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Conceived and designed the experiments: MR MS TH MT KK AJA. Performed the experiments: MR MS TH MT KK AJA ID VK. Analyzed the data: MR MS TH MT KK AJA. Wrote the paper: MR MS TH MT AK AJA AH.
Oncolytic adenoviruses can be engineered for better tumor selectivity, gene delivery and be armed for imaging and concentrating radionuclides into tumors for synergistic oncolysis. We constructed Ad5/3-hTERT-hNIS where replication is controlled by hTERT-promoter. Ad5/3-hTERT-hNIS expresses hNIS for imaging of transgene expression and for treatment of infected tumors by radioiodine. Ad5/3-hTERT-hNIS efficiently killed prostate cancer cells and induced iodine uptake in vitro and in vivo after intratumoral virus administration. Survival of mice treated with intravenous Ad5/3-hTERT-hNIS significantly prolonged survival over mock or radioiodine only but the combination of virus with radioiodine was not more effective than virus alone. Temporal and spatial changes in hNIS-expression during therapy were detected with SPECT, demonstrating feasibility of evaluation of the combination therapy with hNIS-expressing adenoviruses and radioiodide.
Gene therapy with oncolytic viruses is an emerging experimental option for treating refractory cancer lacking curative therapies. This is the case for castration resistant prostate cancer that killed estimated 27,000 men in 2009 in the U.S (http://www.cancer.gov/cancertopics/types/prostate). Oncolytic adenoviruses are promising therapeutic tools since the infection results in cytolysis of transduced cells and in the release of therapeutic progeny for further spread into target tumors. The feasibility of genetic alteration of the adenoviral genome has led to the development of several modifications that render these agents cancer selective , . Consequently, oncolytic adenoviruses have been successfully used in clinical trials, including prostate cancer patients . However, although proven safe, the efficacy of the treatments still needs to be improved. One means to achieve this is to combine them with chemotherapeutics and radiation , , .
Human sodium/iodide symporter (hNIS) is a transmembrane protein that is located on the basolateral membrane of thyroid cells and actively transports iodine (I−) for thyroid hormone synthesis. The ability to accumulate I− via hNIS has provided the basis for diagnostic scintigraphic imaging in thyroid cancer and has been an effective means to target radioiodine for its treatment. The structure of oncolytic adenoviruses is compatible with the insertion of therapeutic molecules as transgenes and this feature has also been exploited for delivery of hNIS , , . Recently, we and others have successfully used adenovirus-encoded hNIS to transport 131I into cancer cells for a combined antitumoral effect , . In addition, hNIS-expression not only provides a therapeutic means to improve efficacy but also might serve as an imaging tool for assessing tumor size and provides information on viral kinetics during the treatment.
Recent developments in dedicated small animal multi-detector and multi-pinhole collimator scanners for single photon emission computed tomography (SPECT) have rendered the modality a powerful tool in preclinical imaging. Decades of clinical use have resulted in many commercially available tracers and kit-formulations for facile tracer radiolabeling easing the adaptation of the technique also to preclinical use. SPECT has been successfully employed in the visualization of various transgenes , but its advantages over other imaging modalities have rarely been more pronounced than for hNIS-imaging, where selective, readily available and inexpensive probes, 131I−, 123I− and 99mTcO4−, can be employed .
Telomeres are structures at the ends of chromosomes consisting of hundreds to thousands of TTAGGG-repeats and associated proteins . During each mitotic cell division several telomeric repeats are lost. However, some cell types, including stem and cancer cells, maintain the capacity of indefinite renewal by expressing telomerase , a ribonucleotide protein that can synthesize telomeres de novo. In fact, genetic mutations leading to constitutively active telomerase-expression have been associated with most human cancers . Human telomerase reverse transcriptase (hTERT) is the catalytic subunit of human telomerase and is the major determinant of telomerase activity . Since hTERT is mostly active in tumor cells, or in stem cells (not effectively killed by oncolytic adenoviruses) , hTERT-activity can be exploited for cancer gene therapy. This approach has been successfully used in the context of genetically modified adenoviruses to obtain tumor-specific replication not only in preclinical models ,  but also in one clinical trial .
Gene expression by oncolytic adenoviruses is determined in part by their capability to enter target cells . However, the native receptor for Ad5, coxsackie and adenovirus receptor (CAR), is often poorly expressed on cancer cells . Alternative targeting strategies have been developed to overcome this and several genetic modifications of the adenoviral capsid and knob have resulted in better tumor transduction . One approach includes the replacement of Ad5 knob with the serotype 3 knob since, as compared to CAR, the Ad3 receptor is expressed to a higher degree on cancer tissue and is different from CAR , , .
In the present study, we constructed Ad5/3-hTERT-hNIS where viral replication is controlled by the hTERT-promoter. Ad5/3-hTERT-hNIS is targeted to the Ad3 receptor for effective tumor transduction and expresses hNIS in replication-permissive cells only, thus allowing imaging of viral replication and treatment of infected tumors by radioactive iodine.
Two new oncolytic adenoviruses, Ad5/3-hTERT-hNIS and its control virus Ad5/3-hTERT- Δgp19K, were constructed to study their antitumor effect against castration resistant prostate cancer. The Ad5 knob was replaced by the Ad3 knob to increase transduction of cancer cells . The native E1A promoter was replaced by an hTERT-promoter for tumor-specific replication. In Ad5/3-hTERT-hNIS, the gp19K and 6.7K in E3 is replaced by hNIS that remains under the native E3-promoter and results in replication-coupled transgene expression that starts circa 8 h post-infection . The control virus harbors the same deletion (gp19K and 6.7K) without insertions.
To test the capability of the viruses to induce the expression of hNIS, castration resistant prostate cancer cells were infected with the new viruses and the cells were collected for hNIS RT-PCR at 24 h or 48 h afterwards (Figure 1a). Ad5/3-hTERT-hNIS displayed strong induction of hNIS at both time points whereas the control virus -infected cells remained negative for hNIS-expression.
Since mRNA-expression does not automatically mean production of functional hNIS, the ability of infected cells to transport and concentrate iodine was evaluated. Ad5/3-hTERT-hNIS-infected prostate cancer cells were incubated with 125I and then analyzed for iodide uptake using a gamma-counter (Figure 1b). 24 h after infection, iodide uptake was significantly higher in Ad5/3-hTERT-hNIS infected than in mock treated cells, p<0.001 for 22Rv1 and PC-3MM2 and p=0.003 and 0.002 for PC-3 and DU-145 cells, respectively. Significant differences were sustained at 48 h (p<0.001 for PC-3 and 22Rv1 and 0.04 and 0.003 for DU-145 and PC-3MM2 cells, respectively). PC-3 cells seemed to accumulate some radioiodine also without virus treatment. The phenomenon has also been reported previously for other cancer types and it is known that many secretory tissues, such as the prostate, feature a weak capacity to actively transport iodide , . This suggests that possibly hNIS-independent uptake of iodine impacted the results of the in vitro study.
To determine the oncolytic capacity of the new viruses, prostate cancer cell lines were infected with viruses and cell viability was assessed by the 3-(4,5,dimethylthiazol-2-yl)-5-(3-carboxymethoxy-phenyl)- 2-(4-sulfophenyl)-2H –tetrazolium inner salt (MTS) assay (Figure 2). Here, cell survival after infection is followed daily and the assay is stopped when the fastest virus has caused almost complete cell killing at the highest dose. In most cell lines, Ad5/3-hTERT-hNIS was more potent than wild-type adenovirus. However, some variation in the killing of different cell lines was observed, as also previously reported .
In the majority of the cell lines, the transgene-less Ad5/3-hTERT-Δgp19K was more efficient in prostate cancer cell killing than Ad5/3-hTERT-hNIS (Figure 2). This may be explained by the larger genome size of Ad5/3-hTERT-hNIS, caused by the transgene, which has been reported to affect oncolytic potency , .
To evaluate the ability of Ad5/3-hTERT-hNIS to direct iodine uptake into prostate tumors in vivo, a subcutaneous tumor model was established. Each mouse had four PC-3MM2 tumors (Figure 3a). Two lowermost tumors were injected twice with Ad5/3-hTERT-hNIS and others with Ad5/3-hTERT-Δgp19K (upper right tumor) or mock (upper left tumor). To follow the kinetics of iodine accumulation into these tumors 24 h later, mice received intravenous 123I followed by a series of gamma-camera imaging between 0.5 h and 13 h after iodine administration. As seen in Figure 3a, Ad5/3-hTERT-hNIS allows in vivo accumulation of systemic radioiodine into tumors. Iodine concentration reached a plateau at 2 h post iodine-injection and remained steady until the last imaging at 13 h (Figure 3a). The variation in signal between the Ad5/3-hTERT-hNIS injected tumors is likely due to difference in tumor size as smaller tumors might have fewer blood vessels (hampering iodine access to the tumor) and may not contain as many tumor cells that allow for hNIS-expression.
123I accumulation was detected in the thyroid and stomach due to endogenous expression of NIS in these organs. Bladder visualization occurs due to excretion of 123I into urine . Due to animal regulations, the experiment was ended at 13 h and did not permit us to study the effect of the treatment on tumor size.
To study the antitumor efficacy of intravenously administered Ad5/3-hTERT-hNIS with 131I in vivo, a survival experiment was set up. PC-3MM2 cells were injected into the left lung of nude/NMRI male mice (n=12 mice/group) to mimic aggressive, castration resistant, lung-metastatic prostate cancer. A week after cell injection, the mice received 5×1010 vp of Ad5/3-hTERT-hNIS or diluent intravenously. The next day, mice were administered 37 MBq of therapeutic radionuclide 131I or PBS intraperitoneally. This treatment-cycle was repeated once a week for a total of three weeks.
The median survival in the mock group was 19.5 days (Figure 3b). Survival prolongation was seen in the Ad5/3-hTERT-hNIS+131I group where the median survival was 28 days. This was confirmed by statistical analyses where the p-value between mock and Ad5/3-hTERT-hNIS+131I was <0.001 and between 131I only and Ad5/3-hTERT-hNIS+131I it was 0.007. As expected, 131I only (20.5 days) did not increase survival. Although intravenous delivery of oncolytic adenovirus presents many challenges, and the model used is particularly aggressive, the overall survival of virus-only treated mice was improved over mock treatment (p=0.04). Also, one mouse was tumor-free and healthy at the end of the experiment. Survival in the virus +131I group was not improved over virus –only treatment.
