethylmethanesulfonate (EMS, CAS no.(WHO, 1999; Gerber et al., 2002). 62-50-0) were purchased from Sigma–Aldrich Co. (St. Deﬁciencies of Mn during the initial periods of develop- Louis, MO, USA).ment can induce skeletal muscle abnormalities and irrevers- Phytohemagglutinin (PHA) was obtained from Abbottible ataxia, in addition to fertility problems (Keen et al., Laboratories, Maidenhead, UK. HAM F-10 growth med-1999). Poisoning by high levels of Mn can lead to some ium and fetal bovine serum were purchased from GibcoÒalterations in organisms, where the lungs and the central (Invitrogen, Carlsbad, CA, USA). Colchicine was pur-nervous system (CNS) are the main target organs (Gerber chased from Sigma–Aldrich Co. (St. Louis, MO, USA).et al., 2002). Chronic exposure to high levels of Mn canalso induce a syndrome known as manganism, character- 2.2. Test controlsized by extrapyramidal dysfunction (bradykinesia, rigidityand dystonia) and neuropsychiatric symptoms that resem- Double-distilled water was used as the vehicle since itble idiopathic Parkinson’s disease (Calne et al., 1994; Barc- neither induced chromosomal aberrations nor reducedeloux, 1999; Gerber et al., 2002). the mitotic index when compared to the cultures without The neurotoxicity induced by Mn is related to the phys- its addition (data not shown).iological dichotomy between its oxidation states, Mn2+ and The cytotoxic and mutagenic agent doxorubicin wasMn3+. The ﬁrst one is necessary for the normal cerebral used as positive control for lymphocyte cultures at a con-activities since is essential for the catalytic activity of super- centration of 0.018 lM (Dhawan et al., 2003) and EMSoxide dismutase that eliminates superoxide radicals (Ose used as positive control for the comet assay at a concentra-and Fridovich, 1976), while the second one enhances the tion of 40 lM (Wagner et al., 2003).oxidation of dopamine, thereby producing neurotoxic bio- ´products (Gutierrez and Salsamendi, 2001). The association between Mn and the risk for the devel- 2.3. Lymphocyte cultureopment of neurodegenerative processes can be related toDNA damage. There are few studies related to the geno- Peripheral blood was collected from four normal,toxic activities of Mn. Its mutagenic potential has been healthy donors, two women and two men, aged 20–27studied by in vitro tests in bacteria and in vivo/in vitro tests years, with no history of smoking/drinking or chronic drugin insect and mammalian cells, showing that some chemical use. A volume of 10 mL of venous blood was collectedforms of this metal have mutagenic potential (De Meo from each donor into heparinized vials (5.000 IU/mL; Liq-et al., 1991; Timchenko et al., 1991; Ogawa et al., 1994; ´ uemine; Roche). Short-term lymphocyte cultures were setBrega et al., 1998; WHO, 1999; Gerber et al., 2002). up according to a standard protocol (Preston et al., Therefore, the aim of this study was to investigate the 1987). The culture medium consisted of 5 mL HAM-F10genotoxic, clastogenic and cytotoxic eﬀects of MnCl2 Á (78%), heat-inactivated fetal bovine serum (20%), phyto-4H2O in diﬀerent phases of cell cycle using short-term cul- hemagglutinin-M (2%) and antibiotics (0.028 lM of peni-tures of human lymphocytes in vitro. These eﬀects were cillin, Sigma–Aldrich Co., St. Louis, MO, USA;determined by the mitotic index (MI), chromosomal aberra- 0.0068 lM of streptomycin, USB, Cleveland, OH). Thetions (CAs) and DNA damage index detected by the comet culture tubes were incubated at 37 °C in a 5% CO2 atmo-assay. The Mn used in the present study was the tetrahy- sphere with 95% relative humidity.drate form of manganese chloride (MnCl2 Á 4H2O), one ofthe most common forms of Mn (WHO, 1999). 2.4. Treatments and biological tests The concentrations of MnCl2 Á 4H2O used in the presentstudy (15, 20 and 25 lM) are based on literature references For cytogenetic analysis, MnCl2 Á 4H2O was studied at(Eriksson and Heilbronn, 1983; Gerber et al., 2002; Goldoni three concentrations (15, 20 and 25 lM) in diﬀerent phaseset al., 2003; Piﬂ et al., 2004; Isaac et al., 2006) adapted to of the cell cycle. In G1, lymphocytes in complete culture med-lymphocyte cell cultures. Besides, preliminary experiments ium were treated with a combination of 0.2 mL phytohemag-indicated that cells treated with MnCl2 Á 4H2O concentra- glutinin-M and MnCl2 Á 4H2O. The cells were ﬁxedtions higher than 25 lM showed inhibition of cell division, following 52 h of incubation at 37 °C. In the transition phasepreventing the cytogenetic and cell cycle kinetics studies. G1–S, the cultures were treated with the diﬀerent concentra- tions of MnCl2 Á 4H2O 24 h after phytohemagglutinin stim-2. Materials and methods ulation and were ﬁxed 52 h after the initiation of the culture. To determine the speciﬁc eﬀects of MnCl2 Á 4H2O in the S2.1. Chemical agents phase, pulse treatments with MnCl2 Á 4H2O for 1 and 6 h were performed 24 h after phytohemagglutinin stimulation. Stock solutions were made by dissolving MnCl2 Á 4H2O Following each pulse treatment, cells were washed once in(CAS no. 13446-34-9 Sigma–Aldrich Co., St. Louis, MO, serum-free medium, re-incubated in complete medium, andUSA) in double-distilled water, immediately prior to use. ﬁxed after 52 h of incubation. In the G2 treatments, 69-h
1034 P.D.L. Lima et al. / Toxicology in Vitro 22 (2008) 1032–1037cultures were treated with MnCl2 Á 4H2O for 3 h, and then 2.7. Statistical analysisﬁxed immediately (72 h total incubation) (Table 1). Student’s t-test was used to compare the frequencies of2.5. Cytogenetic studies CAs observed in cells exposed to the various concentra- tions of manganese with those of respective controls. The In order to obtain a suﬃcient number of metaphases to F-test (ANOVA) was used to detect signiﬁcant diﬀerencesbe analyzed, colchicine was added at a ﬁnal concentration in the MI. For comet assay, data were analyzed by one-of 0.0016%, 2 h prior to harvesting. The cells were har- way ANOVA followed by Tukey’s test. The level for statis-vested by centrifugation and treated with 0.075 M KCl at tical signiﬁcance (p) was established at 5% (p < 0.05). Bioe-37 °C for 20 min. The cells were then centrifuged and ﬁxed statÒ was the statistical software used in this study (Ayresin 1:3 (v/v) acetic acid:methanol. Finally, slides were pre- et al., 2000).pared, air-dried and stained with 3% Giemsa solution(pH 6.8) for 8 min (Moorhead et al., 1960). 3. Results Slides were examined with an optical microscope, andstructural and numerical CAs were determined in metapha- 3.1. Chromosome aberrations and mitotic indexses from the manganese-treated cultures and from therespective controls. The frequency of CAs (in 100 metapha- At G1, G1/S and S-phase treatments of 1 and 6 h,ses per culture) and the MI (number of metaphases per marked cytotoxic eﬀects of manganese chloride were2000 lymphoblasts per culture) were determined. observed as decreases in the MI of cultured lymphocytes treated in all the tested concentrations (p < 0.01) (Tables2.6. Comet assay 2 and 3). In G2 phase, only the concentrations of 20 lM (p < 0.05) and 25 lM (p < 0.01) were cytotoxic to the lym- Peripheral venous blood was collected in heparinized phocyte cultures (Table 4).vials as above from four normal, healthy donors, two The frequency of CAs was signiﬁcantly increased onlywomen and two men, aged 23–28 years, with no history during G2 treatment, with the high concentration ofof smoking/drinking or chronic use of medication. Periph- 25 lM (p < 0.01) (Table 4). Chromatid gaps and chromatideral blood lymphocytes were isolated by Ficoll density gra- breaks were the most frequent CAs. With the other treat-dient (Histopaque 1077; Sigma Diagnostics Inc., St. Louis) ments, no genotoxic eﬀects of MnCl2 Á 4H2O were observedincubated for 3 h with diﬀerent concentrations of (Tables 2 and 3). No signiﬁcant endoreduplication or poly-MnCl2 Á 4H2O (15, 20 and 25 lM) and then mixed with ploidy was observed (Tables 2–4).low-melting point agarose. The alkaline version of the comet assay (single-cell gelelectrophoresis) was performed as described by Singh 3.2. Comet assayet al. (1988) with minor modiﬁcations (Hartmann andSpeit, 1997). Slides were prepared in duplicate and 100 cells Only the concentration of 25 lM showed statisticallywere screened per sample (50 cells from each duplicate diﬀerent (p < 0.05) results in relation to the negative con-slide) with a ﬂuorescence microscope (Zeiss) equipped witha 515–560 nm excitation ﬁlter, a 590 nm barrier ﬁlter, and a Table 2 Chromosome aberrations (CAs) and mitotic index (MI) in cultured human40Â objective. Undamaged cells appeared as intact nuclei lymphocytes treated with MnCl2 Á 4H2O during the G1 and G1/S phaseswithout tails, whereas damaged cells had the appearance of the cell cycleof a comet. Comets were classiﬁed visually as belonging MnCl2 treatment MI (%) CAs Polyp Endto one of ﬁve classes according to tail size and given a score Gaps Breaks Totalof 0, 1, 2, 3 or 4 (from undamaged = 0, to maximally dam-aged = 4). Thus, the total damage score for 100 comets G1 NC 6.0 2 0 2 0 0ranged from 0 (all undamaged) to 400 (all maximally dam- 15.0 lM 2.4** 2 0 2 1 0aged) (Speit and Hartmann, 1999). 20.0 lM 1.3** 0 0 0 0 0 25.0 lM 1.2** 3 1 4 1 0Table 1 Dox 3.1** 5 4 9* 2 4*Treatment protocols of MnCl2 Á 4H2O applied to short-term cultures ofhuman lymphocytes G1/S NC 6.0 2 0 2 0 0Treatment PHA (h) Mn (h) Wash (h) COL (h) HAR (h) 15.0 lM 4.0** 5 0 5 0 0G1 0 0 – 50 52 20.0 lM 3.0** 6 1 7 1 0G1/S 0 24 – 50 52 25.0 lM 3.0** 6 2 8 0 0S1 (1 h pulse) 0 24 25 50 52 DOX 3.2** 17 6 23* 5* 0S1 (6 h pulse) 0 24 30 50 52 NC: negative control; Polyp: polyploid cells; End: endoreduplication;G2 0 69 – 70 72 DOX: doxorubicin (positive control). *PHA: phytohaemagglutinin; FBS: fetal bovine serum; COL: colchicine; p < 0.05. **HAR: harvest. p < 0.01.
P.D.L. Lima et al. / Toxicology in Vitro 22 (2008) 1032–1037 1035Table 3 Table 5Chromosome aberrations (CAs) and mitotic index (MI) in human Eﬀects of MnCl2 Á 4H2O or doxorubicin (DOX) on cell damage index inlymphocytes treated with MnCl2 Á 4H2O during the S phase of the cell comet assaycycle Substance Treatment Damage Damage frequencyMnCl2 treatment MI (%) CAs Polyp End (lM) indexa (%)a Gaps Breaks Total DOXb 151 ± 2.8** 49.80 ± 0.25** NCc – 24.70 ± 5.3 16.25 ± 1.551hNC 6.0 2 0 2 0 0 MnCl2 Á 4H2O 15 52.30 ± 6.9 25.70 ± 4.1715.0 lM 1.8** 1 0 1 0 0 20 51.75 ± 12.0 27.67 ± 5.2520.0 lM 1.9** 1 0 1 0 0 25 82.00 ± 14.0** 33.25 ± 2.17*25.0 lM 1.6** 4 0 4 0 0 Data signiﬁcant in relation to NC at: *p < 0.01 **p < 0.001.DOX 2.4** 10 7 17* 1 1 a Mean values and standard deviation obtained from average of 100 cells6h per experiment À total of four experiment per dose for each substance. bNC 6.0 2 0 2 0 0 Doxorubicin, positive control.15.0 lM 0.8** 0 0 0 0 0 c Negative control.20.0 lM 0.8** 1 0 1 0 025.0 lM 0.6** 3 0 3 0 0DOX 1.9** 14 10 24* 3* 0 toxic for human lymphocytes at all the concentrationsNC: negative control; Polyp: polyploid cells; End: endoreduplication; and phases of the cell cycle tested (Lima et al., 2007).DOX: doxorubicin (positive control). * p < 0.05. Mn was chosen for the present study because it is a** p < 0.01. metal of natural occurrence, and a common chemical ele- ment, necessary for the initial periods of development (Keen et al., 1999; WHO, 1999; Gerber et al., 2002). SinceTable 4 there are studies indicating a probably relationship betweenChromosome aberrations (CAs) and mitotic index (MI) in human Mn exposure and increased risk of neurodegenerative dis-lymphocytes treated with MnCl2 Á 4H2O during the G2 phase of the cellcycle orders witch symptoms are similar to Parkinson’s disease (Calne et al., 1994; Barceloux, 1999; Gerber et al., 2002).MnCl2 treatment MI (%) CAs Polyp End The results of the present study showed a high cytotoxic Gaps Breaks Total potential of Mn in several phases of the cell cycle, as dem-NC 6.0 2 0 2 0 0 onstrated by decreases on