Théâtre amateur et théâtre professionnel en Saskatchewan : d’Unithéâtre à La Troupe du Jour

Founded in 1970 by Ian Nelson, David Edney, and students from the University of Saskatchewan’s French Circle, the Unithéâtre amateur theatre troupe took as its mandate the promotion of French and French culture at the university and community level in Saskatchewan, and quickly became noticed by French and English audiences. Their successes in the amateur theatre world of Saskatchewan led to the creation of a professional French theatre group in 1985, La Troupe du Jour. Its founders, Carmen Gareau, Alphonse Gaudet, and Michel Quirion, were all members of Unithéâtre, and their mission was above all to reflect the Fransaskois reality. As a result of the work carried out by its members, artistic directors, and administrators since its inception, notably by Denis Rouleau and Dany Rousseau, La Troupe du Jour has gone from strength to strength, culminating in the inauguration of its production centre in January 2011. La Troupe has opened its theatre doors to other companies and is forming a relationship between its Fransaskois roots and the work of theatres from elsewhere, be they French or English. The introduction of the Writers’ Circle in 2000 contributed to the creation of a Fransaskois drama repertoire.Fondée en 1970 par Ian Nelson, David Edney et des étudiants du Cercle français de l’Université de la Saskatchewan, la troupe de théâtre amateur Unithéâtre adopte le mandat de promouvoir la langue française et la culture francophone dans le cadre universitaire et communautaire en Saskatchewan, et se fait rapidement valoir aux yeux du public francophone et anglophone. Son succès artistique dans le milieu théâtral amateur de la Saskatchewan favorise la création en 1985 d’une compagnie théâtrale professionnelle, La Troupe du Jour, dont les fondateurs Carmen Gareau, Alphonse Gaudet et Michel Quirion, anciens membres d’Unithéâtre, se donnent comme mission de refléter avant tout la réalité fransaskoise. Grâce au travail monumental de ses membres et de ses directeurs artistiques et administratifs, notamment Denis Rouleau et Dany Rousseau, La Troupe du Jour a connu depuis sa fondation un épanouissement qui l’a menée vers l’inauguration de son Centre de production en janvier 2011. Elle a su de plus ouvrir les portes de sa scène théâtrale pour établir une relation entre ses racines fransaskoises et les traces d’un ailleurs ou de l’autre, qu’il soit francophone ou anglophone. Grâce au Cercle des écrivains, qu’elle met sur pied en 2000, la troupe travaille à l’élaboration d’une dramaturgie fransaskoise

Emergency Contracting: Themes from Agencies’ Disaster and Pandemic Response Efforts

Symposium PresentationApproved for public release; distribution is unlimited

Emergency Contracting: Themes from Agencies’ Disaster and Pandemic Response Efforts

Excerpt from the Proceedings of the Nineteenth Annual Acquisition Research SymposiumThe federal response to the rising number of natural disasters coupled with other emergency response efforts, such as those for COVID-19, have illustrated the important role that federal contracts have in providing life-saving and life-sustaining goods and services. However, contracting during an emergency can pose a unique set of challenges as contracting officials face significant pressure to provide these services as quickly as possible. Leveraging several U.S. Government Accountability Office (GAO) reviews of emergency contracting issues, this paper examines (1) contract and agreement mechanisms agencies used to facilitate response efforts; (2) challenges planning and executing contracts in an emergency environment; and (3) how tracking contract obligations and contracting lessons learned can inform future response efforts.Approved for public release; distribution is unlimited

Preferred practice location at medical school commencement strongly determines graduates’ rural preferences and work locations

Abstract: Objective: To identify factors influencing whether Australian medical graduates prefer to, or actually, work rurally Design: Secondary analysis of longitudinal data from the Medical Schools Outcomes Database (MSOD) using univariate and multivariate logistic regression. Setting: Twenty Australian medical schools. Participants: Australian or New Zealand citizens and Australian permanent residents who completed MSOD questionnaires between 2006 and 2013. Main outcome measures: Preferred and actual work locations one (PGY1) and three (PGY3) years post-graduation. Results: Of 20,784 participants, 4028 completed a PGY1 and/or PGY3 questionnaire. Self-reported preference for rural practice location at medical school commencement was the most consistent independent predictor of whether a graduate would have a rural location preference at PGY1 (odds ratio [OR] 6.07, 95% CI 4.91-7.51) and PGY3 (OR 7.95, 95% CI 4.93-12.84), and work rurally during PGY1 (OR 1.38, 95% CI 1.01-1.88) and PGY3 (OR 1.86, 95% CI 1.30-2.64). The effect of preferred practice location at medical school commencement is independent of, and enhances the effect of, rural background. Graduates of graduate-entry programs or with dependent children were less likely to have worked rurally during PGY1 and PGY3, respectively. Conclusion: The most consistent factor associated with rural preferences and work location was students’ preferred location of practice at medical school commencement; this association is independent of, and enhances the effect of, rural background. Better understanding of what determines rural preference at medical school commencement and its influence on rural workplace outcomes beyond PGY3 is required to inform Australian medical school selection policies and rural health curricula

Interaction between galectin-3 and cystinosin uncovers a pathogenic role of inflammation in kidney involvement of cystinosis.