As radioidide might also accumulate into organs passively, or as a result of non-tumor-specific hNIS-expression, we measured the radioactivity of different organs - including tumors - from three mice from the Ad5/3-hTERT-hNIS+131I group, killed 24 hours after the first iodide injection (48 h after first virus injection). Due to the endogenous expression of NIS in the thyroid and stomach, about 320% and 15% of the injected dose per gram of tissue (ID/g) was concentrated in these organs, respectively. Iodide uptake into tumor was 1.3% of the injected dose (Figure 3c). The high ID/g of thyroid reflects the uneven distribution of iodine: if iodine would accumulate evenly into each organ, the ID/g would be 100%/organ.
While there was a survival improvement in both virus groups over no treatment or iodine only, radioiodide did not improve survival significantly. Therefore, we performed imaging-experiments to investigate reasons for this. This permitted us also to assess the feasibility of hNIS-mediated imaging. A similar setting to the survival-experiment was employed, where mice received either vehicle, Ad5/3-hTERT-hNIS only or Ad5/3-hTERT-hNIS+131I. In addition, each group received 24 h after each virus/vehicle administration an intravenous bolus of 123I− for imaging, followed by a SPECT/CT-scan and quantitation of the 123I− signal. After the first injection, 123I− uptake in the lungs was low and no clear tumor uptake was observed in mice treated with Ad5/3-hTERT-hNIS ± 131I. At this early point, 123I− uptake to the tumors was not distinguishable from the background activity, which remained at 0.00138±0.0006%ID/mm3 throughout the study (Figure 4a). This result is in accordance with the observed low tumoral iodine uptake in the biodistribution assay (Figure 3c). After the second viral injection, 3/5 of the virus-treated animals showed increased 123I− uptake in tumors, however the level of 123I− accumulation was modest. The clearest 123I− accumulation was reached after the third virus-injection, reaching at highest 0.0035%ID/mm3 (Figures 4a and 5a, c). There was no difference in tumoral 123I− accumulation between the two Ad5/3-hTERT-hNIS treated groups, regardless if they received also the therapeutic isotope 131I in addition to the imaging isotope (Figure 4a). In comparison to mice that were not treated with the virus, the difference in tumor signal was clear (Figure 5). The 123I− uptake-results are summarized in Table 1.
These data suggest that intravenous injections of Ad5/3-hTERT-hNIS allow tumor transduction, virus replication, hNIS-expression and radioiodide accumulation to such degree that it can be detected with SPECT/CT. The signal volume detected by SPECT was rather small and the mice nevertheless died, which led us to perform autopsies at the end of the therapeutic experiment. There was a discrepancy between actual tumor size seen in autopsy and the radioiodide accumulation dependent SPECT signal: tumors seemed larger than what was observed by SPECT signal. Possible explanations for this include incomplete penetration of the tumor by either virus or by 123I−.
All animals showed normal endogenous NIS expression in the thyroid, stomach, salivary and lachrymal glands. With the exception of the thyroid in 131I-treated animals, iodide accumulation into tissues expressing endogenous NIS was not affected. As the thyroid was not protected from radioiodide uptake in this experimental design, animals treated with 131I showed diminished thyroid activity in the second and third SPECT scan, as expected (Figure 4b). In addition, some mice showed physiological 123I− uptake in the esophagus, which was easily differentiated from the tumoral uptake using the anatomical information of the co-registered CT scan (Video S1).
Dose ratios (approximated as uptake ratios) thyroidbloodkidneytumor were approximately 10001.41.00.8 (Figure 3c). If the thyroid is protected or thyroid ablation accepted, the dose limiting normal tissue would be the red bone marrow. Assuming that the blood dose can be used as a surrogate for the bone marrow dose (i.e., assuming no active iodine trapping from blood to bone marrow and cross-dose omitted), the typical highest allowed blood dose (2 Gy/treatment cycle) would contribute 1.1 Gy to the tumor which is perhaps unlikely to result in therapeutic effect. These figures can be compared with the standard human kinetics applied for the dosimetry of internal radiopharmaceuticals (sodium iodide, oral administration, ) assuming 25% uptake of iodine in the thyroid at 24 h. These calculations result in thyroidbone marrowkidney ratios of 10002.41.05, respectively, which are in the same range as the mouse figures reported here.
After intravenous adenovirus injections, a large proportion of the dose is taken up by the liver . Therefore, we analyzed the hepatic radioiodide signal which would reflect “leaky” expression of virally-encoded hNIS in a non-target organ, keeping in mind that our virus-design predicts hNIS-expression mostly in cells that allow virus replication. Only two out of five virus-treated animals showed any degree of liver accumulation of 123I− after the first virus-treatment. This is in dramatic contrast to non-regulated expression of transgenes following intravenous adenovirus injection . After subsequent virus injections during the next two weeks, no iodide uptake was detected (Figure S1) and the signal difference compared to non-virus treated mice was insignificant (p=0.24). This demonstrated that hNIS-expression from Ad5/3-hTERT-hNIS was mostly restricted to tumor cells and leaky expression in normal tissues was minimal (Video S1).
Several tissue-specific promoters have been exploited for targeting oncolytic adenoviruses and restricting their gene expression to target tumors . While stringent tissue-specificity has been reported, the drawback of this approach lies in the selectivity of replication in only one or a few tumor types. However, hTERT-expression is ubiquitous in most human tumors while limited in normal somatic cells , making it an attractive promoter for specific adenoviral replication in human tumors. Importantly, good safety data has been obtained in a human trial featuring an hTERT-controlled oncolytic adenovirus . hTERT is expressed in stem cells. However, since stem cell toxicity is not an established feature of wild type adenovirus infection , we can assume that stem cells have other ways to protect themselves against virus as suggested by preliminary experiments performed in normal breast stem cells . Although this study used Ad5/3-hTERT-hNIS to treat castration resistant prostate cancer, Ad5/3-hTERT-hNIS could also be used to kill hTERT-positive cancer cells of different origins.
The rationale for using hNIS in cancer gene therapy has already been established , , , . In our virus, replication-induced hNIS–expression from the adenoviral E3-region couples radiographic imaging via hNIS to viral replication kinetics. We found it feasible to assess these aspects by using SPECT. Moreover, hNIS-expression by Ad5/3-hTERT-hNIS could allow dual-modality destruction of infected tumors: therapeutic radioiodide-treatment and oncolysis. While the same cell does not need to be killed twice, the biggest utility might come from the two different bystander effects. Oncolysis can amplify the input virus dose and in theory the process continues as long as permissive cells exist. However, tumors are complex, heterogeneous and contain areas impassable for the virus, including stromal and necrotic areas. Radiation, however, could exert effects on, over and through such areas. Also, some cells are or become resistant to radiation or oncolysis , . In this context, the strong synergy between oncolytic adenoviruses and radiation could be useful ,  as suggested in previous reports , , , . However, since there was no significant difference to the virus only in our experiment, construct design issues may play a role in the relative impact of oncolysis versus iodine mediated killing. In the context of optimized viral replication, a large sample size or an immune competent organism (where the efficacy of oncolysis could be less prominent) may be needed for demonstrating if there is any benefit of the combination in terms of efficacy.
Autopsies performed at the end of imaging experiment suggested that tumor masses were larger than what were observed by SPECT-imaging. Thus, the virus might not have been simultaneously replicating in the entire tumor and only the part of the tumor that sustains active replication at the time of imaging would be positive for hNIS-expression – uninfected or dead tissue would not be detected. The heterogeneity of the tumor mass might also contribute: although hTERT-activation would be detected in the parental tumor cells, the rapidly growing tumor bulk could allow for variation in hTERT-promoter activity, and thus in hNIS expression, due to mutations and inactivations of regulatory factors like the E-box motifs, which have been suggested to be the major determinants of hTERT-expression , . Furthermore, intratumoral barriers including stromal, necrotic, hyperbaric and hypoxic areas are likely to hamper the penetration of the virus to the entire tumor resulting in an uneven distribution of hNIS-expression. Incomplete tumor transduction due to polarized expression of viral receptors could also play a role . Finally, as predicted by the mechanism of the virus, only tumor areas through which the virus replication front is proceeding would be expected to be positive for hNIS. Areas in which virus replication has already occurred, would not be hNIS-positive, as cells that allowed for replication would have been lysed. Alternatively, oncolytic treatment might render tumor vasculature leaky or create local hypobaric areas resulting in areas of hNIS-independent iodine influx. This possibility could not be excluded since treatment with control virus was not assessed in the systemic approach. Also, in some tumors, only a small proportion of cells are malignant , , while the rest are murine-derived stromal (not permissive for adenovirus replication) and the latter would remain after oncolysis.
Visualization of the thyroid confirmed the utility of SPECT imaging in the context of radioiodide therapy. Notably, all mice treated with 131I showed diminished 123I− uptake by the thyroid during 2nd and 3rd week of the treatment. There are, however, differences regarding hNIS-expression as a transgene or as a regulator of the endocrine system. Importantly, extrathyroidal tissues expressing hNIS are unable to organify iodide and their hNIS-expression is not regulated by thyroid stimulating hormone (TSH) . In contrast, hNIS-expression in the thyroid is directly regulated by serum iodine concentration and TSH . TSH expression and secretion, in turn, are regulated by thyroxin and triiodothyronine, and their relationship is inversely correlated . Thus, the thyroid could be protected from 131I either by iodine- or thyroxin-supplementation prior to therapy. The latter has been successfully used in glioma treatment with a lentiviral vector expressing hNIS . The study reported a lack of thyroidal NIS-expression and function after a thyroxin supplemented diet whereas hNIS-transduced tumor tissue could be simultaneously visualized.