MI. The cytotoxicity of a chem-15.0 lM 5.4 5 2 7 1 0 ical mutagen can be estimated from several endpoints and20.0 lM 5.0* 5 3 8 0 025.0 lM 4.9** 8 4 12* 0 0 one of the most used is MI (Galloway, 2000). When usingDOX 5.2* 24 8 32** 7* 4 lymphocyte cultures, the use of MI is acceptable as a tox-NC: negative control; Polyp: polyploid cells; End: endoreduplication; icity measure, especially when other toxicity measurementsDOX: doxorubicin (positive control). are cumbersome or impractical (Galloway et al., 1994). * p < 0.05. Chromosome aberrations (CAs) were observed only at** p < 0.01. the highest dose (25 lM) at G2 phase after 3 h treatment. Cytogenetic results corroborated the comet assay ﬁndings, where genotoxicity was also observed only at the highesttrol (p < 0.01), but no signiﬁcant diﬀerences were seen dose after 3 h of drug exposure. It is possible that the repairbetween the diﬀerent manganese concentrations tested. system in the other phases of the cell cycle protects cells All concentrations of manganese tested were shown to from CAs since, after treatment, the cells are kept in cul-diﬀer from that of the positive control (dox) (p < 0.001) ture until the next cell cycle occurs. In cells treated in G2,(see Table 5). this did not happen mainly because the cells were exposed to colchicine treatment. We suggest as a main mechanism of manganese toxicity4. Discussion by DNA synthesis blocks, since the cytotoxicity was observed on small doses on phases G1, G1/S an S of the In an industrialized world, there are many types of met- cell cycle, on this phases, this metal was not clastogenic,als in use (such as manganese, iron, aluminum, mercury, but interferes on cell replication. Mn does not presentcopper, lead, zinc and others) and humans are exposed to direct genotoxicity; we believe that CAS found when cellsthem at work, or as a result of contamination of food, were treated on G2 is due to the blockage of the repairwater or environment (Veldman et al., 1998; Purdey, of DNA, thus, Mn does not relate directly to DNA. We2004; Shi et al., 2004). The clinical symptoms and the pos- can prove our hypotheses noticed that the cells treated withsible mutagenic eﬀects produced by acute poisoning and Mn in the other phases even in high doses, do not exhibitchronic exposure to metals are of considerable interest CAs.(Ganrot, 1986; Ferrer, 2003). Recently, our research group From metabolic, the presence of the microsomal liverdemonstrated that aluminum chloride (AlCl3) was geno- fraction S9 in treatments with the same concentrations
1036 P.D.L. Lima et al. / Toxicology in Vitro 22 (2008) 1032–1037cited in this work did not show signiﬁcant diﬀerences with 0.5 mM) (WHO, 1999). In vivo studies have demonstratedthe previous results (data not shown), which reinforces that that oral doses of manganese sulfate or potassium perman-in general heavy metals do not suﬀer inﬂuence of metabolic ganate induces CAs in the bone marrow of animals,activation in the induction of CAs (Chen et al., 2006; De whereas no CAs have been observed after oral doses ofMeo et al., 1991). With respect to cytotoxicity, the S9 frac- manganese chloride on concentrations over than 12 lMtion not alters the eﬀect of the presence of the metal in cul- (WHO, 1999). These results show that the mutagenicture, regardless of the phase of the cycle. Our results potential of Mn may be diﬀerent between permanganateindicates that despite Mn be a toxic agent to liver cells salts and manganese salts.(Khan et al., 1997; Rovetta et al., 2006), your genotoxic De Meo et al., 1991 evaluated the genotoxicity of potas-action do not need metabolic activation. sium permanganate (KMnO4), manganese sulfate and New studies must be conducted to verify the relationship manganese chloride using the Ames test with the testerof intoxication with Mn and other metals present physio- strains TA97, TA98, TA100 and TA102 with and withoutlogically in the body. Chen et al., 2006 showed that Mn metabolic activation. The presence of direct-acting muta-induces an increase in the iron level on rat brain. gens was detected in all the samples of Mn with the tester It is important to point out that polyploidy and endore- strain TA102 without metabolic activation. Only manga-duplicated cells were not observed at any of the doses nese chloride induced DNA damage in human lymphocytestested, suggesting that Mn does not aﬀect mitotic spindle with a dose–response relationship as determined by theformation. These observations show that Mn does not have comet assay. The mutagenic potential was 2.4 revertant/an antipolymerizing eﬀect on tubulin dimers. nmol. This eﬀect was also found in this work using the Gerber et al. (2002) demonstrated that high dose comet assay with the higher concentration of 25 lM.(0.05 M) of various compounds of Mn can aﬀect DNA rep- According to the WHO (1999), other chemical forms oflication and repair in bacteria. As for mammalian cells, Mn have mutagenic potential in vitro and in vivo. Morehigh doses of Mn (compared with respect to concentration studies must be done to elucidate the probable mutagenic-of manganese recommended for daily consumption).can ity of Mn and its chemical forms in human health.aﬀect fertilization and is toxic to the embryo and fetus, In conclusion, MnCl2 Á 4H2O shows strong cytotoxicitydemonstrating its teratogenic potential (Gerber et al., in all phases of the cell cycle. The genotoxicity observed2002). Manganese chloride (MnCl2) was also subjected to at G2 phase and in the comet assay, may be related tothe wing spot test of Drosophila melanogaster and was the lack of time for the cellular repair system to act or toshown to be clearly eﬀective in inducing spots with one some other mechanism not studied in this work. Theor two mutant hairs (small spots) on concentrations over absence of CAs in the other phases of the cell cycle suggeststhan 12 lM (Ogawa et al., 1994). These ﬁndings, at high that Mn-mediate damage may be repaired in vitro.Mn concentrations, are in agreement with our results,where only treatment with the high concentration showed Acknowledgmentsgenotoxic potential. Previous studies by Brega et al. (1998) demonstrated This work was supported by Financiadora de Estudos ethat farm workers exposed to pesticides containing Mn, Projetos (FINEP CT-INFRA/FADESP) (Grant No. 0927-even at a low level, increased the mutagenic potential of ´ 03), Conselho Nacional de Desenvolvimento Cientıﬁco ethose pesticides, as evidenced by an increased number of ´ Tecnologico (CNPq) and by Coordenacao de Aperfeicoa- ß˜ ßCAs. It is possible that chronic exposure to low doses of ´ mento de Pessoal de Nıvel Superior (CAPES). We thankMn induces CAs over years, since they are not acutely cyto- Dr. A. Leyva for English editing of the manuscript.toxic. The assay used in this work did not reproduce along-term exposure, thus the cytotoxic eﬀects may havehindered the appearance of CAs in the cells. References It is possible that Mn causes genotoxic eﬀects at low Ayres, M., Ayres, Jr., M., Ayres, D.L., Santos, A.S., 2000. Bioestat 2.0.doses only with long-term exposure, and this may be rea- ´ ´ Belem. Sociedade Civil Mamiraua, p. 272.son why Timchenko et al. (1991) did not ﬁnd CAs in nasal Barceloux, D.G., 1999. Manganese. Journal of Toxicology: Clinicalmucosa of mammals exposed to Mn dioxide aerosol (40– Toxicology 37, 293–307.12,000 Hz, 80–100 dB). Brega, S.M., Vassilieﬀ, I., Almeida, A., Mercadante, A., Bissacot, D., Cury, P.R., Freire-Maia, D.V., 1998. Clinical, cytogenetic and We agree that the genotoxic eﬀects of Mn can be inﬂu- toxicological studies in rural workers exposed to pesticides inenced by the presence of other chemical agents such as that Botucatu, Sao Paulo, Brazil. 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Cytotoxicity and chromosome aberrations in vitro: lymphocyte assay for assessing the clastogenicity of chemical agents. experience in industry and the case for an upper limit on toxicity in the Mutation Research 189, 175–183. aberration assay. Environmental and Molecular Mutagenesis 35, 191– Purdey, M., 2004. Elevated levels of ferrimagnetic metals in food chains 200. supporting the Guam cluster of neurodegeneration: do metal nucleatedGanrot, P.O., 1986. Metabolism and possible health eﬀects of aluminum. crystal contaminants evoke magnetic ﬁelds that initiate the progressive Environmental Health Perspectives 65, 363–441. pathogenesis of neurodegeneration? Medical Hypotheses 63, 793–809.Gerber, G.B., Leonard, A., Hantson, P., 2002. Carcinogenicity, mutage- Roth, J.A., Garrick, M.D., 2003. Iron interactions and other biological nicity and teratogenicity of manganese compounds. Critical Reviews in reactions mediating the physiological and toxic actions of manganese. Oncology/Hematology 42, 25–34. Biochemical Pharmacology 66, 1–13.Goldoni, M., Vettori, M.V., Alinovi, R., Gaglieri, A., Ceccatelli, S., Mutti, Rovetta, F., Catalani, S., Steimberg, N., Boniotti, J., Gilberti, M.E., A., 2003. Models of neurotoxicity: extrapolation of benchmark doses ` Mariggio, M.A., Mazzoleni, G., 2006. Organ-speciﬁc manganese in vitro. Risk Analysis 23, 505–514. toxicity: a comparative in vitro study on ﬁve cellular models exposed ´ ˆGutierrez, J.B., Salsamendi, A.L., 2001. Fundamentos da Ciencia Toxi- to MnCl2. Toxicology in Vitro 21, 284–292. ´ cologica. Diaz de Santos, Madri, 123 pp.. Shi, H., Hudson, L.G., Liu, K.J., 2004. Oxidative stress and apoptosis inHartmann, A., Speit, G., 1997. The contribution of cytotoxicity to DNA metal ion-induced carcinogenesis. Free Radical Biology & Medicine eﬀects in the single cell gel test (comet assay). Toxicology Letters 90, 37, 582–593. 183–188. Singh, N.P., Mccoy, M.T., Tice, R.R., Schneider, E.L.A., 1988. SingleIsaac, A.O., Kawikova, I., Bothwell, A.L.M., Daniels, C.K., Lai, J.C.K., technique for quantitation of low levels of DNA damage in individual 2006. Manganese treatment modulates the expression of peroxisome cells. Experimental Cell Research 175, 184–191. proliferator-activated receptors in astrocytoma and neuroblastoma Speit, G., Hartmann, A., 1999. The comet assay (single-cell gel test). A cells. Neurochemical Research 31, 1305–1316. sensitive genotoxicity test for the detection of DNA damage andKhan, K.N., Andress, J.M., Smith, P.F., 1997. Toxicity of subacute repair. Methods in Molecular Biology 113, 203–212. intravenous manganese chloride administration in beagle dogs. Tox- ´ ´ Timchenko, O.I., ParanKo, N.M., Shantyr, E.E., KuzMenko, S.D., 1991. icologic Pathology 25, 344–350. The cytogenetic eﬀects of separate and combined exposures to aKeen, C.L., Ensunsa, J.L., Watson, M.H., Baly, D.L., Donovan, S.M., manganese dioxide aerosol and wide-band noise. Gigiena i Sanitariia Monaco, M.H., Clegg, M.S., 1999. Nutritional aspects of manganese 11, 70–72. from experimental studies. Neurotoxicology 20, 213–223. Veldman, B.A., Wijn, A.M., Knoers, N., Praamstra, P., Horstink, M.W.,Lima, P.D., Leite, D.S., Vasconcellos, M.C., Cavalcanti, B.C., Santos, 1998. Genetic and environmental risk factors in Parkinson’s disease. R.A., Costa-Lotufo, L.V., Pessoa, C., Moraes, M.O., Burbano, R.R., Clinical Neurology and Neurosurgery 100, 15–26. 2007. Genotoxic eﬀects of aluminum chloride in cultured human Wagner, E.D., Anderson, D., Dhawan, A., Rayburn, A.L., Plewa, M.J., lymphocytes treated in diﬀerent phases of cell cycle. Food and 2003. Evaluation of EMS-induced DNA damage in the single cell gel Chemical Toxicology 45, 1154–1159. electrophoresis (comet) assay and with ﬂow cytometric analysis ofMoorhead, P.S., Nomell, P.C., Mellman, W.J., Battips, D.M., Hunger- micronuclei. Teratogenesis, Carcinogenesis and Mutagenesis 2, 1–11. ford, D.A., 1960. Chromosome preparations of leukocytes cultured World Health Organization (WHO), 1999. Manganese and its com- from human peripheral blood. Experimental Cell Research 20, 613– pounds. Concise International Chemical Assessment Document 12. 616. WHO, Geneva.