Inflammation is involved in the pathogenesis of many disorders. However, the underlying mechanisms are often unknown. Here, we test whether cystinosin, the protein involved in cystinosis, is a critical regulator of galectin-3, a member of the β-galactosidase binding protein family, during inflammation. Cystinosis is a lysosomal storage disorder and, despite ubiquitous expression of cystinosin, the kidney is the primary organ impacted by the disease. Cystinosin was found to enhance lysosomal localization and degradation of galectin-3. In Ctns-/- mice, a mouse model of cystinosis, galectin-3 is overexpressed in the kidney. The absence of galectin-3 in cystinotic mice ameliorates pathologic renal function and structure and decreases macrophage/monocyte infiltration in the kidney of the Ctns-/-Gal3-/- mice compared to Ctns-/- mice. These data strongly suggest that galectin-3 mediates inflammation involved in kidney disease progression in cystinosis. Furthermore, galectin-3 was found to interact with the pro-inflammatory cytokine Monocyte Chemoattractant Protein-1, which stimulates the recruitment of monocytes/macrophages, and proved to be significantly increased in the serum of Ctns-/- mice and also patients with cystinosis. Thus, our findings highlight a new role for cystinosin and galectin-3 interaction in inflammation and provide an additional mechanistic explanation for the kidney disease of cystinosis. This may lead to the identification of new drug targets to delay cystinosis progression

8-modified-2\u27-deoxyadenosine analogues induce delayed polymerization arrest during HIV-1 reverse transcription

The occurrence of resistant viruses to any of the anti-HIV-1 compounds used in the current therapies against AIDS underlies the urge for the development of new drug targets and/or new drugs acting through novel mechanisms. While all anti-HIV-1 nucleoside analogues in clinical use and in clinical trials rely on ribose modifications for activity, we designed nucleosides with a natural deoxyribose moiety and modifications of position 8 of the adenine base. Such modifications might induce a steric clash with helix &alpha;H in the thumb domain of the p66 subunit of HIV-1 RT at a distance from the catalytic site, causing delayed chain termination. Eleven new 2&prime;-deoxyadenosine analogues modified on position 8 of the purine base were synthesized and tested in vitro and in cell-based assays. In this paper we demonstrate for the first time that chemical modifications on position 8 of 2&prime;-deoxyadenosine induce delayed chain termination in vitro, and also inhibit DNA synthesis when incorporated in a DNA template strand. Furthermore, one of them had moderate anti-HIV-1 activity in cell-culture. Our results constitute a proof of concept indicating that modification on the base moiety of nucleosides can induce delayed polymerization arrest and inhibit HIV-1 replication.<br /

Two Distinct Pathways Leading to Nuclear Apoptosis

Apaf-1−/− or caspase-3−/− cells treated with a variety of apoptosis inducers manifest apoptosis-associated alterations including the translocation of apoptosis-inducing factor (AIF) from mitochondria to nuclei, large scale DNA fragmentation, and initial chromatin condensation (stage I). However, when compared with normal control cells, Apaf-1−/− or caspase-3−/− cells fail to exhibit oligonucleosomal chromatin digestion and a more advanced pattern of chromatin condensation (stage II). Microinjection of such cells with recombinant AIF only causes peripheral chromatin condensation (stage I), whereas microinjection with activated caspase-3 or its downstream target caspase-activated DNAse (CAD) causes a more pronounced type of chromatin condensation (stage II). Similarly, when added to purified HeLa nuclei, AIF causes stage I chromatin condensation and large-scale DNA fragmentation, whereas CAD induces stage II chromatin condensation and oligonucleosomal DNA degradation. Furthermore, in a cell-free system, concomitant neutralization of AIF and CAD is required to suppress the nuclear DNA loss caused by cytoplasmic extracts from apoptotic wild-type cells. In contrast, AIF depletion alone suffices to suppress the nuclear DNA loss contained in extracts from apoptotic Apaf-1−/− or caspase-3−/− cells. As a result, at least two redundant parallel pathways may lead to chromatin processing during apoptosis. One of these pathways involves Apaf-1 and caspases, as well as CAD, and leads to oligonucleosomal DNA fragmentation and advanced chromatin condensation. The other pathway, which is caspase-independent, involves AIF and leads to large-scale DNA fragmentation and peripheral chromatin condensation

Chk2 is a tumour suppressor that regulates apoptosis in both an ataxia telangiectasia mutad (ATM)-dependent and an ATM-independent manner