Excess iodine decreases NIS mRNA and protein expression , reduces radioiodide accumulation into the thyroid and can protect the thyroid for 24 h when administered up to two hours prior to 131I . If the same timing of Ad5/3-hTERT-hNIS and 131I would apply in a clinical setting, extra-iodine administered 4–6 hours after virus injection would saturate the thyroid without hampering transgene-mediated transportation of radioiodide into the tumor after 131I administration (eg. at 24 hours as in our experiments). However, lack of organification of radioiodide into cancer tissues is also a drawback as it reduces accumulation and subsequent dose to the tumor. A rapid radioiodide efflux from tumor cells has been associated with exogenous hNIS-expression  and it is clear that this issue is critical in our approach. Another problem may arise from viral oncolysis resulting in the death of the hNIS-expressing cells that limits the duration of the hNIS-expression window. The “timed” expression system used in Ad5/3-hTERT-hNIS, where transgene-expression starts at circa 8 h after infection (and thus closer to oncolysis), may limit the window further. In this regard, a ubiquitous CMV-promoter with high early activity might result in higher hNIS-expression levels , . When adenoviral vectors are delivered systemically, they are rapidly taken up by liver Kuppfer cells (KC) . The phenomenon is dose dependent and saturation occurs after high intravenous doses  leading to efficient transduction of hepatocytes and other tissues. Adenoviral entry into hepatocytes together with KC activation can result in an immune response that is suggested to be the major determinant of adenovirus induced toxicity . However, if the injected doses are small enough to avoid acute hepatotoxicity, but sufficient to saturate KC, transgene expression in hepatocytes occurs. This provokes a second, adenovirus-protein -specific immunoresponse . Thus, the use of tumor-specific promoters to restrict expression of adenoviral proteins to tumors is important from a safety perspective. Indeed, previous work has shown that hTERT-regulated expression of E1A in an oncolytic adenovirus did not induce liver toxicity . Accordingly, minimal hepatic hNIS-expression was seen in our study.
Human adenovirus is fairly human-specific and thus mice are poor models for studying toxicity. Ultimately, human trials may be needed to evaluate the feasibility and safety of intravenous injection at doses compatible with efficacy. Oncolytic adenoviruses might currently be the best administered intratumorally or intracavitary, perhaps in combination with intravascular delivery. Nevertheless, there are some tantalizing cases suggesting efficacy even after intravenous delivery alone , . However, immunogenicity of adenoviruses is an issue with regard to systemic re-administration .
In conclusion, Ad5/3-hTERT-hNIS was found to have anti-tumor activity in vitro, and in vivo it extended the survival of mice. Intriguingly, SPECT/CT imaging suggested that hNIS-expression could be detected only in a proportion of the tumor mass, which is likely due to incomplete penetration after systemic administration. Accordingly, combination therapy was not more effective than virus alone. However, an increasing level of hNIS-expression during therapy was detected using SPECT/CT, demonstrating the utility of the method for dynamic imaging of radioiodide therapy in animals with complex orthotopic human cancer xenografts. Before considering the possible clinical translation of the combination therapy to humans, further work is needed for improving tumoral hNIS expression levels and consequently 131I-targeting efficiency .
Castration resistant prostate cancer cell lines 22Rv1, PC-3 and DU-145 and human embryonic kidney epithelial cell line 293 were purchased from American Type Culture Collection (ATCC, Manassas, VA). PC-3MM2 cells are a metastatic, castration resistant subline of PC-3 (courtesy of Isaiah J. Fidler, M. D. Anderson Cancer Center). 911 cells were obtained from Dr. Alex J. van der Eb (University of Leiden, The Netherlands). All cell lines were cultured as previously described . PC-3 and DU-145 cells have been confirmed to have hTERT-expression .
Wild type adenovirus serotype 5 (Ad5 WT) was purchased from ATCC. Ad5/3luc1 has been described earlier .
hTERT-fragment was amplified by PCR from pBT255 (Courtesy of Izumi Horikawa, National Cancer Institute) to create a shuttle vector for E1-region. The following primers were used to result in 361 bp sized amplification product: forward primer, 5′-TTA GCG GCC GCA GAA CAT TTC TCT ATC GA-3′ and reverse primer, 5′-ACC GGA ATG CCA AGC TTA CTT AGA T -3′. NotI-XhoI- digested hTERT-fragment was inserted into NotI-XhoI -digested and calf intestinal alkaline phosphatase (CIAP) -treated pSE1AmpR (constructed previously in the laboratory) to obtain phTERTE1AmpR. Next, both PmeI -linearized phTERTE1AmpR and circular pAdEasy-1.5/3-Δ24  were electroporated into BJ5183 cells for homologous recombination resulting in pAdEasy-hTERT-E1-5/3. DNA from selected recombinant clones was electroporated into DH5α cells for DNA production and further analysis.
To obtain phTERT-E1-5/3-hNIS and phTERT-E1-5/3-Δgp19K, SrfI-linearized pAdEasy-hTERT-E1-5/3 and FspI –linearized pTHSN-hNIS or FspI –linearized pTHSN-Δgp19K  were electroporated into BJ5183 cells for homologous recombination. The DNA from selected recombinant clones was electroporated into DH5α cells for DNA-production and further analysis. phTERT-E1-5/3-hNIS and phTERT-E1-5/3-Δgp19K were linearized and transfected into 911 cells using Superfect (Qiagen, Hilden, Germany). The viruses were plaque-purified and propagation was performed on A549 cells followed by standard CsCl purification to obtain a concentration of 4.8×1011 viral particles/ml (vp/ml) and 1.8×1010 plaque forming units/ml (pfu/ml) for Ad5/3-hTERT-hNIS and 5×1011 vp/ml and 5.1×1010 pfu/ml for Ad5/3-hTERT-Δgp19K.
Prostate cancer cells were infected with 10 vp/cell of Ad5/3-hTERT-hNIS or Ad5/3-hTERT-Δgp19K for 2 h in 37°C. 24 h and 48 h after infection total RNA was isolated (RNeasy Kit, Qiagen). The samples were treated with DNase before subjected to RT-PCR. 350 ng of RNA was used for each reaction. Amplification was done using OneStep Reverse Transcription –PCR Kit (Qiagen) with 35 cycles and annealing at 54°C. The hNIS-PCR product size (453 bp) was obtained using hNIS-specific primers (forward 5′-CTTCTGAACTCGGTCCTCAC-3′ and reverse 5′-TCCAGAATGTATAGCGGCTC-3′). For ß-actin, (482 bp product size) was obtained using for human ß-actin-specific primers (forward 5′-CGAGGCCCAGAGCAAGACA-3′ and reverse 5′-CACAGCTTCTCCTTAATGTCACG-3′).
1×105 PC-3, PC-3MM2, DU-145 and 22Rv1 cells/well were plated, incubated overnight, and next day infected with 10 vp/cell of Ad5/3-hTERT-hNIS or Ad5/3-hTERT-Δgp19K for two hours. 24 h or 48 h later the cells were washed with PBS and [125I]NaI (MAP Medical Technologies Oy, Finland) was added for 20 min at RT. Cells were washed twice with PBS and 300 µl/well of Cell Culture Lysis Reagent (Promega, Fitchburg, WI) was added. Radioactivity was quantified as described in .
10,000 cells/well were seeded on 96-well plates, incubated overnight and next day infected with Ad5/3-hTERT-hNIS, Ad5/3-hTERT-Δgp19K, Ad5/3luc1 or Ad5 wild type (0.01–100 vp/cell) for 2 h. The viability of the cells was assessed on day 6 (PC-3MM2), day 7 (PC-3 and DU-145) or day 9 (22Rv1) using the MTS-assay (CellTiter 96 Aqueous One Solution cell proliferation assay, Promega). The cell survival after infection was followed daily with internal controls and the stopped when an almost complete cell killing was seen with the fastest virus .
The protocol was identical as described in . NMRI/nude mice (Taconic, Ejby, Denmark) were injected with 7×108 vp of Ad5/3-hTERT-hNIS, Ad5/3-hTERT-Δgp19K or saline.
NMRI/nude mice (n=15/group) were purchased from Taconic. 1.5×106 PC-3MM2 cells were inoculated into the left lung of the mice under medetomidine-ketamine anesthesia (day 0) , . On day 7, mice were randomized into four groups; mock, 131I alone, Ad5/3-hTERT-hNIS alone or 131I+Ad5/3-hTERT-hNIS and received 5×1010 vp of Ad5/3-hTERT-hNIS or DMEM intravenously. The next day, animals were injected with 36±5 MBq of [131I]NaI (MAP Medical Technologies) in 1×PBS or vehicle intraperitoneally. Three animals from each group were sacrificed 24 hours after the first 131I-treatment for the biodistribution study where radioactivity was measured with an automated gamma-counter (Perkin Elmer Wizard 3, Perkin Elmer, Waltham, MA). Results are expressed as percentage from the initial iodine-dose/g of tissue. 12 mice/group continued in the survival experiment and the same doses were repeated once a week for 3 weeks.
NMRI/nude male mice (Harlan, Indianapolis, IN) were treated identical to the survival-experiment. The animals were scanned with SPECT/CT a day after each intravenous Ad5/3-hTERT-hNIS or DMEM injection, three times in total. The 131I (32±6 MBq) or PBS-injections were given after the SPECT/CT-scan.
18±2 MBq of sterile [123I]NaI (MAP Medical Technologies) was injected intravenously under isoflurane-anaesthesia for SPECT-imaging (that was performed 2 h after 123I injections). SPECT/CT was acquired using multi-pinhole nanoSPECT/CT-system with four heads (Bioscan, Washington DC). SPECT-acquisition collected 30000 counts per projection (16-projections) and the scan-time was 20–25 min. After the third scan mice were sacrificed and the tumors were harvested. All images were reconstructed with MEDISO-software and analyzed using In Vivo Scope-software (both Medical Imaging Systems, Kingsbury, England). Voxel-guided regions of interest (ROI) were drawn using the fused SPECT/CT-images and the results are expressed as percentage of radioactivity in the ROI from the injected activity (at time of the SPECT-scan), divided by the volume of the ROI (in mm3).
Student's t-tests were performed to analyze in vitro iodide uptake and cell killing using Microsoft Excel (Microsoft Corporation, WA). Survival analyses were conducted by plotting Kaplan-Meier curves, and the comparisons between groups were done pairwise by the log-rank procedure with PASW statistics 17.0 (SPSS Inc., Chicago, IL). For all analyses, a two-tailed p-value<0.05 was deemed statistically significant.
The animal experiments were approved by the National Committee for Animal Experimentation in Finland (State Provincial Office of Southern Finland), permit number ESLH-2008-00590-Ym-23.
hNIS-expression from Ad5/3-hTERT-hNIS is restricted to tumor cells. A mouse treated with Ad5/3-hTERT-hNIS shows minimal liver 123I− accumulation after the first intravenous injection of the virus (week 1). The next treatments (weeks 2 and 3) did not result in hepatic uptake.
The video shows tumor-specific hNIS-expression on the third treatment week in the lung of a mouse treated with Ad5/3-hTERT-hNIS and 131I−. Some physiological uptake is seen in esophagus, thyroid and salivary glands.
Competing Interests: A. Hemminki is a co-founder and shareholder in Oncos Therapeutics ltd. This does not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials. There are no patents, products in development or marketed products to declare.
Funding: The study was supported by the Helsinki Biomedical Graduate School (www.hbgs.helsinki.fi) and grants from Finnish Foundation for Research on Viral Diseases (www.virustauti.fi), Emil Aaltonen foundation (www.emilaaltonen.fi), Biomedicum Helsinki Foundation (www.biomedicum.fi), Irja Karvonen's Cancer Foundation (www.karvonensaatio.fi), Jalmari and Rauha Ahokas Foundation (www.ahokkaansaatio.org), The Finnish Medical Foundation (www.laaketieteensaatio.fi), K. Albin Johansson Foundation (www.foundationweb.net/johansson/), Jenny and Antti Wihuri Foundation (www.wihurinrahasto.fi), Drug Discovery Graduate School (ddgs.utu.fi), European Research Council (erc.europa.eu), ASCO Foundation (www.asco.org), HUCH Research Funds (EVO), Sigrid Juselius Foundation (www.sigridjuselius.fi/foundation), Academy of Finland (www.aka.fi), Biocentrum Helsinki (www.helsinki.fi/biocentrum), Biocenter Finland (www.biocenter.fi) and University of Helsinki (www.helsinki.fi). Akseli Hemminki is K. Albin Johansson Research Professor of the Foundation for the Finnish Cancer Institute. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