domain: chemistry


text:
SARASOTA, Fla. (Sept. 12, 2019) – The University of South Florida Sarasota-Manatee has created a committee to engage more fully with the diverse community it serves and assist more students of color in achieving their academic goals.
Called EMBRACE, the committee is comprised of community and educational leaders from Manatee and Sarasota counties, including Rachel Shelley, principal of Emma E. Booker High School in Sarasota; Brandon Johnson, principal of North Port High School; Carolyn Griffin, director of strategic impact, United Way Suncoast; Catrese Estes, vice president of program services, Boys & Girls Clubs of Manatee County and Suzanne W. Burke, director of college career and life readiness, the Education Foundation of Sarasota County.
The committee is led by USF Sarasota-Manatee Diversity, Equity and Inclusion Officer Corey L. Posey. It met for the first time on Friday, Sept. 6, led by Posey and USFSM Regional Chancellor Karen A. Holbrook, PhD.
The committee’s goal is to develop recommendations on how the campus can strengthen ties with underrepresented communities in Sarasota and Manatee and increase enrollment of students from those communities.
“Dr. Holbrook and I thought that it was really important that we share the direction that our university wanted to go in,” Posey told the group, which met at USFSM’s Selby Auditorium. “We didn’t invite you just because we’re low in certain areas and we need black and brown faces on our campus. We need your feedback to spark change.
“We need diversity of experience in our student body so that we can all learn from one another, so that when our students do enter the workforce, working with other people, they will know they’ve had similar conversations before and are comfortable with them.”
After an overview, Posey asked committee members to form two work groups, the College and Career Readiness group and the Community Impact group, to begin to strategize and develop recommendations in the coming months.
“Essentially there will be two arms of the same committee looking to tackle things we identify as barriers in the community,” he said.
Looking ahead, Posey said he envisioned:
- More diversity-focused discussions among students and faculty at USFSM
- More campus events to foster dialogue with local communities, including at the annual USFSM Carnival
- A diversity-themed speaker series
- Greater outreach and support of minoritized populations at local high schools through initiatives such as the Gamma Xi Boule Journey to Success program
- The formation of a “Legacy Builder” scholarship to support minority students at USFSM
He added that he hoped to establish a long-term partnership with local communities to create a pipeline of underrepresented students to USFSM.
“In the end, USFSM wants to do its part in strengthening communities through education,” he said. “This meeting was a strong first step.”
For more about USF Sarasota-Manatee, visit usfsm.edu.

domain: sociology


text:
Behind the Hype of the Dysfunctional Premier League and Unfriendly VAR
As Aston Villa find out that one Premier League referee is certainly no friend of their's, we reflect back to Villa's start to the season and events at Crystal Palace and beyond.
On top of VAR problems, English football has other issues as Bury vanish from the football league. We also look to the USA and Iran for other football stories.
Back in the Villa-verse we question Douglas Luiz's role in the team and Villa's early season teething problems.
And then there's an epic Scott Hogan Touch Count Meter battle, proudly sponsored by the Warwickshire Gin Company
Plus, as always, lots, lots more.
SUPPORT THE SHOW
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For more details and to become a Patron, click here: Join MOMS Patrons
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domain: sports


text:
LAST UPDATED : May 23, 2019, 12:00 AM IST
- ‘Hari Chunari Chaupal was Dushyant’s idea’
Referring to a group of women, who had come in large number to hear her at Jind’s Pegan village that fall under Uchana assembly segment of Hisar parliamentary seat, she said, “You can understand the plight of a mother and the circumstance under which your son Dushyant is contesting this time. We need more support this time than the 2014 parliamentary polls, when you had given massive lead from Uchana that ensured Dushyant’s victory.”
- Lack of freedom, security aspect most frustrating thing about living in Pakistan: Grant Flower
Grant Flower said the "lack of freedom and security aspect" is the most frustrating thing about living in strife-torn Pakistan, where he has served as the national team's batting coach for five years. In 2014, the former Zimbabwe opener was roped in to coach the Pakistan batsmen, but the country's cricket board last week decided not to renew his contract.
- Cluster bus conductors to go to passengers to collect fare, not so in DTC, Delhi HC told
The AAP government has made it mandatory for conductors in cluster buses to go to passengers and collect the fare, but the same is not a requirement in Delhi Transport Corporation (DTC) buses, the Delhi high court was told on Tuesday.