In response to ionizing radiation (IR), the tumor suppressor p53 is stabilized and promotes either cell cycle arrest or apoptosis. Chk2 activated by IR contributes to this stabilization, possibly by direct phosphorylation. Like p53, Chk2 is mutated in patients with Li-Fraumeni syndrome. Since the ataxia telangiectasia mutated (ATM) gene is required for IR-induced activation of Chk2, it has been assumed that ATM and Chk2 act in a linear pathway leading to p53 activation. To clarify the role of Chk2 in tumorigenesis, we generated gene-targeted Chk2-deficient mice. Unlike ATM-/- and p53-/- mice, Chk2-/- mice do not spontaneously develop tumors, although Chk2 does suppress 7,12-dimethylbenzanthracene-induced skin tumors. Tissues from Chk2-/- mice, including those from the thymus, central nervous system, fibroblasts, epidermis, and hair follicles, show significant defects in IR-induced apoptosis or impaired G1/S arrest. Quantitative comparison of the G1/S checkpoint, apoptosis, and expression of p53 proteins in Chk2-/- versus ATM-/- thymocytes suggested that Chk2 can regulate p53-dependent apoptosis in an ATM-independent manner. IR-induced apoptosis was restored in Chk2-/- thymocytes by reintroduction of the wild-type Chk2 gene but not by a Chk2 gene in which the sites phosphorylated by ATM and ataxia telangiectasia and rad3+ related (ATR) were mutated to alanine. ATR may thus selectively contribute to p53-mediated apoptosis. These data indicate that distinct pathways regulate the activation of p53 leading to cell cycle arrest or apoptosis

Large genomic rearrangements in the CFTR gene contribute to CBAVD

<p>Abstract</p> <p>Background</p> <p>By performing extensive scanning of whole coding and flanking sequences of the <it>CFTR (Cystic Fibrosis Transmembrane Conductance Regulator</it>) gene, we had previously identified point mutations in 167 out of 182 (91.7%) males with isolated congenital bilateral absence of the vas deferens (CBAVD). Conventional PCR-based methods of mutation analysis do not detect gross DNA lesions. In this study, we looked for large rearrangements within the whole <it>CFTR </it>locus in the 32 CBAVD patients with only one or no mutation.</p> <p>Methods</p> <p>We developed a semi-quantitative fluorescent PCR assay (SQF-PCR), which relies on the comparison of the fluorescent profiles of multiplex PCR fragments obtained from different DNA samples. We confirmed the gross alterations by junction fragment amplification and identified their breakpoints by direct sequencing.</p> <p>Results</p> <p>We detected two large genomic heterozygous deletions, one encompassing exon 2 (c.54-5811_c.164+2186del8108ins182) [or <it>CFTRdele2</it>], the other removing exons 22 to 24 (c.3964-3890_c.4443+3143del9454ins5) [or <it>CFTRdele 22_24</it>], in two males carrying a typical CBAVD mutation on the other parental <it>CFTR </it>allele. We present the first bioinformatic tool for exon phasing of the <it>CFTR </it>gene, which can help to rename the exons and the nomenclature of small mutations according to international recommendations and to predict the consequence of large rearrangements on the open reading frame.</p> <p>Conclusion</p> <p>Identification of large rearrangements further expands the <it>CFTR </it>mutational spectrum in CBAVD and should now be systematically investigated. We have designed a simple test to specifically detect the presence or absence of the two rearrangements identified in this study.</p

Potent Nonnucleoside Reverse Transcriptase Inhibitors Target HIV-1 Gag-Pol

Nonnucleoside reverse transcriptase inhibitors (NNRTIs) target HIV-1 reverse transcriptase (RT) by binding to a pocket in RT that is close to, but distinct, from the DNA polymerase active site and prevent the synthesis of viral cDNA. NNRTIs, in particular, those that are potent inhibitors of RT polymerase activity, can also act as chemical enhancers of the enzyme's inter-subunit interactions. However, the consequences of this chemical enhancement effect on HIV-1 replication are not understood. Here, we show that the potent NNRTIs efavirenz, TMC120, and TMC125, but not nevirapine or delavirdine, inhibit the late stages of HIV-1 replication. These potent NNRTIs enhanced the intracellular processing of Gag and Gag-Pol polyproteins, and this was associated with a decrease in viral particle production from HIV-1-transfected cells. The increased polyprotein processing is consistent with premature activation of the HIV-1 protease by NNRTI-enhanced Gag-Pol multimerization through the embedded RT sequence. These findings support the view that Gag-Pol multimerization is an important step in viral assembly and demonstrate that regulation of Gag-Pol/Gag-Pol interactions is a novel target for small molecule inhibitors of HIV-1 production. Furthermore, these drugs can serve as useful probes to further understand processes involved in HIV-1 particle assembly and maturation