domain: literature


text:
The Power of Subconscious and How It Relates to Bell's Theorem
There are four books that changed my understanding of the way we think, and what motivates our success. These four books showed me how so many of our actions are rooted in subconscious thoughts and how understanding this fact can drive accomplishment. Throughout my career, I have maintained one objective: to help young people--particularly those at risk--to achieve financial independence, stability and ultimately success. In addition to the business skills and tools that programs like NFTE provide, I think young people can realize their success by understanding the power of their own minds and the importance of remaining resolute in your work.
The first one is The Power of Your Subconscious Mind by Dr. Joseph Murphy, written in 1963. Murphy outlines the extent to which behavior is a direct result of the subconscious mind; in other words, you act based on the thoughts deep in your subconscious. The text offers methods to extract and focus these thoughts so that all of your internal focus is directed toward a common energy.
The Power of Your Subconscious Mind by Dr. Joseph Murphy
The second book is Think and Grow Richby Napoleon Hill, written in 1937. Famously, in the book Hill uses extensive information gathered from countless interviews with successful men; he then translates that into laws for success--not just financial but the completion of whatever objective you choose. Incredibly, what Hill found was the power of subconscious thought. For me, the key pages are 25 to 32, which describe how Napoleon's own son started a business on his own. Hill traces exactly how the subconscious mind fixates on success in order to grow a business and a fortune. Much of my own work with NFTE has been based on this section--since I hope at-risk youth too can use this knowledge to overcome their own economic barriers. If a young person knows what they want, they can harness that knowledge to achieve their goals.
Think and Grow Rich by Napoleon Hill.
The third one is Brian Tracy's magnificent book, Maximum Achievement. Tracy elaborates on the ways that the subconscious mind determines action or inaction in our lives. He stresses his own key to success: the importance of establishing clear goals through positive thought. He uses realistic examples pertaining to sales and business to show readers how understanding positive outcomes can help you achieve them.
Maximum Achievement by Brian Tracy.
Finally, all young people should understand the concepts discussed in John Bell's seminal 1964 paper entitled "On the Einstein Polensky Rosen paradox." John Bell, one of the greatest physicists of all time, gave one lecture in 1990 explaining his theorem, which has since been validated in most laboratories around the world, and was actually one of the Dalai Lama's arguments in his book The Universe in a Single Atom. He argues that everything is physically interconnected--in other words, a particle is infinitely entangled to another after just one interaction, even if they are light-years apart. I see this as the physical manifestation of the earlier ideas--that ideas are interconnected and that these thoughts are what drives both individuals and nations, to people, and perhaps, the universe as well.
John Bell (http://en.wikipedia.org/wiki/John_Stewart_Bell).
What I learned from these books, and what I can say now with more perspective on my career, is that we should remain hungry to uncover the thoughts and genius of our own minds. Could it be that the entrepreneur is the master of this? Perhaps he or she is more adept at accessing their subconscious minds? And, perhaps, this allows the entrepreneur to break goods and services onto a market? Every young person should be taught about the power of their own minds in motivating and realizing success. I know now that business genius comes not just from the great entrepreneurs and corporate leaders, but also perhaps from quantum physics!


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Lorie Logan gives nod that The Blind Spot’s intraday liquidity thesis is accurate.
As the United States confronts an impending government shutdown amid an unwelcome outbreak of bond vigilantism, an unexpected remedy to global financial implosion might just lie in a murky corner of long forgotten financial history. Dormant for decades, the Blind Spot understands the overlooked issue of defaulted Chinese imperial debt is quietly turning heads on […]
By Victor Jack, Abby Wallace · Aug 18, 2023 BRUSSELS — The U.K. and EU are likely to miss their 2030 wind energy installation targets as the sector runs into increasing difficulties, putting Europe’s green transition at risk. Surging inflation, supply chain bottlenecks, hold-ups in getting permits, problems with government-backed subsidy schemes and mounting competition […]
Clubcard Nation: how supermarket loyalty schemes make cash-strapped Brits an offer they can’t refuse (POLITICO)
By Ben Munster · Aug 8, 2023, MANCHESTER — Belvita fruit crunch, Crimble’s Big Choc Macaroons, Elvive Colour Protect shampoo — all among the many goods Brits purchase in vast quantities everyday, and all painfully expensive in U.K. supermarkets as the cost-of-living crisis continues to take its toll. At a growing number of supermarkets, relief […]
The Blind Spot’s Dario Garcia-Giner probes just how big a deal UAPs are for the safety of our skies and what authorities across the world are doing to track the phenomena. An exhaustive months-long investigation reveals the risk is on the way to being treated more seriously by civil and military aviation institutions — a robust about-turn after decades of pretending it didn’t exist.
By Ben Munster · May 26, 2023 Panic in Europe? Over a U.S. debt default? Surely not … well, maybe. Just a little. OK, quite a lot, to judge by an awkward exchange at the International Capital Markets Association’s annual bash in Paris on Thursday. “My question,” AXA Investment Management fixed-income chief Hans Stoter told […]
By Bjarke Smith-Meyer, Ben Munster · May 19, 2023 BRUSSELS — Few expected Tether, the world’s most prominent stablecoin, to survive the crypto market meltdown. Instead, the issuer of dollar-pegged digital tokens revealed it was thriving by this month posting a first-quarter profit of $1.5 billion that left most of its rivals in its wake. […]
By Bjarke Smith-Meyer – May 5, 2023 There’s a turf war going on for your savings. At stake are over $16 trillion worth of deposit balances in the European Union alone, vital to banks’ capacity to keep credit flowing to small businesses and individuals. This is especially the case in Europe which relies far more […]
By Izabella Kaminska · Apr 26, 2023, 2:22 PM To read remarks made by a string of treasury officials and central bankers in recent weeks, one thing becomes clear: It’s no longer an exaggeration to suggest the global economic system is heading toward a shift unlike anything since World War II. And what’s more, what’s […]
By Giorgio Leali – Apr 21, 2023 (POLITICO) PARIS — France’s feisty Economy Minister Bruno Le Maire has another opportunity to pick a fight with Washington as a sensitive investment screening case is about to land on his desk. The French government wants to prevent nuclear-submarine parts supplier Segault from falling into American hands just […]

domain: finance


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Greenheck now offers an option for its ceiling exhaust fan and ceiling radiation damper to be combined at the factory into one unit shipped ready to install. Model CRD-310WT, a UL Classified ceiling radiation damper for wood truss applications, can be factory-mounted to one of six Greenheck ultra-quiet SP-A fan models (size 50 to 190 cfm) eliminating field assembly for fast, easy installation. The CRD-310WT damper is UL approved for use in 20 UL classified floor/ceiling and roof/ceiling assemblies making the CRD-310WT and SP-A combination a versatile code compliance option, ideal for bathrooms and storage areas in multifamily structures, condos, hotels, hospitals and schools.


Want to have doctors wrapped around your finger? MIT mechanical engineers Harry Asada and Phillip Shaltis have developed a “ring sensor” that monitors the wearer’s temperature, heart rate, and blood oxygen level. About the size of a class ring, the device is equipped with two light-emitting diodes that beam pulses of red and near infrared light through the user’s finger. A detector on the opposite side of the ring measures the intensity of the transmitted light. Just how much light passes through depends on the oxygen levels and the volume of the blood in its path. Volume changes over the course of a heartbeat and can indicate small changes in heart rate. The battery-powered ring contains a wireless link that can transmit vital signs to a cell phone or computer, allowing a caregiver to determine remotely whether a patient needs assistance. The ring could be used in emergency rooms to monitor patients waiting for treatment, in homes to watch patients after heart surgery, and even in cars to check drivers’ fatigue levels. The researchers have finished a round of clinical tests and are working with companies to commercialize the device within five years.
A Roomba recorded a woman on the toilet. How did screenshots end up on Facebook?
Robot vacuum companies say your images are safe, but a sprawling global supply chain for data from our devices creates risk.
A startup says it’s begun releasing particles into the atmosphere, in an effort to tweak the climate
Make Sunsets is already attempting to earn revenue for geoengineering, a move likely to provoke widespread criticism.
10 Breakthrough Technologies 2023
These exclusive satellite images show that Saudi Arabia’s sci-fi megacity is well underway
Weirdly, any recent work on The Line doesn’t show up on Google Maps. But we got the images anyway.
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text:
Philadelphia Mayor John Street, facing the prospect of another violent year, told the Philadelphia Inquirer that he plans expanded efforts to combat truancy and curfew violations as a way to stem the violence. Candidates to succeed Street are rolling out their own crime-fighting plans, which often contain implied criticism of the mayor. Former City Councilman Michael Nutter has pledged to declare a crime emergency in crime-plagued neighborhoods on his first day in office. Street says declaring a state of emergency would be “a tragic and unfortunate error” because it would damage the city economically and set police-community relations back by decades. A declaration would tell residents, Street said, that “you’re less free in this neighborhood than other neighborhoods.”
Street also derided calls for massive increases in the number of police hires and police surveillance cameras, saying that proponents do not understand, or are not being honest about, how prohibitively expensive those actions would be. U.S. Rep. Chaka Fattah has proposed putting up 1,000 crime cameras within 8 years. The city has 18 cameras now. Crime has become the top issue in the mayoral campaign because of the surge in shootings and killings since 2002, when the city had reached a 17-year low with 288 homicides. Last year, Philadelphia had 406 homicides. There have been 26 slayings in 2007 through Tuesday, compared with 16 for the same period last year.

domain: sociology


Another tool in the engineer tool belt is the trade study. Need a decision among many alternatives? Do a trade study. The hardest part, what criteria to use. For instance, looking for the best car for the environment? Well you want to look a gas mileage, fuel used, and emissions emitted. But here's a trade study which took a more holistic view by taking into account the environmental impact of the cars production and most importantly, DISPOSAL. The winner: The Hummer. Controversial but true. Trade Studies, specially a 479 page report, can't lie. Can it?