domain: news


text:
Baldness can be a menacing problem, specifically for women and younger people. Proven choices for treatment are varied through medications, to hair repair surgery, to wigs. Occasionally a multifaceted approach is essential for optimal results however the most definitive treatment continues to be hair transplantation. Recent improvements in technique have made the process nearly painless and in a position to produce very natural outcomes. Coming technology promises better still results if we are able to effectively clone human hair. There is absolutely no optimal age for a tresses transplant. If people are going through balding, hair transplants could be a good option. The key to remember is the fact that balding will continue even though transplanted hair will remain. This is very important for two reasons. First, actions should be taken to slow down the reduction rate as much as possible.
Care should be taken in the design of the Fue Hair Transplant Recovery treatment to optimize the hair used. If attention is simply compensated to the area of hair loss without having taking into account future hair loss, the actual transplant will not look organic in the not too faraway future. And remember, once the donor hair is used up, this cannot be regenerated. Absolutely. Females can have just as a good an outcome as men with curly hair transplants. It is important to be handled by a doctor with experience for hair loss, not just transplantation. Ladies tend to suffer from more health conditions which can cause hair loss. It is crucial to determine if there is a medical problem causing the hair loss and dealing with that condition before going forward with a transplant.
With brand new techniques in hair transplantation, the actual days of hair plugs tend to be long gone. The hairline made up of today’s techniques are very normal and even your hair stylist will never know you had a implant when done by a reputable doctor. The transplanted hairs is not going to fall subject to regular female or male pattern balding. The all-natural balding will continue, nevertheless. Again, this is important to remember preparing a hair transplant so the donor site can be kept and a natural hairline could be created for a lifetime, not just the following years.
The techniques for One Month After Hair Transplant are not difficult to master. The important thing to hair transplantation has a good staff of specialists, as a large part of the process is done by technicians, as well as having a background that provides the training necessary to understand the hair loss procedure, not just the technical facets of hair transplantation. If you are thinking about a hair transplant, make sure to research the physician you are going to. That person should be able to not only carry out the procedure but also to understand baldness to give you a result that will not final just a year or two but an whole lifetime.
Drt Hair Transplant Clinic
Adress: Istanbul, TURKEY

domain: medical


text:
Fasti Ecclesiae Anglicanae 1066-1300: Volume 9, the Welsh Cathedrals (Bangor, Llandaff, St Asaph, St Davids). Originally published by Institute of Historical Research, London, 2003.
This free content was digitised by double rekeying. All rights reserved.
Son of bp. Sulien (above, list 34), and described as 'high-pr.' of Llanbadarn in notice of his d., 30 March 1137 (Brut Peniarth Text p. 88b; Brut Peniarth Transl. p. 52; Brut Red Book pp. 116-17). Perhaps archdcn. of Cardigan. Gerald of Wales states that half the chapter, the faction that opposed him, was descended from Ieuan (Gir. Cambr. III 312).]
Son of Daniel archdcn. of Powys (i.e. Meifod, St Asaph dioc., above, list 26) and grandson of bp. Sulien, d. as archdcn. of Cardigan 1163 (Brut Peniarth Text pp. 109b-110a; Brut Peniarth Transl p. 62; Brut Red Book pp. 144-5; Ann. Camb. p. 49).
First occ. as archdcn. of Cardigan, then in Ireland, 10 Nov. 1203 (Gir. Cambr. III 323). Occ. as archdcn. 7 Dec. 1203 x 1214 (St Davids Acta no. 69, at p. 93). Prob. to be identified with Maredudd ap Rhys ap Gruffudd, archdcn. of Cardigan, son of the Lord Rhys, (fn. 1) who 'prospered too much from the favour of princes' (De Invectionibus pp. 224-5), (fn. 2) and d. 1227 (Brut Peniarth Text p. 189a; Brut Peniarth Transl. p. 101; Brut Red Book pp. 226-7).
Said to occ. as archdcn. of Cardigan 1283 (Menevia Sacra p. 221, citing Browne Willis MS Collect.) Perhaps to be identified with Owen son of Griffith, son of Madoc, parson of 'Bankbiry', nor called archdcn., who had protection 24 May 1282 (CPR 1281-92 p. 23) and 8 Sept. 1282 (ibid. p. 35).

domain: history


text:
WELCOME TO PTSP!
An organization dedicated to serving the Pilipinx transfer community through our three pillars: recruitment, retention, and research.
PILIPINO TRANSFER STUDENT PARTNERSHIP
Pilipino Transfer Student Partnership
aims to ease the transition of transfer students to life at UCLA and providing a space for student support during their Bruin lives. We seek to raise awareness about cultural and academic issues regarding the transfer experience by advocating the needs of transfer students and encouraging leadership, community responsibility, and accessibility to higher education through academic services and community building.


text:
*This review contains spoilers.*
Superhero Movie is about how a teenage guy is bitten by a radioactive insect, gains its powers, and uses it to stop crime. In other words, a spoof of Spider-Man.
I'm not a very big fan of the "_____ Movie" series that was started by Jason Friedberg and Aaron Setzer. All of their movies boil down to shallow parodies of numerous cinema franchises. By no means is Superhero Movie a unique entry in the series that abandons this formula, as you can see from the poster and DVD box art. However, while Superhero Movie is yet another forgettable entry in the series, its director, Craig Mazin, is actually a much better director and writer than the founders of the series themselves.
For one thing, Craig Mazin actually does other things beside making parody movies like Superhero Movie. He worked on the Hangover sequel, for example, which wasn't too terrible. The only other "Movie" movies that he worked on were Scary Movie 3 and 4, which were still bad, but compared to Meet the Spartans and the aptly named Disaster Movie, they're not as bad. Another small merit that Mazin has over Friedberg and Setzer is that the latter two's movies, such as Disaster Movie and Epic Movie, have only a couple of disaster or epic movies lampooned and the rest are other films that came out at the time. These other movies not relevant to the parody's title are less apparent in Mazin's "Movie" entries, though they're still there.
Sometimes, Superhero Movie has some decent gags in it, like the parody of Steven Hawking and a few others, but these instances are very rare and it requires the audience to sit down for more than twenty minutes with this movie. The rest of the gags range from generic to dated to unbearable. Many of them are poorly done sex jokes or pop culture references, though when I say "many", I mean "almost all of them". There's a scene in the movie with two human-shaped balloons in a...suggestive position as the main character is walking by. That's the joke. There's no buildup, no punchline, just two balloons making love to each other, no rhyme or reason. Trust me, this is how a lot of the jokes in this movie are going to turn out.
The plot is a parody of the original Spider-Man movie: kid gets superpowers, things don't go so well at the beginning, villain shows up to do something horrible to the hero (in this case, it's killing his aunt), hero wins against villain, hero gets the girl. Everything else is irrelevant.
Drake Bell stars as Rick Riker, the main character in this movie, and Sara Paxton as Jill Johnson, his love interest. They're not that bad in this movie, but not too good either. Drake Bell has certainly seen darker moments in his acting career (Yours, Mine and Ours and College come to mind), though this is probably the darkest moment in Sara Paxton's (Even Shark Night 3D was better than this garbage.)
If you're a fan of the "Movie" series (though I don't think there are many), you may like this. If you're a big superhero fan and want to see someone parody Marvel Comics properties, there's a slim chance that you'll like this. Other than that, Superhero Movie has a strictly teenage target demographic. It's too mature for kids, yet too immature for adults. However, even if you fall into the target audience, you probably won't like this movie. There's much better parody out there.

domain: artistic


Boffins at the Massachusetts Institute of Technology (MIT), collaborating with staff at the Texas Advanced Computing Center (TACC), have created an application which will allow them to run a supercomputer from their smart phones.
The team managed to use their Android smartphones to carry out a series of expensive high-fidelity simulations on the Ranger supercomputer. It appears they used the phones like a dumb but mobile terminal.
The supercomputer was told to generate a small “reduced model” which was transferred to a Google Android smart phone.
The boffins were able to solve problems on the phone and visualise the results instantly.
David Knezevic, a post-doctoral associate in mechanical engineering at MIT said that once you’ve created a reduced model, you can do all the computations on a phone.
At the centre of the idea is a reduction algorithm which simplifies the complexities of large-scale physical simulations. Knezevic’s system tells a user the range of possible solutions, and provide a metric of whether an answer is accurate or not. The error bounds are based on mathematical theory developed at MIT over a number of years.


text:
Small collection from 2014
Inspired by a shirt recycle idea they made scarves and necklaces out of old shirts.
I found the idea interesting, and later I had an idea to apply these rounded fabric strips on clothing sometimes add beads, or plait. The patterns are simple the added fabric strips make them unique. this is the original collection, but I kept making a wearable variations as well. I wanted to apply those strips on various parts of clothing like on neckline, opened back and skirt etc.
I'm a huge fan of Dr Martens and believe that it works with everything. That's why I usually use them with my collections.
I prefer natural lights and the weird contrast of my designs and abandoned places. My friend helped me take photos of this project .She took half of these photos.
Please note: I'm not a photographer and I don't want to be one either. Considering I can't afford to hire one yet I have to manage the photos and edits myself. So please put your photographer eyes away and try to look at the clothes only.


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Every book has a list of contents and other information to give you a solid idea of what it's about. Download chatgpt site itself is pretty boring, search the database by author name. Unlike other sites on this list, anything from romance novels to computer technology manuals. You can save each page if you want an offline 9780321933546 pdf download.
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Textbook solutions for Introductory Chemistry (6th Edition) 6th Edition Nivaldo J. Tro and others in this series. View step-by-step homework solutions for.

domain: library


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Vinegar WC / Toilet Bowl Cleaner$ 4.99
Frosh Vinegar WC / Toilet cleaner is a strong, fast, and effective natural toilet cleaner. The vegan formula with natural vinegar removes dirt, limescale, urine scale and unpleasant odors, leaving behind a fresh scent.
Just squirt the natural toilet cleaner in your WC bowl, let sit for a few minutes, then use a toilet brush or just flush away.
This natural toilet cleaner is safe for septic systems.
- 750 ml, 25.4 oz.
- Powerfully removes dirt, limescale and urine scale, even underneath the rim.
- The powerful formulation with vinegar optimally removes limescale residues and leads to a thorough cleanliness in the toilet.
- Eliminates unpleasant odors and leaves a pleasant scent.
- Safe for septic systems.
- Vegan formula.
- Squeeze safety cap ("1") and unscrew ("2").
- Squirt the cleaner into the toilet bowl and underneath the rim, let sit for a few minutes, use toilet brush if necessary, and flush away.
- For heavy soiling, leave in toilet overnight.
- < 5 % anionic surfactants, perfumes.
- Vinegar, biodegradable thickener, cosmetic-grade colorant.