text:
這「一部份」，用英文說就是part and parcel - 重要的、主要的 - 不能恣意捐棄。即如學術研究一樣，不能從我的生命中抽走。飯後我買了杯咖啡，沿著小徑回返桃園樓的研究室，途中遇見同事，微笑寒暄，步履如常，這也是生命的一部份。
這「一部份」，在時間如沙粒從手指間漏失的存在中悠悠呼吸，呼出去不必要的誇飾,吸進來舒坦的自在。用矛盾語來說，是「無意識的意識」(unconscious consciousness) ，可以細如檐滴，可以闊如江海。
By Gabriel Wu
Following a sunset poetry reading organised by a local literary group called the Kubrick Poetry Club, a member of the audience asked me what poetry meant to me. I had been reading from my recent collection Ban Cun Zai (A Half-Existence) at a bookstore in Yau Ma Tei, and in reply I said, “It is part of my life”.
Perhaps my reply was too dull and unexciting, and didn’t satisfy the audience’s expectations. But I thought it aptly described how my pulse beat and my blood flowed when I replied to the question. Although physically indoors, standing between the spotlight and microphone, I could sense a spring breeze gently blowing to bring forth leaves so green that they could not be greener as I seemed to see the ever-changing sunlight radiating through the twigs and branches.
I could never relinquish this “part”, expressed as part and parcel in English, something which is important and essential, just as I could not ever give up academic research, which is part of my life, too.
I bumped into a colleague after I bought a coffee following my meal, and was heading back to my office in the To Yuen Building. We exchanged greetings and then said our goodbyes, and I returned to my usual footsteps. Such an encounter is also part (and parcel) of life.
This “part” gently breathes in an existence where time slips, like grains of sand through one’s fingers, exhaling unnecessary exaggerations and inhaling a soothing sense of calm. Unconscious consciousness—if I may use an oxymoron—can be felt to be as fine as a single droplet of water clinging to the eaves of a house or as vast as deep rivers and expansive oceans.
Night falls. My kitten leaps onto my lap, curling up to sleep. The only sound is that of my fingers tapping at the keyboard. “I am a part of poetry,” I write.
Special thanks to Linkage from City University for the English version.

domain: artistic


text:
Commonly reported side effects of pimozide include: akathisia, akinesia, sedated state, and visual disturbance. See below for a comprehensive list of adverse effects.
Applies to pimozide: oral tablet
Along with its needed effects, pimozide may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.
Check with your doctor immediately if any of the following side effects occur while taking pimozide:
Less common or rare
Get emergency help immediately if any of the following symptoms of overdose occur while taking pimozide:
Symptoms of overdose
Some side effects of pimozide may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:
Applies to pimozide: oral tablet
The most common side effects include somnolence, hyperhidrosis, nocturia, and dizziness.
Very common (10% or more): Somnolence (up to 25%), dizziness (up to 11%)
Common (1% to 10%): Extrapyramidal disorder, akathisia, headache, lethargy, tremor, hyperkinesia, limb tremor, torticollis
Uncommon (0.1% to 1%): Bradykinesia, cogwheel rigidity, dyskinesia, dystonia, dysarthria
Frequency not reported: Neuroleptic malignant syndrome, grand mal convulsion, tardive dyskinesia, electroencephalogram abnormal, motor restlessness, hyperreflexia, opisthotonos, drowsiness, sedation, speech disorder, handwriting change, taste change, akinesia, parkinsonism, fainting
Postmarketing reports: Seizure
Extrapyramidal symptoms typically occurred during the first few days of treatment and involved mild to moderate Parkinson-like symptoms. This disorder is usually dose-related, with an increased occurrence and severity of symptoms with high doses; symptoms decreased or disappeared with lower doses. While these symptoms were usually reversible, a few cases of persistent symptoms required discontinuation.
Grand mal seizures occurred at doses greater than 20 mg/day.
Very common (10% or more): Adverse behavior effect (up to 22.2%)
Common (1% to 10%): Depression, agitation, insomnia, abnormal dreams, restlessness, nervous
Frequency not reported: Libido decreased/lost, excitement
Sudden, unexpected deaths have occurred at doses greater than 20 mg/day.
Very common (10% or more): Asthenia (up to 13.8%)
Common (1% to 10%): Extreme exhaustion
Uncommon (0.1% to 1%): Face edema
Frequency not reported: Neonatal drug withdrawal syndrome, body temperature dysregulation, hypothermia
Postmarketing reports: Sudden, unexplained death, hyperpyrexia, thirst
Very common (10% or more): Hyperhidrosis (up to 13%)
Common (1% to 10%): Sebaceous gland overactivity, rash
Uncommon (less than 1%): Pruritus
Frequency not reported: Urticaria, skin irritation
Very common (10% or more): Nocturia (up to 12%)
Common (1% to 10%): Urinary frequency, erectile dysfunction
Uncommon (0.1% to 1%): Amenorrhea
Frequency not reported: Galactorrhea, menstrual disorder, breast secretions, impotence
Common (1% to 10%): Constipation, dry mouth, vomiting, increased salivation/salivary hypersecretion, dysphagia
Frequency not reported: Diarrhea, nausea, gastrointestinal distress
Postmarketing reports: Gingival hyperplasia
Gingival hyperplasia occurred in animal models at high doses, but was reversible after discontinuation.
Common (1% to 10%): Muscle rigidity, myalgia
Uncommon (0.1% to 1%): Muscle spasms
Frequency not reported: Rigidity, neck rigidity, muscle cramps, muscle tightness, stooped posture
Common (1% to 10%): Vision blurred, visual disturbance
Uncommon (0.1% to 1%): Oculogyric crisis
Frequency not reported: Sensitivity of eyes to light, decrease accommodation, spots before eyes, periorbital edema, cataracts
Hyperglycemia occurred in patients with preexisting diabetes.
Common (1% to 10%): Anorexia, weight increased
Frequency not reported: Hyperglycemia, hyponatremia, appetite increase, weight loss
Electrocardiographic changes include prolongation of the QT interval, flattening/notching/inversion of the T wave, and the appearance of U waves.
Common (1% to 10%): ECG abnormal
Frequency not reported: Torsade de Pointes, ventricular tachycardia/tachycardia, ventricular fibrillation, chest pain, postural hypotension/hypotension, hypertension, palpitations
Postmarketing reports: Cardiac arrest, venous thromboembolism, deep vein thrombosis
Frequency not reported: Blood prolactin increases, gynecomastia
Frequency not reported: Glycosuria
Postmarketing reports: Hemolytic anemia
Postmarketing reports: Pulmonary embolism
Medically reviewed by BestRx Medical Team Last updated on 1/1/2020.
Source: Drugs.com Pimozide

domain: medical


Illinois Hatcheries Stocking Alligator Gar to Combat Carp by Debbie Kay
The state of Illinois has a monster carp problem. What better way to fight a monster than with a bigger monster? So goes the logic, as the state’s hatcheries gear up to begin stocking alligator gar in many of the state’s rivers that have invasive fish problems. Though the fish are native to Illinois, they have not been seen in the state’s waters since 1966. Their return is hoped not only to curb the growing carp population with one of the few native predators, but to return a major trophy fish to Illinois waters.
About Alligator Gar
Alligator gar are one of the most ancient species still living today, with fossil records of these fish dating back to over 100 million years ago. They can grow up to ten feet long and weigh up to 300lbs. From the 1930’s to the 1980’s, they were considered “trash fish” and a detriment to sport fishing. They are known as stalking predators, and will target large fish, small mammals and waterfowl. They were targeted for extermination in many waters of the US and Mexico during this period. When better knowledge of the interaction of ecosystems came in the 80’s, the emphasis went from extermination to protection and reintroduction. Today, many states have an alligator gar fishery.
Reintroduction into Illinois
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Illinois has waters that run into two massive interstate watersheds. Some waters run toward Lake Michigan and into the Great Lakes waterway, while others head toward the mighty Mississippi. There is a large pool of federal funding money that has been set aside to deal with the scourge of Asian Carp as it quickly repopulates through the area. The gar reintroduction program is using that funding to help deal with this issue. As a bonus, hatcheries stocking alligator gar will serve as a large trophy fish that can bring state revenue through fish endorsement licenses and tourism dollars.
Will it Work?
The gar is not a complete solution to the carp problem. Population-wise, the carp outnumber the gar by a massive amount. The largest carp are too large to be swallowed by the narrow-throated gar. Also, populations of gar will not breed until they reach sexual maturity at age 11, while carp begin reproducing at age 3. This means that they can take a small portion of the population, but they will never be the main control mechanism for these fish. However, after several years, once they have firmly reestablished their numbers, the gar can be a preventative measure in areas without Asian carp if smaller, younger fish try and expand their territory. Instead, netting and fish kills seems to be the only way to keep this majorly invasive fish species at bay.
When Will Gar Reintroduction Begin?
The hatcheries stocking alligator gar program has been approved since 2010, but funding has only recently been secured. Hatcheries are prepping to begin grow-out and release as early as next year. From there, Illinois will need to decide how to handle fishing seasons for this once extinct species.


text:
Artsnight - October 8, 2016
Veteran broadcaster Michael Palin travels to north Wales to interview the legendary travel writer Jan Morris. Originally born as James Morris, Jan shot to fame as part of the team that successfully climbed Mount Everest in 1953. She spent the rest of the decade as a journalist travelling the world, interviewing figures such as Che Guevara, and producing reports for BBC Panorama from Hong Kong and Japan. In the 1960s, she turned her attention to writing books about cities and countries, before undergoing gender reassignment in 1972, a process chronicled in her autobiography Conundrum. Now in her 90th year, Michael Palin meets Jan and finds out the secret to her long and happy life.
Artsnight was broadcast on BBC2 at Saturday 8 October 2016, 21:00.
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- Playback time31:00
Artsnight is a TV show on British national television from BBC2 with an average rating of 3.0 stars by TelevisionCatchUp.co.uk's visitors. We have 48 episodes of Artsnight in our archive. The first episode of Artsnight was broadcast in December, 2016. Did you miss an episode of Artsnight but don't you wan't that to happen in the future? Please set an alarm and add Artsnight to your favourites, so we can remind you by email when there's a new episode available to watch. For free!

domain: entertainment


Green Organic Dutchman Holdings Ltd., a leading producer of premium certified organic cannabis, is building a new greenhouse facility in Jerseyville, ON. The development is in the process of construction with the entire area to be serviced by a private groundwater well that was drilled in May 2017. The well will supply water for both their growth process and the domestic water supply for the building staff. The requirement is for 40,000 L/day and is to be treated to Ontario drinking water standards (O. Reg 903).
Interpump has worked with Doherty Engineering to design a FULL water treatment train to meet both the site water needs and any special design constrains or requirements. Our solution included a well pump, a skid package for water treatment for the incoming flow rate of 11.2 USGPM from the drilled well on site, a day tank and domestic water booster pump. Well water is pumped through bag filters, into an ozone system, through additional filters to capture oxidized sediment, into a duplex water softener system, through a polishing filter and finally through a commercially sized & validated UV system for disinfection. The final storage tank ensures that the water being pulled into the building does not exceed 40,000L/day at anytime. The system also incorporates a dedicated and customized Interpump control panel with colour HMI screen and communication to the Building Automation System.
Consistently high quality of water is essential to a successful cannabis growing facility. Interpump incorporates robust, reliable and flexible designs that can handle any possible water quality changes throughout the year.
Interpump provided concepts, options, drawings and written specifications. As part of all Interpump turn-key solutions, system commissioning, testing and training is included in the purchase of the system to ensure system operation and reliability for years to come.


text:
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Date: 1930 ca.
Description: A drawing on green cardboard, labeled No. 1, of a design for a triangular brooch. The mounting of yellow and white gold holds a multicolored cabochon, poss...
Description: Stage Plot for the band U2. The famed Irish rock band that formed in 1976 performed on April 14, 1981 at Merlyn’s, 311 State Street, Madison, Wisconsin. U2...
Date: date unknown
Description: An original ink drawing of William Donahey's "Teenie Weenies." This colorful drawing features several Teenie Weenies gathered around a mallard duck with te...
Description: Dimensional drawing or chassis diagram for International K-8-COE and KR-11-COE trucks.
Date: 1896 ca.
Description: Rendering of the library reading room in the State Historical Society, now the Wisconsin Historical Society. This was the final, accepted design by Ferry a...
Description: Two drawings of The National Republican Convention Headquarters in Chicago, Illinois, at the Grand Pacific Hotel. The Blaine Headquarters.
Description: Illustration of the west side of East Water Street.
Description: Drawing of a section of a completed part of Fort Cairo facing the confluen [sic] of the Mississippi and Ohio rivers.
Date: 1885 ca.
Description: Illustrated view of Superior.
Date: 1863 ca.
Description: A watercolor illustration of a combined thermometer, hygrometer, barometer, and pyrometer.
Description: Topographic map of Park Lands in Glenwood Plat, Land for Glenwood Children's Park. Design by Jens Jensen. Oringinal drawing 35 x 34 inches.
Description: Preliminary sketch, drawn by Frank Lloyd Wright, for the Floating Gardens Resort. The drawing may be an early concept for the resort of a detail for the re...
Date: 1944 ca.
Description: Artist's rendering of the research and development tower and administration building of the S.C. Johnson and Son Wax Co.
Description: A small, preliminary sketch of a gathering of people.
Description: Ink drawing of the Governor's Residence, 130 East Gilman Street. The stone building features a porch and wrap around balcony.
Description: Design in purple for the Wisconsin Centennial 3 cent postage stamp. There is a farming theme, with stacks of grain and a barn.
Date: 1920 ca.
Description: Color illustration of a view from the Wisconsin State Capitol (which was the fourth State Capitol and the third in Madison) showing the Hotel Loraine and W...
Description: Pencil and ink plan and elevation sketch, drawn by Frank Lloyd Wright, for a firescreen for the Hillside Theater. The drawing includes a dimensioned plan a...
Date: 1900 ca.
Description: View of St. Paul's Cathedral.
Description: Ledger Drawing. Two men in battle. Two horses, one with a rider dressed entirely in black.
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domain: geography


text:
Rapper and actor T.I. (Clifford Harris) has opened a new restaurant in downtown Atlanta called Scales 925. Following its soft opening on April 1st, plans are for an official grand opening party to be held April 14th.
Serving “upscale Southern cuisine,” Scales 925 is located at 30 Ivan Allen Plaza on Ivan Allen Jr. Blvd. Executive Chef Messiah Gonzalez is a veteran of popular Atlanta restaurants The Spence and Le Bilboquet, while culinary team member “Chef Ashley” is the longtime personal chef and caterer for T.I.

domain: news


text:
Transfer News: Coventry linked with Manchester City's Alex Henshall
Sky Sports understands Coventry City are considering a loan move for Manchester City teenager Alex Henshall.
Last Updated: 30/01/13 9:32pm
The winger joined City from Swindon Town in the summer of 2010, but has yet to make the breakthrough into the Premier League champions' first-team set-up.
He could now be given the opportunity to gain experience back in the Football League, with Coventry boss Mark Robins acknowledging a loan signing from the top flight is an option.
"I may have a look at a youngster from a Premier League side," Robins told the club's official website. "That might be after the transfer window has closed though, we'll have to see.
"There are one or two players I wouldn't mind. They are on our radar but it just remains whether I will be able to anything or not."
Meanwhile, Robins is taking a look at Danny Philliskirk after the striker was released by League One rivals Sheffield United last week.
Philliskirk played for the Under 21s against Sheffield Wednesday on Monday and Robins said: "I am just having a look at him. He is here for a week or so and we just want to see if he can offer anything to the side.
"He played well in the game but for now, we just want to see how he gets on having just left Sheffield United."


text:
Published December 3, 2018
The CannonDesign project team chosen for the global design firm’s partnership with UB on the university’s signature One World Café brings expertise in transformative renovation and award-winning, culinary-focused design, as well as experience working on major architectural projects across Western New York.
And as UB graduates, team members Peter McCarthy, Luke Johnson and Amir Rezaei also bring a unique understanding and appreciation for the university to the project.
The opening of One World Café (OWC), now planned for spring 2021, will meet the demand for expanded dining facilities among a growing campus population, while also bringing to UB an international eatery and community space where students, faculty, staff and visitors can enjoy a diverse selection of foods from around the world in a welcoming, multicultural environment.
OWC will mark completion of the third phase of Heart of the Campus, the UB2020 initiative to enhance the student learning experience by creating a learning landscape in the center of the academic spine.
Project manager Frank Sica, who holds a BS in architecture from the University of Virginia, is one of the most knowledgeable and technically experienced architects in Buffalo, having worked on signature projects for the city, including Buffalo Niagara International Airport, Gates Vascular Institute and academic buildings for UB, Buffalo State College, Canisius College and others.
“Beyond their skills and expertise, the team’s familiarity with and passion for the campus and its community are invaluable,” says Sica, whose close relationship with UB grew out of his design work on the Clinical and Translational Research Center and laboratory master plans for the South Campus.
“Quite literally, three of our team members have walked the UB campus as students and know what it means to be a UB student day in and day out,” he says.
Graham Hammill, vice provost for educational affairs, dean of the graduate school and chair of the OWC steering committee, says student interest and demand for cuisine from around the world has increased.
“At One World Café, students will find authentically prepared foods, and it is expected that different menu cycles will be offered throughout the academic year to keep the experience fresh,” he says.
CannonDesign has extensive experience with campus food service facilities within the SUNY system, Hammill says, and has partnered with UB on major recent projects, including William R. Greiner Hall on the North Campus and the Clinical and Translational Research Center on the Buffalo Niagara Medical Campus.
“We are very pleased to be working with CannonDesign’s world-class design team on this unique addition to the campus,” he says.
The team’s approach is truly customized to the bold aspirations of One World Café, says McCarthy, project architect, who holds a master’s degree in architecture from the School of Architecture and Planning and brings a passion for the culinary arts.
“The biggest ideas only succeed when they’re built upon the smallest human-scale moments, like knowing the fastest way through the Spine, the best quiet study spot, or how to find a wider variety of menus at mealtimes,” says McCarthy, who has worked on multiple award-winning, culinary-focused design projects.
“For those of us who lived and learned on the UB campus for so long, this project is a journey and experience that few designers ever embark upon.”
Project designer Johnson strengthens the team with expertise in designing transformational additions to existing facilities and integrating stakeholder feedback into a project’s vision and ultimate design solution.
“As a graduate of UB’s School of Architecture and Planning, my education and time there has enabled me to become an advocate for the profession within our community,” says Johnson, who holds a master’s degree in architecture.
Committing a great deal of time to the Buffalo Architecture Foundation and local public schools, Johnson focuses on creating engaging educational programming that introduces students to the importance of the built environment.
As an engineer, Rezaei specializes in empowering design teams to think about high-performance buildings through the application of data-driven insights.
“A chief goal for me is to help the design team consider different scenarios that can reduce the energy consumption in a new or redesigned building,” says Rezaei, who holds a PhD in civil and environmental engineering from the School of Engineering and Applied Sciences.
“We are excited about the possibilities and potential of this unique addition to the university.”
“We’re proud to see our graduates return to UB to bring to life this vision for One World Café, inspired by CannonDesign and the UB community, as a new center of celebration for global culture across our university,” says Robert G. Shibley, dean of the School of Architecture and Planning.
“The School of Architecture and Planning has for decades benefited from the partnership of CannonDesign, a global institution deeply committed to its home community in Buffalo. This transformative initiative will now help the university prepare for an even brighter future.”
The project will create a “front door” at one of the busiest crossroads of the North Campus, around and under the existing overhangs of Capen Hall and the Founders Plaza courtyard.
Hammill says One World Café will fill a student desire for a less-congested place for eating, gathering and spending time with fellow students, faculty and friends.
“In addition, One World Café will offer opportunities to integrate impactful research being conducted at the university on issues such as sustainability, food security and food equity.”
Hammill says from the onset of the project there has been a priority to include students in the process.
“And from that has come invaluable ideas and feedback that helped shape the design and plan the international cuisine choices to be offered at One World Café,” he says.
Hammill notes there will be an opportunity for additional campus input on the project at an event planned during the spring 2019 semester.
“The design team is excited to see the high level of enthusiasm that has been exhibited by the UB community for this project,” McCarthy says. “We are especially impressed by the many thoughtful and insightful ideas and suggestions that have come from UB students.”
“For those of us on the team who are UB graduates, this is an incredible opportunity to give back to UB in a special way,” Rezaei says. “It’s rare to be able to so directly use the skills you developed at a college or university to then enrich it.”
“We are lucky to each realize how special this opportunity is while we’re in it, and not years down the line,” adds Johnson. “That recognition also drives us to push the boundaries and deliver something remarkably valuable for the campus.”
“This team works together fantastically,” Sica notes. “It is all adding up to a remarkably rich design process and a valuable final design solution for the UB campus and the community.
“We are extremely confident this team will deliver the best possible design solution for One World Café to create a space that future students can be proud of for generations.”

domain: design


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ZAVIDOVO (Tver region), May 24./TASS/. Russia is ready to help the countries affected by terrorism, including the UK and the Philippines, in their investigation activity, Russian Security Council chief Nikolai Patrushev told the 8th international meeting of high-level security officials in the Tver region, central European Russia.
"Literally over the past few days, bloody terrorist attacks have been carried out in a number of states, including in the UK the day before yesterday and yesterday in the Philippines," Patrushev reiterated. "I believe it is important to express our solidarity and support for the families of the killed and injured," he went on. "The masterminds of the terrorist acts must incur the deserved punishment," he said.
"Russia, as I hope your countries as well, is ready to help the states affected by terrorist activity through comprehensive assistance in their probe into these crimes," Patrushev told the participants in the forum.
Terrorism remains among the main threats for the whole global community, the Security Council chief marked. "This evil necessitates our collective response and joint approaches," he noted.
An explosion rocked an indoor arena in the English city of Manchester at 22:35 local time (21:35 GMT) on Monday right after a concert by American pop singer Ariana Grande, killing 22 people and leaving 59 wounded. Salman Abedi was named as the Manchester suicide bomber. According to media reports, he was born in the UK in the family of refugees from Libya.
Martial law was declared in Mindanao (a Philippines island) on Tuesday following clashes between government forces and a group affiliated with the Islamic State (outlawed in Russia). A government operation is underway against fighters of the Maute Group.
According to secret services, Isnilon Hapilon, the leader of another extremist group, Abu Sayyaf, is among the gunmen blocked by military in Marawi. Maute and Abu Sayyaf have pledged allegiance to the Islamic State. In view of the situation, President of the Philippines Rodrigo Duterte has cut short his official visit to Russia.