Pictures of the GunBuilds Goryunov SG Series
The following pictures are for your enjoyment. I hope they give you a good idea about what I'm doing with this well built and rugged ComBlock firearm. If I can answer any questions you may have regarding building a special version for you, please let me know.
This is my personal Gory. As you can see, I've taken a few liberties with it.
The gun is more of a SGM than a SG-43. I have added an ammo box carrier and a case catcher to the mix. Both clip onto the mount so as to not damage the original unit.
The camo attempt is still being looked at with the idea of re-painting it.
Here's a close up of the fire control unit. The crank and internal cam can be left out if your state won't allow them. The FCG box must stay. I can also paint the crank to match the gun if you want it to be less noticable.
Here's a top view showing the FCG box and the safety lever at the top left of the FCG box. It locks the trigger so neither the crank or butterfly trigger work. Note the SGM style charging handle on the right side.
The reason for the mix of parts is I started with a SGMT (tank and vehicle mount version) parts kit. The SGMT came with no sights so I added the SG-43 sights and removed the electric soleniod from the spade grips. This required me to make a butterfly trigger from scratch. This is why I recomment buying a SG-43 or SGM parts kit to start with.
Return to Home Page


text:
Bhairavi (Vivi) Tolani, Ph.D., M.S. is a Principal Investigator in the Thoracic Oncology Lab, having initially joined the lab in June 2014 as a postdoctoral scholar. Dr. Tolani's research is focused on developing targeted therapies, small molecule inhibitors and biologics, for lung cancer.
Dr. Tolani provides research mentorship and supervision to surgical residents in UCSF's program as well as visiting thoracic surgeons, technicians and high school students. Prior to beginning her second postdoctoral fellowship at UCSF, she worked on cancer immunology as a postdoctoral fellow at the Stanford Research Institute.
Dr. Tolani earned her Ph.D. in Molecular Biology from the University of Southern California's Keck School of Medicine under the mentorship of Preet Chaudhary M.D., Ph.D., chief of the Nohl Division of Hematology and Blood Diseases at Keck. A self-starter, she convinced the lab to undertake a new project involving small molecule BET epigenetic inhibitor drugs to target blood cancers in collaboration with Dr. James Bradner at Harvard's Dana Farber Cancer Institute. Her doctoral research resulted in 5 peer-reviewed publications, and presentations at The American Society of Hematology (ASH) and The Gordon Research Conference.
Awards & Honors
Keller Entrepreneurship Fellow, UC Davis, 2014
"Best Poster" at Biology Interdepartmental Graduate Symposium, University of Southern California, 2010
"Outstanding Poster Presentation" at the Spring Research Festival, The National Cancer Institute, 2004
Over the past 10 years, Dr. Tolani's cancer research experience has been diverse including breast cancer, ovarian cancer, cervical cancer, lung cancer and hematological malignancies spanning academia, industry and the National Institutes of Health. Prior to graduate school, she worked at 3 biotechnology companies [Invitrogen Life Technologies, Lonza, & Digene (Qiagen)] for 3 years. While at Digene, she contributed to the development of a test to detect cervical cancer in women. Her work in industry earned her "Job Excellence" and "No Matter What it Takes" awards at Invitrogen Life Technologies and Lonza respectively. Concurrently she earned her M.S. in Biomedical Sciences while conducting her thesis research on cancer stem cells and the Hedgehog pathway in breast cancer at the National Cancer Institute.
UC Berkeley, US FDA, Drug Dev., Public Health/Policy, 2015
Li H, Yue D, Jin JQ, Woodard GA, Tolani B, Luh TM, Giroux-Leprieur E, Mo M, Chen Z, Che J, Zhang Z, Zhou Y, Wang L, Hao X, Jablons D, Wang C, He B. Gli promotes epithelial-mesenchymal transition in human lung adenocarcinomas. Oncotarget. 2016 Aug 12. View in PubMed
Yue D, Li H, Che J, Zhang Y, Tolani B, Mo M, Zhang H, Zheng Q, Yang Y, Cheng R, Jin JQ, Luh TW, Yang C, Tseng HH, Giroux-Leprieur E, Woodard GA, Hao X, Wang C, Jablons DM, He B. EMX2 Is a Predictive Marker for Adjuvant Chemotherapy in Lung Squamous Cell Carcinomas. PLoS One. 2015; 10(7):e0132134. View in PubMed
Gopalakrishnan R, Matta H, Tolani B, Triche T, Chaudhary PM. Immunomodulatory drugs target IKZF1-IRF4-MYC axis in primary effusion lymphoma in a cereblon-dependent manner and display synergistic cytotoxicity with BRD4 inhibitors. Oncogene. 2016 Apr 7; 35(14):1797-810. View in PubMed
Mo ML, Ma J, Chen Z, Wei B, Li H, Zhou Y, Shi H, Tolani B, Jin JQ, Tseng HH, Shen D, Zhan Y, Li J, Jablons DM, Zhang RQ, Guo Y, He B, Zhou HM. Measurement of genome-wide DNA methylation predicts survival benefits from chemotherapy in non-small cell lung cancer. J Cancer Res Clin Oncol. 2015 May; 141(5):901-8. View in PubMed
Tolani B, Matta H, Gopalakrishnan R, Punj V, Chaudhary PM. NEMO is essential for Kaposi's sarcoma-associated herpesvirus-encoded vFLIP K13-induced gene expression and protection against death receptor-induced cell death, and its N-terminal 251 residues are sufficient for this process. J Virol. 2014 Jun; 88(11):6345-54. View in PubMed
Tolani B, Gopalakrishnan R, Punj V, Matta H, Chaudhary PM. Targeting Myc in KSHV-associated primary effusion lymphoma with BET bromodomain inhibitors. Oncogene. 2014 May 29; 33(22):2928-37. View in PubMed
Graham C, Matta H, Yang Y, Yi H, Suo Y, Tolani B, Chaudhary PM. Kaposi's sarcoma-associated herpesvirus oncoprotein K13 protects against B cell receptor-induced growth arrest and apoptosis through NF-?B activation. J Virol. 2013 Feb; 87(4):2242-52. View in PubMed
Matta H, Gopalakrishnan R, Graham C, Tolani B, Khanna A, Yi H, Suo Y, Chaudhary PM. Kaposi's sarcoma associated herpesvirus encoded viral FLICE inhibitory protein K13 activates NF-?B pathway independent of TRAF6, TAK1 and LUBAC. PLoS One. 2012; 7(5):e36601. View in PubMed
Please note: UCSF Profiles publications are automatically derived from MEDLINE/PubMed and other sources, which might result in incorrect or missing publications. Researchers can login to make corrections and additions, or contact CTSI for help.
Posters & Oral Presentations
Gopalakrishnan R, Matta H, Tolani B, Triche T, Bradner JE, Chaudhary PM (2014) Immunomodulatory Drugs are Efficacious against Primary Effusion Lymphoma by Targeting IZKF1, IRF4 and MYC in a CRBN-Dependent Manner and are Synergistic with BRD4 Inhibitors. [ASH poster abstract]
Tolani B, Ly J, Dangaj D, Powell DJ Jr, Danet-Desnoyers G, et al.. (2014) Characterization of the Tumor Microenvironment of a Humanized Mouse Model of ovarian cancer after treatment with anti-B7-H4 recombinant Antibodies. [AACR poster abstract published online]
Tolani B, Goodman M (2010) Binding & Deamination by Activation-Induced Cytidine Deaminase (AID) [Gordon Research Conference poster]