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Waves and Pearls Beach cake
I made this cake for the SoFlo cake expo in Miami a few months ago. The bottom tier has petals, curved and accented with brush embroidery to look like waves. The next tier a a swirled pearl and shell pattern, the next tier has gum paste orchids and shells on a brushed luster tier with a cake lace sea fan. The top tier has a brush embroidery pattern to look like waves on the shore and it was topped with a starfish ball.
cake lace gumpaste fondant beach summer cake summer wedding summer wedding cake beach wedding cake beach wedding beach cake shells shell cake orchids gumpaste flowers gumpaste orchids cake lace cake # cake brush embroidery petals waves cake wave effect wave ruffles pearls pearl wedding cake wedding cake wedding thevagabondbaker

domain: food


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Author(s): Dhami GK, Liu H, Galka M, Voss C, Wei R,
Abstract Share this page
Abstract Although Numb exhibits its tumor-suppressive function in breast cancer in part by binding to and stabilizing p53, it is unknown how the Numb-p53 interaction is regulated in cells. We found that Numb is methylated in its phosphotyrosine-binding (PTB) domain by the lysine methyltransferase Set8. Moreover, methylation uncouples Numb from p53, resulting in increased p53 ubiquitination and degradation. While Numb promotes apoptosis in a p53-dependent manner, the apoptotic function is abolished when Numb is methylated by Set8 or the Lys methylation sites in Numb are mutated. Conversely, the Numb-p53 interaction and Numb-mediated apoptosis are significantly enhanced by depletion of Set8 from cancer cells or by treating the cells with doxorubicin, a chemotherapeutic drug that causes a reduction in the mRNA and protein levels of Set8. Our work identifies the Set8-Numb-p53 signaling axis as an important regulatory pathway for apoptosis and suggests a therapeutic strategy by targeting Numb methylation. Copyright © 2013 Elsevier Inc. All rights reserved.
This article was published in Mol Cell
and referenced in Journal of Carcinogenesis & Mutagenesis


For description of our Artistic Merit Scholarship Discounts, please see the camp website. Tuition, fees, and classes subject to change without prior notice. Camp enrollment is limited in all programs. Click on Register Here button and complete the online Registration Application.
Hi, Jim, Your Song Surgeon really is a huge help for me. I was a professional musician my whole life. Fortunately I have very good hearing, I can tell absolute pitch exactly when I hear a tone I can say which one it is, without help of a keyboard or other instrument.
So soon my friends asked me to put on a paper the melody they had on a record. Even very long ago, when there were no tape recorders yet. As I grew up in Czechia taken by Nazis at that time, any kind of American music was prohibited, there were no records.
Listening to the American radio or London was punished, even by death. So I developed an ability to write down a melody simultaneously with listening to it in the American radio.
Fortunately they repeated the program periodically, twice or three times and so we could listen to it more than just once. Naturally it was not perfect, but it was the only way how to get the melodies played by Benny Goodman, Glenn Miller and many others.
Later the communists in my country tried to eliminate western culture as well Americans were bad guys againbut already we had tape recorders and it was a great help.
Later I studied music at a conservatory of music, became a pianist, then a bandleader and a conductor at a musical theater in Germany. Now I am retired, but still active, of course adequately to my age. I write, transcribe arrangements for bands.
Though some standard scores are in print and available, but mostly not original. They are often rearranged to be easier or in a lower key. But most musicians want to sound "exactly like" XYZ.
I open the music in Surgeon, can choose a short part, slow it down and listen to it repeatedly until I am sure which instruments play which tones. I can repeat the procedure later, a day or two and make the necessary corrections.
The equalizer is a great thing as well. I have to decipher a big, fat sound, say, Count Basie full band voicing. I do it, part after part, not only vertically, but with the help of the equalizer horizontally as well.
I emphasize high pitches and attenuate the low ones and thus hear mostly the trumpets without being disturbed by bass, trombones and baritone sax.
Similarly with low sounding instruments. Of course, stereo record is helpful as it allows to concentrate on one channel only. Best of the best.Search the world's information, including webpages, images, videos and more. Google has many special features to help you find exactly what you're looking for.
Ukulele Lessons - How to Play the Uke! Learn to play the songs you love, easy video lessons for beginners. Instructions for strumming, chords and more. Ukulele Lessons - How to Play the Uke!
Learn to play the songs you love, easy video lessons for beginners. Instructions for strumming, chords and more. Childhood. Niccolò Paganini was born in Genoa, then capital of the Republic of Genoa, the third of the six children of Antonio and Teresa (née Bocciardo) yunusemremert.comni's father was an unsuccessful trader, but he managed to supplement his income through playing music on the yunusemremert.com the age of five, Paganini started learning the mandolin from his father, and moved to the violin by the.
Filippa Giordano (born February 14, in Palermo, Italy) is an Italian crossover singer. Simply stated Schnabel's Beethoven cycle is widely regarded as a classic. There are two primary schools of classical piano training. The Viennese (Beethoven's lineage) School and the Liszt School.


Green Mountain Coffee: Roasted by Competition
Green Mountain Coffee Roasters, Inc took advantage of blue ocean strategy by expanding the coffee market with the introduction of the Keurig. However, recently Green Mountain Coffee has experienced plummeting stock prices and a less than idea market position. This is due, at least in part, to a poor corporate strategy and flawed demand forecasts.
Many individuals thought that the Keurig would remain on top for several years. Green Mountain still has the brewer patented and makes high profit margins on each K-cup. Furthermore, there are few competitors in the space. These factors led Green Mountain executives to think that they had cornered the K-cup segment of the coffee market. At the time of Keurig’s invention there were no competitors in the space and a high demand for on-the-spot coffee. However, recent projections of demand have been significantly higher than actual demand which has led to financial woes. One analyst notes that he has recently seen expired K-cups on Amazon, a sign that inventory is unsustainably high. To add insult to injury, Green Mountain will soon lose its patent protection of K-cups. This means that the blue ocean that Green Mountain dominated a few years ago will quickly turn red. Furthermore, Starbucks has just announced a new product, the Verismo, which will introduce direct competition.
Green Mountain Roasters has yet to fail. However, they are well on their way if they continue down their most recent trajectory. Will they take heed of the advice provided in Why Good Companies Fail to Thrive in Fast-Moving Industries, before it is too late? What can Keurig change with regards to its corporate strategy to ensure that they remain on top of the K-cup industry?


|This NASA image shows unexplained holes in the surface of some ice in the Beaufort Sea.
It's never super comforting when you hear some of the world's top scientists say things like, "I have never seen anything like that before." But luckily, this puzzling picture of holes in a sheet of Arctic ice appears to be more of an interesting brain teaser than the discovery of, say, giant ice worms.
NASA has been running aerial surveys over the Arctic for 10 years now, but the vast icy wilderness is still throwing up inexplicable surprises nobody's ever seen before.
Case in point: just what are these weird circular formations spotted from a P–3 research plane flying over the Beaufort Sea last week?
The image above and below was captured by cryospheric scientist John Sonntag, who heads up NASA's Operation IceBridge, which charts sea ice levels and behaviour at both of Earth's polar regions.
Sonntag's held this unique gig for a while now, but even he still gets a curveball now and then – like with these mysterious holes he first glimpsed two Saturdays ago, about 80 kilometres (50 miles) northwest of Canada's Mackenzie River Delta.
"We saw these sorta-circular features only for a few minutes today," Sonntag wrote from the field.
"I don't recall seeing this sort of thing elsewhere."
The holes, spotted while charting sea ice levels along the eastern Beaufort Sea, are as yet unexplained, but there are a few things researchers are speculating they might be.
First up, there are a couple of signs that indicate we're looking at relatively young ice here, which is newly formed over a previously open body of water.
"The ice is likely thin, soft, and mushy and somewhat pliable," says sea ice geophysicist Don Perovich from Dartmouth College in the UK.
"This can be seen in the wave-like features in front of the middle 'amoeba'."
Another tell-tale sign is the 'finger rafting' on the right-hand side of the image, which suggests what could be a general left-to-right motion of the ice.
This kind of distinctive zig-zag patterning occurs when two layers of ice collide with one another, forming finger-like protrusions on the surface as the two sheets are forced to splice together.
"It's definitely an area of thin ice, as you can see finger rafting near the holes and the colour is grey enough to indicate little snow cover," says IceBridge project scientist Nathan Kurtz, explaining the ice landscape surrounding the holes.
As for the holes and circles themselves, though, Kurtz is also uncertain.
One idea is they could have some kind of animal origin. For example, seals gnaw breathing holes into ice, which give them a clear space to come up and surface within the otherwise unbroken ice floes.
If that's the case, it's possible the larger circles that surround the holes come from the behaviour of the seals, forming freezing puddles as the animals emerge from their frigid dip.
"The encircling features may be due to waves of water washing out over the snow and ice when the seals surface," explains oceanographer and climate scientist Walt Meier from the National Snow and Ice Data Centre.
"Or it could be a sort of drainage feature that results from when the hole is made in the ice."
If the phenomenon isn't caused by seals or other animals – and discounting any tantalising conjecture of extra-terrestrials dabbling in the ice – deduction suggests it's some kind of naturally occurring weather phenomenon we just haven't had a chance to study up close yet.
"This is in pretty shallow water generally, so there is every chance this is just 'warm springs' or seeps of ground water flowing from the mountains inland that make their presence known in this particular area," explains NASA glaciologist Chris Shuman from the University of Maryland at Baltimore County.
"The other possibility is that warmer water from Beaufort currents or out of the Mackenzie River is finding its way to the surface due to interacting with the bathymetry, just the way some polynyas form."
Polynyas are areas of open water surrounded by sea ice – which in strong wind conditions behave like outdoor 'ice factories', producing as much as 10 times more sea ice than usual – including exotic, rare forms of ice that almost seem magically inspired.
While we may not have a confirmed explanation for the latest evidence of this kind of phenomena, you can bet it's something that's captured the attention of scientists, and sooner or later we'll get a more thorough understanding of just what the heck is going on here.
The above story is based on materials provided by The Earth Observatory.


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The Modern Picks Scholar as Pivotal Curator
By GRACE GLUECK
Published: February 11, 1988
In a long-expected move but one attended by staff controversy, the Museum of Modern Art has named Kirk Varnedoe, a professor at New York University's Institute of Fine Art, to the powerful post of director of painting and sculpture.
Mr. Varnedoe will succeed William S. Rubin, who will become director emeritus of the department in August after 22 years at the Modern. He also inherits the mantle of Alfred H. Barr Jr., the founding director of the museum, who was instrumental in gathering a painting and sculpture collection of international stature.
Anointed for some time as Mr. Rubin's heir apparent, Mr. Varnedoe, who is 42 years old, will assume what is considered the key curatorial position in the field of modern art. The department, the largest and most influential of the museum's six curatorial divisions, is an institution in itself, with an unparalleled collection, a dazzling exhibition record, access to wealthy donors and an enviable situation in the world's most prestigious museum of 20th-century art. An Adjunct Curator Since '84
Mr. Varnedoe will oversee the department's collections, installations, exhibitions and acquisitions.
Since 1984, Mr. Varnedoe has been adjunct curator in the department and was involved in organizing two major exhibitions at the Modern, '' 'Primitivism' in 20th-Century Art,'' jointly with Mr. Rubin, and ''Vienna 1900: Art, Architecture and Design'' on his own.
He is widely recognized as an outstanding writer and historian, and four years ago received a MacArthur Foundation Fellowship, a coveted award given to high achievers in the arts and sciences. Staff Suggested Alternatives
Some months ago, as his appointment seemed imminent, the staff of the painting and sculpture department submitted to Richard Oldenburg, the Modern's director, a list of other names for consideration. They were supported by a clause in the union contract between the museum and the Professional and Staff Association of the Museum of Modern Art that allows for consultation on new department heads.
Among the names reportedly proposed were John Elderfield, director of the department of drawings at the museum, and Christian Geelhaar, director of the Kunstmuseum in Basel, Switzerland.
While no one from the painting and sculpture staff would speak for attribution, it is understood that department members not only wanted to open the job to other qualified candidates but also took exception to Mr. Varnedoe himself, including the fact that while the Modern is a museum of 20th-century art, his engagement was primarily with art of the 19th century.
In an interview, Mr. Varnedoe acknowledged ''the possibility of antagonism built into the situation of my being heir apparent for a couple of years.
''And any time there's change,'' he added, ''there's a lot of anxiety. But it's not my impression that the problems I have with the staff are insurmountable. I have a lot of respect in general for them, and I will certainly make every effort to see that the relationship is good.''
As for his ''19th-century orientation,'' Mr. Varnedoe said, ''If you look at my published record, it's a completely fair assumption. But if you look at the courses - such as seminars in contemporary sculpture and art of the 1960's - I give at the Institute of Fine Art, there's a great deal on art after 1945.''
In a separate interview, Mr. Oldenburg and Mr. Rubin said they had considered other candidates, including those submitted by the department staff, but remained convinced that Mr. Varnedoe was the right man.
''Kirk is very well qualified for the position,'' Mr. Oldenburg said yesterday. ''In the tradition of Alfred Barr and of Bill Rubin, he is a highly respected art historian with a distinguished record of publications as well as creative and significant exhibitions.'' Mr. Varnedoe was also hailed by Donald B. Marron, president of the Modern, as ''a worthy successor to the remarkable individuals who have held this important post.'' The Barr-Rubin Legacy
It was Mr. Barr who laid the foundation for the Modern's primacy in the field of 20th-century art, acquiring at least two-thirds of the works in the painting and sculpture collection. Among them were such seminal contributions to the development of modern art as Picasso's ''Demoiselles d'Avignon,'' the 1907 painting that signaled the birth of Cubism; the large Matisse canvas ''The Dance'' and Mondrian's ''Broadway Boogie-Woogie.''
He also built the Modern's Picasso collection into the largest and most important in the world. Among the department's early innovative exhibitions, organized by Mr. Barr, were the 1936 shows ''Cubism and Abstract Art'' and ''Fantastic Art, Dada and Surrealism,'' which gave these crucial movements their first significant exposure in America.
Under Mr. Rubin, the department consolidated and expanded its 20th-century holdings. Aside from several major Picassos obtained from the artist and his widow, Jacqueline, Mr. Rubin brought in such stellar works as Miro's ''Birth of the World,'' an early Surrealist painting; two late large-scale Matisse collages, ''The Swimming Pool'' and ''Oceania,'' and Jackson Pollock's ''Number 1,'' a mural-size canvas that is one of the great icons of Abstract Expressionism.


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06:00 | 29/11/2021 Events
(VEN) - Recently, Dong Nai Women's talkshow on entrepreneurship and innovation took place successfully in the province, attracting the participation of many women who are eager and passionate about starting a business.
The talkshow is jointly organized by the Dong Nai Department of Science and Technology and the Provincial Women's Union Association, and is part of the TechFest Dong Nai 2021 series of events.
At the event, Ms. Le Thi Thai, Chairwoman of the Provincial Women's Union Association, informed about the implementation of the Project to support women starting a business in the period of 2017 - 2025, and said that the Association has always accompanied and helped women members overcome barriers to start a business. Besides the activities to support capital and knowledge, every year the Association organizes activities such as: Women's Day of Creativity - Entrepreneurship; contest to find women's startup ideas/projects to create more opportunities and motivation for women to start a business to exchange, connect, share experiences and learn from each other.
The participants also shared more about content such as issues related to mechanisms and policies to support the innovation startup ecosystem, the role of intellectual property, advantages and disadvantages in accessing and implementing policies to support women’s startup. In addition, attendees also mentioned issues such as women starting a business associated with the one-commune-one-product (OCOP) program, adding value to OCOP products, advantages and disadvantages of women's entrepreneurship, successful business experiences through the application of technology and social networks, activities to improve knowledge and skills for women starting a business.
At the talkshow, the Provincial Women's Union Association also launched the women's startup program in 2022. Through the program, the Association called on members to continue effectively implementing the plan, the conclusion related to supporting women in starting a business, in order to continue to promote the achieved results, widely spread the start-up movement among women in the province. At the same time, the Association calls on everyone to propaganda and mobilize women to implement the Party's guidelines, policies and State laws on entrepreneurship, starting a business. The members are encouraged to actively participate in start-up activities organized by the Association and activities to develop innovative and creative start-up ecosystems organized inside and outside the province, as well as activities to connect and exchange businesswomen in the province. The association also mobilizes women members to join the provincial women's start-up support club to have more opportunities to exchange, learn and grasp timely policies on supporting startups, supporting women in production and business.


The 100 meter long and nearly 3m high wall once protected the Neolithic people when the sea level rose at the end of the Ice Age.
Traces of crumbling walls of ancient waves.(Photo: Newsweek).
The team, led by Dr. Ehud Galili at Haifa University, discovered an ancient wave wall built by the Neolithic people to protect the village against rising sea levels more than 7,000 years ago. The 100-meter-long wall off the coast of Carmel was built with pebbles taken from a river bed more than 1.6 km away, forming a barrier between the Mediterranean Sea and Tel Hreiz village.
In a study published in PLOS One, Galili's team said it was the oldest coastal protection system in the world and the technical achievements reflected the villagers' level of awareness, organization and construction. Neolithic period. At the time of Tel Hreiz's existence, sea levels rose due to rising global temperatures at the end of the last Ice Age. Mediterranean sea water rises by 7 mm each year.
"The rise of the sea level leads to more frequent storms, ravaging the village. Over time, the villagers pay attention to the changes in the environment. The annual sea level rise promotes a response." from humans, including the construction of coastal protection walls similar to today's breakwaters, " Galili explained.
Tel Hreiz was first discovered in the 1960s, but researchers only knew about the seawall when the project was discovered in 2010 after a strong storm. Galili and colleagues analyzed the ruins of the underwater wall. They calculate the building is nearly 3m high and was born around the same time as the village. After decades, the seawall was eroded by seawater. When the sand at the foot of the wall was washed away, waves and storms may have crushed the boulders.


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Alliance Council Member
Why did you want to be a Council Member?
I love this sport and want to see it grow anyway it can. I thought about running in 2009 than some people told me I should so hopefully I can try and help fans get more info to the Sounders Front Office and vice versa and provide input to the club on what fans would like to see happen on game days and in certain directions OUR Club goes.
What are your goals as a Council Member?
To help the Sounders be the Biggest and Best club in the USA. Who knows someday even bigger than that! Being on the council provides opportunities to try and help supporters and fans achieve this with the Front Office and ownerships help. “Also let’s not forget to get Fans Cheaper beer at the Stadium.”
When did you know that the Sounders would be a 'big deal?'
As soon as we got a club back in Seattle at the Pro level and everyone wanted to call it the “SOUNDERS”
Favorite club (outside of Seattle): Fortuna Dusseldorf 1895
Favorite player (outside of Seattle): Miraslov Klose Favorite US Player: Clint Dempsey
Favorite Sounder player: Jhon Kennedy Hurtado
Where is your seat?: GA usually with family other ECS/ASG 10 rows up in 123

domain: hobby


A Function rule defines a Java method that is accessed through rule resolution. By using rule resolution at run time, a function can express different behavior depending on the application ruleset list. You can invoke functions from expressions, from activities, and from Java.
Functions are defined within a library; both the library and its functions must be defined in the same ruleset. A Function rule defines the parameters and the Java code that is invoked when calling the function.
After you define a function, you can define one or more function aliases to customize the parameter descriptions and default values.
Pega Platform includes many predefined functions. To see if a function you need has already been defined, you can use the Expression Builder to list the functions that are defined in each library.