domain: biology


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At Zephyr Health, we are integrating diverse healthcare data by using two databases: MongoDB and Neo4j. Our database does many positive and powerful things with data, including connecting patients to the healthcare treatments and therapies they most need.
Below I’ll go over the architecture of Zephyr’s platform, the problems we encountered and addressed while building our comprehensive platform, how different profiles appear in both MongoDB and Neo4j and the invaluable lessons we learned along the way.
Zephyr Health takes healthcare data from pharmaceutical companies and transforms it into information. This allows us to derive real-time analytics that help patients connect with different therapies and pharmaceutical companies connect with different healthcare providers.
Founded in 2011, we have over 100 employees in the U.S., Europe and Asia. We are backed by KPCB, Icon Ventures and Google Ventures, and we work with a number of clients — primarily pharmaceutical companies — within the U.S. and Europe.
Emerging Healthcare Data Challenges
There are a number of challenges faced by the pharmaceutical industry today. More doctors and hospitals are moving away from generic therapies in favor of precision medicine, a form of treatment that requires a lot of information on the part of pharmaceutical companies in order to be successful. These companies need to know what clinical trials are being conducted and who the key opinion leaders are in order to connect them to the products these companies are going to launch.
Consider the following (fictitious) example: Leslie Johnson at GlaxoSmithKline wants to launch a drug that treats asthma. She has an extensive amount of data available, including information from both CRM systems and Salesforce that includes RMS data, prescription information and doctor and hospital network information. While she has all this data, she is only able to look at it in a very disconnected way.
Leslie wants to know who the clear opinion leaders are right now. She knows who they were in the past because of her institutional knowledge, but based on the information that is presently available to her, she isn’t able to identify the emerging leaders.
Zephyr allows her to take the data from all the different places it’s stored and integrate it into one data platform. Now she can identify key opinion leaders, emerging doctors for a specific therapy and the best hospitals and referrals to contact.
We’ll use the following example throughout this blog post to illustrate how Zephyr can integrate unstructured heterogeneous data to help Leslie distribute her new life-saving drugs to the best people and places.
In this example, we have data for the doctors Tom and Ray.
The first column, NPI (National Provider Identifier), is a unique identifying number for doctors similar to a social security number. We also have data for the doctor’s’ first name, last name and specialty. As we get more data, the unique NPI number allows us to connect different doctors to different clinical trials and publications.
This example data points us to a number of questions:
How can we answer all of these questions with one platform? Building a more generic platform to cover all these different domains is rather difficult. It needs to be flexible, extensible and adaptive, but it can’t be too cumbersome or complex to maintain or use.
To address this, at Zephyr, we started using something called ontology.
Ontology-Driven Data Integration Platform
Ontology is essentially a formal representation of a specific domain and contains a vocabulary. This vocabulary includes the definitions of all the different entities that exist in our domain, along with the entities’ attributes and the relationships that exist between them.
It also includes a taxonomy based on all the information you have in your vocabulary. Ontology drives Zephyr’s data platform and helps us integrate unknown and unseen data in a more consistent way.
In the pharmaceutical world, your entities include doctors, hospitals, patients, medications, medication side effects, clinical trials, etc. With each entity, you also have data points, or organic attributes, which are unprocessed raw data coming from outside client or public data sources. This includes specific doctor information such as first name, last name, specialty, address and associated institution.
But having organic data or attributes isn’t enough; you need to create more analogies. We created data from the data points, which we called derived information, which essentially takes the existing data and creates more information.
A good example of this is sales data, in which you take monthly sales data and turn it into quarterly and yearly projections – which means you’re integrating a lot of information.
Finally, there are entity relationships, which are very important. For example, we want to know which representatives, hospitals, etc. a certain doctor is connected to. How do we define that information? We can allow our system to build whatever relationships it finds, or we can be very specific by requesting only doctors connected to certain hospitals.
We started building this vocabulary in 2011, and we’re still building it. As more and more data comes in, our vocabulary has to be self-evolving so that it can handle new types of information, and have the ability to take unseen data and automatically build out the vocabulary.
Where and how do we store this vocabulary and data? We explored a number of different options, including relational databases and NoSQL tools.
Relational databases have strict schemas, and while NoSQL stores are technically schema-less, the program still needs to understand how the data is organized.
With relational databases, the more hardware you have available, the better performance you get. If you run out of hardware, you can start making clusters, begin charting or create an application to improve your performance. You can increase the performance of NoSQL stores by using applications and charting through Cassandra, HBase, MongoDB and Neo4j applications.
In relational databases, you are able to use a large number of clusters for relational work, but you also have to use a large number of JOINs in order to respond to queries, which slows down your database. You can add more indexes, create materialized views and define more data points — but you may only reduce 20 joins to 15.
With NoSQL stores, you have to look at the different scenarios and use cases to determine which are best to solve your problems. For example, Cassandra, Neo4j and MongoDB are all very good for different functions.
Adopting Polyglot Persistence
For Zephyr, we knew that no one single database would be sufficient for all of our use cases, so we chose two in a polyglot persistence database: MongoDB and Neo4j. MongoDB is our document store, which holds all the wholistic profile information for each doctor.
There are a number of strengths of MongoDB: the JSON format supports temporary indexes and strict consistencies; MapReduce capabilities are continually improving; and queries are very powerful, albeit difficult to write. However, there are no JOINs. These can be mimicked by passing IDs, but it’s still very cumbersome.
Neo4j helps address most of MongoDB’s limitations because it allows us to easily build both explicit and inferred relationships. Because it’s a heavy index database, performance is very consistent whether you’re working with a few thousand nodes or a few million.
If you’re thinking about throwing more hardware at your relational data sources, you might as well throw more hardware at Neo4j and keep everything in your memory. Up until now, all of our graphs — even 40 million nodes with two billion relationships — fits in our RAM.
Zephyr uses MongoDB and Neo4j in the following ways:
All the data points go into MongoDB, while a subset of the data goes into Neo4j, because we don’t need all the data points for every doctor or entity. All we need are some key points in our graph database so we can do “slice and dice” queries. Once we have your subset of those entities, we can go to MongoDB to pull all the information about those entities.
Zephyr Health Platform Architecture
Our platform was written from scratch in Java and Groovy. The platform derives itself through the vocabulary, taxonomy and ontology, which we sewed into MongoDB. It’s easy to read the whole vocabulary or taxonomy from MongoDB; you don’t have to do anything to make the platform understand the vocabulary.
Typical datasets are sent to the system as XML or CSV files via Dropbox or Box, and we are constantly adding more connectors that allow us to import data. Once the data is uploaded, a number of transformations occur.
For example, the system automatically standardizes and normalizes values such as the names of medical specialties (for example, cardiologist vs. cardiology) and the addresses for hospitals and doctors (the platform reaches out to different address services to standardize the data).
We also start building relationships through the exact match. For example, the NPI number helps us connect entities because each doctor has a unique ID. But what if we come across doctors named Tom and Tommy? Are they the same person? Tom works at Stanford Medical Center, while Tommy was in a clinical trial at that center.
How can we determine if these are the same people? The platform uses fuzzy match logic to make an educated guess about how closely these to people are related, and then lets us combine those entities.
While it is performing these queries, it stores the documents and profiles as JSON documents in MongoDB. At the same time, it also starts pushing data into the Neo4j graph database as nodes and edges.
The number of nodes or attributes that go in the graph database are controlled through the vocabulary and ontology. MongoDB and Neo4j are kept in sync so that any time there are changes to data in MongoDB, it will be automatically updated in Neo4j as well, and vice versa.
Below is a very high-level classification of the data. A full profile typically contains the main profile along with an identity section, which is similar to a business card type view and has very few key attributes. All the other data points go into the attribute sections.
We have a separate document for entity relationships, which are stored in both MongoDB and Neo4j. Our applications also determine where different entities are located in terms of address, and if more than one address comes up, it also determines which is the most accurate.
The vocabulary and ontology helps us ingest the data into our databases. Sometimes our clients have questions about why and how we made certain connections between different data points. Attribute references allow us to go back through the lineage and determine how we found the different relationships.
An Example: Doctor Tom
Continuing with our Tom example: Once his information has been ingested, his profile will look something like the diagram below. There is a much larger amount of metadata involved in the document than would fit on the slide, but the general structure is still the same.
MongoDB assigns an ID, and there are sections for identity and attribute. We can control which attributes go into the identity section and continue to make changes.
But how does this profile look in Neo4j? Below, the dark node at the center is the entity — Tom — while the light grey nodes that revolve around it are Tom’s four aggregate nodes.
Now we are going to add the clinical trial and any associated trial information into the platform, which understands the NPI number. Because the NPI numbers are exactly the same, it’s going to add the trial to Tom’s profile, which leads the document to evolve.
As you can see below, the identity section remains the same but the attribute section expanded with added information from the new dataset.
In the graph, the platform checks to see if the particular attribute already exists in the system; if not, it will create a new node. Below, new nodes have popped up for institutions, and the clinical trial start and end dates.
But how does this help us answer the questions we started with, all of which relate to how flexible our platform is? We’ve shown that this platform is flexible because Tom’s profile contains all his information; the documents exist in the same collection, and we don’t have to build a different collection to account for new data points.
It is extensible and adaptive because the system evolves to account for new vocabulary. The system makes the vocabulary richer, accommodates new attributes and entities, and data is available automatically and immediately to our applications.
Zephyr’s Current Data Challenges
Over the last three or four years since we built this data platform, we’ve learned a lot.
We learned that no one single database was going to work for all use cases, so we embraced polyglot persistence. While we started with a more generic platform, we started putting more effort into building specialized algorithms to populate our data more intelligently.
Ontology-driven development has proven very powerful for Zephyr, but we still have some challenges related to data modeling and organization.
One of the main challenges we continually face is indexing. How do you index something you’ve never seen before? As the profiles get bigger, we approach MongoDB’s 60MB size limit for each document, which poses another huge challenge.
If we reach that limit, we essentially have to start the data modeling and organizing over again, and then tweak the system so it will understand that all different pieces go into different collections.
Watch below for a glimpse of what our applications can do with Neo4j:
Neo4j and New Healthcare Relationships
In the below graph, the purple node is a healthcare provider and the bluish node is the institution entity node. Our graph helps us figure out the relationships between our different entities.
When you click on that institution node, the graph just explodes, which gives us more insight. The green node below is the client representative, which is connected to the same (dark blue) institution.
If you click again on the green client rep node, a number of new relationships pop up. You can see that the rep is not only connected to the dark blue institution node, but it is also connected to a number of other institutions and hospitals.
This is where Neo4j plays a vital role in healthcare; it helps you explore relationships that you have never seen before. And you don’t have to go through a number of JOINs to find them; they can be bared in one single hop in the graph database.
Summary and Demo
In the healthcare field, there is a lot of disconnected data that we need to bring together in order to determine relationships. We have embraced a generic entity-attribute-value (EAV) model and looked at prescription data, claims data, network influence, CRM data and Salesforce data, all of which fits well into this model.
We focused on data integration through specialized algorithms that make sense of the data, we’ve split storage with documents that provide a 360-degree view of the profile, and we use Neo4j as the query mechanism for determining relationships.
Standards are incredibly important for graph databases, and as a community we can hopefully come up with Cypher as the standard for graph databases. It’s also important to come together and build a standard vocabulary for the pharmaceutical and healthcare world.
In the healthcare domain, data has been and will continue to keep changing. And we have to make decisions today based on the data we have.
Inspired by Mahesh’s talk? Register for GraphConnect Europe on April 26, 2016 at for more industry-leading presentations and workshops on the evolving world of graph database technology.


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iSCSI: EUI64 slides from Feb6 IPS WG meet
Sorry for taking so long to post the slides that I presented on Feb. 6 on the EUI64 identifier (wasn't I supposed to do this BEFORE the meeting?), but you can find the slides I presented at ftp://email@example.com/ in draft-grant-iscsi-eui64node-00.ppt. The userid is ietfpresentations and the password is ietf. The titles should even be on the top :-) !
Last updated: Wed Feb 13 19:18:09 2002
8742 messages in chronological order


text:
Find a Director
Film Monkey Productions
(310) 922-3646 phone
Los Angeles, CA
Having directed three award-winning features and seven shorts, Tricia Lee is an accomplished and versatile director, with Canadian and British citizenship, who earned her US Green Card as an “artist of extraordinary ability.” Lee is currently attached to direct a feature for Viola Davis' company JuVee Productions. BLOOD HUNTERS sold to Hulu and was presented in Cannes by Frontieres. SILENT RETREAT was theatrically released across Canada with a two-week run in Toronto and sold to NBC Universal’s Chiller Network. MEETING MOMMY, which was a semi-finalist in the NBCUniversal Short Film Festival, reached the top 28 on Youtube’s Trending List. EDGE OF INTERNMENT, her musical short that was written, shot
and edited for the 51-hour Film Challenge was selected by the Producer's Guild of America as a Top 3 Finalist.
Lee’s feature screenplay “Spoken” made the Top 5 on the 2019 BitchList, was a quarter-finalist in the Screencraft Film Fund Contest and was selected for the Stowe Story Lab. "Mother-Daughter" is a finalist for the Athena Screenwriting Lab. “Okay Annex,” her short screenplay, was a
semi-finalist in the Hollyshorts Screenplay Contest. Tricia was one of the six selected directors for the inaugural AWD Shoot ‘Em Up Challenge, where she directed THE ROOM IN THE ELEPHANT to a successful screening at Walt Disney Animation Studios.
* AWD encourages forthright business practices and accurate self-representation but assumes no responsibility, nor liability for any member’s individual content, nor business relationships made through AWD’s website, events, or social media accounts.

domain: entertainment


text:
I STILL haven't made that stupid spaghetti squash and it's staring me in the face, mocking me. I WILL make it this week!!
The Bobby Flay Chicken Parm recipe that I made wasn't bad, though it needed quite a lot of tweaking to minimize waste and it could've used a little more flavor.
The 12-Hour Salad is also going to be a carryover to use up leftover bits and pieces of veggies in the fridge.
My veggie casserole TASTED good... but that's about where it ended. It was more like veggie soup in a casserole dish. I'll have to try it again and figure out how to get rid of some of the liquid.
Shoarma is always good and I got to try the whole wheat pitas I bought in Belgium a couple weeks ago. I think I'll stock up on more next time I go since I know they're good now.
click the banner and "Menu Plan Monday" for more menu planning ideas
This week I am choosing recipes that will use up stuff that I have in the fridge, freezer, and pantry. I do have to buy a few things for the Daring Cooks Challenge but otherwise the grocery load should be pretty small.
Ham and Leek Cobbler
Spaghetti Squash & Red Sauce
Fried "Rice" & Lemon Chicken
Tuna Muffins & Asparagus Soup
Daring Kitchen Challenge- It's a secret til the 14th!

domain: food


text:
Every once in a while, I get emails. Recently Dupe asked for resources to help understand the lives of Yoruba men and women in the 19th century.
From her email;
I’m especially interested in understanding the lives of Yoruba women and men in the 19th century. How gender relations worked. Childcare practices. Practices of farmers/traders. Religious practices for Ondo and Epe people. Etc, etc.
Basically, I’m trying to get into the heads of my ancestors who were from Ondo and Epe, so if there’s anything at all that you can recommend that can help me with that, I’ll be immensely grateful.
Off the top of my head I recommended, “The Evolution of Ondo Kingdom Over 500 years” by Oladidipo Akinkugbe as that’s a book I’ve been eyeing and waiting to buy. Dupe shared more about the project she’s working on (which is going to be a dope work of historical fiction, I’m waiting to read it!) and mentioned a book called “The Makers of Ode-Ondo” by Rasheed Olabamidele Fawehinmi.
I’m putting this out there in case anyone can help. Do you have any sources on Yoruba lives in the 19th century that we don’t know about (i.e. haven’t been mentioned here)? Please let us know in the comments!


text:
Godolphin colt Beau Geste continued the promising start to his career by outgunning a quality field of up-and-comers at Rosehill.
Although the three-year-old was guilty of ove racing early in a Benchmark 74 Handicap (1300m), he regained his composure under Brendton Avdulla to claim a clustered finish.
Beau Geste, the $2.40 favourite, had main rival Paret covered on the run home, a task made easier by the Chris Waller-trained colt losing focus at the 100m.
"That was a really strong bunch of three years olds," trainer James Cummings said.
"Our race wasn't really run to suit him , he wanted to overdo things in the early stages.
"Brenton was probably sensing that he had (Paret) behind him and he could hold him safely.
"I'm impressed with the way he was able to knuckle down and get the win."
Our Mantra ($18) finished strongly to finish second, a half-neck behind Beau Geste and Paret ($2.50) was a half-neck third.
Cummings was unsure where Beau Geste would head next after his second win in three starts.
"We'll have a good think about it, one thing I don't like doing is stepping these horses up in distance too quickly when they're still learning," he said.


text:
‘RHOBH’ star Faye Resnick is ignoring the new special about O.J. Simpson. Nicole Brown’s close friend told HL EXCLUSIVELY that she thinks it’s just a stunt.
HollywoodLife.com spoke with Faye Resnick, who said that she will not be tuning in to Fox’s March 11 special,O.J. Simpson: The Lost Confession?. Faye was one of Nicole Brown Simpson‘s best friends, and she’s still horrified by the 1994 murders of her and Ron Goldman. “I can’t watch that! I miss my girlfriend and I am sure that it is not going to be about her or domestic violence. I’m sure it is going to be another O.J. stunt and I can’t watch that!” she told us EXCLUSIVELY.
O.J. was famously accused of killing his ex-wife and her friend at her home in 1994. He was acquitted of murder and set free. It was a divisive case, to say the least, with many people believing he was innocent, and others confident he committed the crime. O.J. Simpson: The Lost Confession? features a 2006 interview with Judith Regan, the publisher of O.J.’s would-be book, If I Did It. That book was cancelled, but later released in 2007 by the Goldman family under If I Did It: Confessions of the Killer.
Regan claims in the interview that O.J. allegedly confessed to the murders. She says that she got a phone call from O.J.’s attorney, who told her that the former football star was “ready to confess.” She continued, “O.J. didn’t want to call the book, I Did It. He wanted to put an If in front of it so he would have deniability with his children. He couldn’t face his children and he couldn’t tell them that he had done it. And that was the way it was portrayed to me. That was his only condition.”
O.J. Simpson: The Lost Confession? airs Sunday, March 11 at 8:00pm on Fox.

domain: celebrity


text:
The majority of Swiss are not in favour of building minarets on new mosques, according to a new opinion poll published on Thursday.
The Lausanne-based MIS Trend market research institute said 46 per cent of people questioned were against the presence of minarets, while 39 per cent were in favour and 15 per cent were undecided. The issue will go to a nationwide vote on November 29.
The poll asked the following question: "If a new mosque is built in Switzerland, would you be for or against the presence of minarets?"
There were differences between German- and French-speaking regions, where 48 per cent and 38 per cent respectively said "no" to minarets. Voters on the left of the political spectrum were mainly supporters (63 per cent), unlike those on the right (69 per cent against).
The first official poll on the issue by the leading gfs.berne polling and research institute at the end of October found 53 per cent of Swiss rejected the anti-minaret initiative.
The new survey covered other issues relating to Muslims in Switzerland. Some 68 per cent of people felt you could be both a "true Swiss" and Muslim, and 51 per cent said the Muslim faith was compatible with the values of Swiss democracy.
Fifty per cent of people said a headscarf should not be worn in the classroom, while a small majority said Muslim women should be allowed to wear a headscarf at work. The vast majority (85 per cent) felt Muslim students should not be exempted from swimming lessons and 74 per cent said the Swiss state should not be involved in training imams.
"Basically, these results are very reasonable – very Swiss," Marie-Hélène Miauton, director of MIS Trend told the French-language 24Heures newspaper. "The message is basically that Muslims are free to live their faith but they have to integrate."
The Lausanne institute, commissioned by 24Heures newspaper, polled 1,004 people aged 18-74 in both French- and German-speaking regions. It includes people who are not eligible to vote.
swissinfo.ch and agencies


text:
Last Friday, Islamic hardline groups headed by the Islamic Defenders Front (FPI) protested at the offices of national news outlet Tempo over a political cartoon published in their magazine that they perceived to be mocking their leader, pornography case fugitive and firebrand cleric Rizieq Shihab.
This morning, Tempo published an editorial piece explaining why they agreed to meet with representatives of FPI but refused to apologize for the cartoon. The editorial, which was published in today’s edition of their newspaper, was also posted online.
These are some of the well-articulated points made by the publication as to why they chose not to say sorry:
“The mass demonstration by FPI against Tempo was over the top. We criticize the way they expressed their intimidating behavior. The police should have processed the protesters in accordance to the law for acting excessively.”
“They believed that the cartoon insulted FPI’s founder, Rizieq Shihab, who went on umrah (pilgrimage to Saudi Arabia) but has not returned to Indonesia after being named a suspect by the police. The picture and text on the cartoon didn’t directly point to anyone’s specific identity.”
Tempo added that FPI’s representatives, when meeting with the editorial team, acted aggressively by banging on the table and one of them even threw a cup of water at the editors.
“They demanded that Tempo’s editors apologize to all Muslims. This demand clearly made no sense. How could FPI claim that all Muslims have the same opinions, behavior, and actions as they do?”
In the end, Tempo’s editors apologized to those who felt offended by the cartoon, but they did not apologize nor do they think they were wrong for publishing it in the first place. Under the code of journalism ethics, Tempo has agreed to give FPI a right to response statement regarding the cartoon, which will be published this week.
“We believe that once intimidation can change editorial policy, it’s not just Tempo’s reputation that is on the line. If we don’t fight back, the intimidators will get addicted. The victims can be Tempo and other media. This endangers press freedom and the right to information for the public.”
On Feb. 26, Tempo published this cartoon which is a clear dig at Rizieq Shihab for anyone who follows Indonesian news:
Kartun Majalah Tempo edisi 26 Februari 2018. pic.twitter.com/D3P09RasYj
— TEMPO.CO (@tempodotco) February 28, 2018
If you don’t get the reference, the cartoon is a parody riffing on an oft-quoted scene from 2016’s mega box office hit ‘Ada Apa Dengan Cinta? 2’. In the scene, main character Cinta tells Rangga, “What you did to me was cruel” after he didn’t call her or something following the romantic climax of the prequel (we don’t really know, we’re one of the few people who didn’t watch the movie).
In Tempo’s cartoon, Rangga was replaced with a man in Islamic clothing. Though we only see his back, it’s clear the artist heavily implied that he’s Rizieq Shihab as he says, “I’m sorry I didn’t end up coming home”, which refers to the firebrand cleric repeatedly canceling his plans to return from Saudi Arabia, disappointing his many followers each time.
Rizieq has been hiding in Saudi Arabia since he was named a pornography suspect in the infamous “baladacintarizieq” pornography case in May 2017. Explaining his long refusal to return to Indonesia, one of the firebrand cleric’s lawyer’s once said Rizieq would rather stay in Saudi and be called a coward than return to Indonesia and get arrested.


text:
|Institutional Source||Beutler Lab|
|Gene Name||neuropeptide Y receptor Y5|
|Is this an essential gene?||Probably non essential (E-score: 0.111)|
|Stock #||R6602 (G1)|
|Chromosomal Location||66679965-66688128 bp(-) (GRCm38)|
|Type of Mutation||frame shift|
|DNA Base Change (assembly)||GCTGTGAAACACTG to GCTG at 66681540 bp (GRCm38)|
|Amino Acid Change|
|Ref Sequence||ENSEMBL: ENSMUSP00000148589 (fasta)|
|Gene Model||predicted gene model for transcript(s): [ENSMUST00000070810] [ENSMUST00000211920] [ENSMUST00000212563]|
AA Change: 196
AA Change: 196
|Meta Mutation Damage Score||0.9755|
|Coding Region Coverage||
|Validation Efficiency||100% (43/43)|
FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] The protein encoded by this gene is a receptor for neuropeptide Y and peptide YY. The encoded protein appears to be involved in regulating food intake, with defects in this gene being associated with eating disorders. Also, the encoded protein is involved in a pathway that protects neuroblastoma cells from chemotherapy-induced cell death, providing a possible therapeutic target against neuroblastoma. Three transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Nov 2015]
PHENOTYPE: Homozygotes for a null allele show increased susceptibility to diet-induced obesity and a reduced orexigenic response to select agonists. Homozygotes for a reporter allele show mild late-onset obesity, increased adiposity, polyphagia, and exacerbated obesity parameters after chronic NPY infusion. [provided by MGI curators]
|Allele List at MGI|
|Other mutations in this stock||
|Other mutations in Npy5r||
(F):5'- GCTTATACTCCTGCAGACACTAG -3'
(R):5'- CAGTGGATGTTCGGCAAAGC -3'
(F):5'- CCTGCAGACACTAGTATGACTTACTG -3'
(R):5'- AGCCATGTGCCATATCATGC -3'

domain: literature


GOVERNOR MARKELL'S WEEKLY MESSAGE
December 6, 2013 - ) In his weekly message, Governor Markell shares ways in which Delaware has earned recognition as one of the top solar states in the country.
“Our growth in solar energy is just one part of our larger shift to cleaner energy,” said Governor Markell. “We’ve shut down, or converted to cleaner and cheaper fuel at nine out of ten coal plants, helping to bring down energy costs. We’re building state of the art power plants and we’ve become a national leader in fuel cell and geothermal energy production, while making investments in energy efficiency.”
GOVERNOR MARKELL AT WORK
October 16, 2013 - The Governor joined Bloom Energy Principal Co-Founder & CEO KR Sridhar and others to celebrate the opening of Bloom’s new Delaware plant. Bloom Energy, an innovative fuel cell company, is producing Bloom Boxes at its new plant, the site of the former Chrysler factory. Bloom generates clean, highly efficient power from natural gas or other fuels. The company employs approximately 80 people at its Newark site; is currently hiring and intends to hire hundreds of Delawareans over the next few years.


text:
A Gorgeous Pink Sapphire and Pavé Diamond Halo Bracelet in 18k White Gold. A great complement to any style, this gemstone bracelet showcases vibrant pink sapphires accented with a sparkling halo of pavé-set diamonds framed in 18k white gold. This gorgeous bracelet is created by Blue Nile Jewelry.
This is the world’s 2nd largest known and most important gem quality NATURAL Copper & Manganese Bearing Paraiba tourmaline with a record setting size. The MUSEUM QUALITY “INVESTMENT GRADE” GIA CERTIFIED 62.12 carat estate cocktail ring features a BEYOND RARE Internally Flawless Clarity Natural Paraiba Tourmaline. The “Absolutely Stunning” 100% natural master cut gemstone offers the highly sought after VIVID Neon Greenish Blue Color weighing in at a GIANT 59.10 carats. Not only is this one of the world’s largest, it is also one of the world’s best Paraiba Tourmalines that is privately owned by Hollywood royalty. The IMPORTANT spectacular gemstone is set in SOLID PLATINUM and surrounded by 192 Near Flawless VS/F-G sparkling accent diamonds totaling 3.02 carats…..There is one Paraiba Tourmaline mined for every 10,000 diamonds making it among the rarest of all gemstones in the world favored by connoisseur collectors worldwide.
GIA CERTIFIED 62.12 carat estate cocktail – engagement ring features a BEYOND RARE – Internally Flawless Clarity – Natural Paraiba Tourmaline. The “Absolutely Stunning” 100% natural master cut gemstone measures 29.22 mm x 22.20 mm x 15.30 mm with the highly sought after VIVID Exotic Neon Greenish Blue Color and an Oval Brilliant Cut weighing a GIANT 59.10 carats. Take a close look at the extraordinary gem & note the amazing rich color and healthy glow. The IMPORTANT spectacular gemstone is set in SOLID PLATINUM and surrounded by Near Flawless sparkling accent diamonds. There are 192 round brilliant natural untreated accent diamonds totaling 3.02 carats set with the Paraiba Tourmaline in a classic style. These “Perfectly Clear” and Completely EYE CLEAN diamonds are graded at Near Flawless “VS1-VS2” Clarity with COLORLESS & NEAR COLORLESS “F-G” Color so you can be assured of the OUTSTANDING quality, excellent brilliance, flash, sparkle & fire. The ring measures 30.80 mm x 24.65 mm at the head and sits up 17.30 mm off the finger.
Oval Brilliant shaped Tanzanite in the center weighing 17.12 ct with very nice and lively deep violet- blue color with lots of sparkles and flash. Nestled in an oval shaped diamond halo setting, sections of pave diamonds on ring sholders. Beautifully handcrafted open-gallery allows plenty of light to enter the bottom of stone. There are 57 diamonds in side stones, weighing a total of 2.14 cts, VS-SI clarity and H-I color Ring Dimensions: 0.85″ x 0.75″ (across top of the ring)
Brand, Seller, or Collection Name Leibish & Co Metal stamp plat-950 Metal Platinum Material Diamond/Platinum/Tanzanite Gem Type blue-tanzanite Minimum total gem weight 6.42 carats Setting other-setting-type Height 1.7 millimeters Width 2.2 millimeters Clasp Other clasp type Total metal weight 5.15 Grams Ring size 6 Sizing lower range 6 Sizing upper range 12 Resizable Yes Number of stones 1 Stone Weight 6.42 carats Certificate number 2175391500 Certificate type GIA
Stone shape Special cut Minimum color Blue Minimum clarity VS2-SI1 Cut fantasy-cut
This absolutely stunning AIGS Certified 7.94 Natural Copper & Manganese Bearing Paraiba Tourmaline is a once in a lifetime collector’s opportunity. Boasting an impressive 4.74 carat (exact carat weight) Near Flawless VVS2 clarity specimen, this gorgeous solid 14k white gold estate beauty has everything an investment grade ring could offer featuring a spectacular array of 9 round brilliant & 45 baguette cut near flawless VVS1-VS2 clarity fine quality G-H near colorless diamonds. The one of a kind “uncompromising” collectors ring has it all including a classic design.
AIGS CERTIFIED 7.94 Carat Engagement – Anniversary – Cocktail Estate Ring featuring a BEYOND RARE Near Flawless VVS2 Clarity Natural Paraiba Tourmaline set into SOLID 14k White Gold and accented with Near Flawless sparkling diamonds. The “Red Carpet Caliber” Paraiba Tourmaline measures 14.56 mm x 9.09 mm x 5.45 mm with the highly sought after EXOTIC Blue Color and a Pear Brilliant Cut weighing a WHOPPING 4.74 carats (exact carat weight). There is also a total of 9 round brilliant and 45 baguette natural untreated accent diamonds totaling an additional 3.20 carats set with the Paraiba Tourmaline in a classic style. These “Perfectly Clear” diamonds are graded at Near Flawless “VVS1-VS2” Clarity with NEAR COLORLESS “G-H” Color so you can be assured of the OUTSTANDING quality, excellent brilliance, flash, sparkle & fire. The ring measures 26.40 mm x 19.80 mm at the head and sits up 9.70 mm off the finger.
All of the beautiful gemstones are 100% genuine totaling a very substantial 7.94 carats and the ring is a U.S. sizable 6.5. The total ring weighs a HEAVY strong & sturdy 7.42 grams and is constructed of solid 14k White Gold with exceptional PRIME QUALITY natural gems.
This fine and impressive ruby marquise ring has been crafted in 18 ct yellow gold. The pierced decorated, marquise shaped setting displays five graduated oval mixed cut rubies, pavé set vertically to the center of the design. The rubies are flanked on either side by a total of sixteen Old European cut diamonds to complete the design. The pierced decorated, scrolling trifurcated ring shoulders are accented with a subtle groove decoration and blend seamlessly with the plain ring shank. This marquise shaped dress ring has been independently tested using state of the art technology (Niton XL2 Analyzer) and verified as 18 ct gold. The ring is supplied with an independent diamond grading report card.
This antique 1900’s cocktail ring is fine quality set with rubies and very well color matched, very high color graded old cut diamonds.
The ring is a very good gauge of gold and is in excellent condition.
Cabochon emeralds alternate with marquise diamonds, in an 18-karat yellow gold setting. Emerald weight: approximately 3.00 carats total; Diamond weight: approximately 0.74 carats total. Created by CELLINI Jewelers
Exceptional in design and execution, this is among the finest tanzanite that we have seen. Nearly resembling a sapphire in certain light, but with dramatic flashes of red in other, the stone captures the attention of all who view it and mesmerizes with its magical allure. The sugarloaf cut forms a distinctive peak at the top, with a gently flared frame of 5.10 carats of round- and marquis cut diamonds at the base. Set in platinum.
This absolutely stunning GIA Certified 3.01 Carat Natural Paraiba Tourmaline is a once in a lifetime collector’s opportunity. Boasting an impressive 1.85 carat (exact carat weight) Near Flawless VVS clarity specimen, this gorgeous solid 14k white gold estate beauty has everything an investment grade ring could offer featuring a spectacular cluster of 14 round brilliant & 4 baguette cut VS1-SI1 clarity fine quality F-G colorless and near colorless diamonds. Click Here To Purchase

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