NCube/papyrus huggingface dataset:
The role of the peptidyl prolyl isomerase Rrd1 in the transcriptional stress response

Transcriptional regulation is a complex process that has evolved over millions of years of evolution. Cells have to sense environmental conditions and adapt to them by altering their transcription. Herein, we study the role of rapamycin, an immunosuppressant and anticancer molecule that mimics cellular starvation. To understand how the action of rapamycin is mediated, we analyzed gene deletion mutants in the yeast Saccharomyces cerevisiae that have an altered response to this drug. Deletion of RRD1, a gene encoding a peptidyl prolyl isomerase, causes strong resistance to rapamycin and this was associated with a role of Rrd1 in the transcriptional response towards rapamycin. The main focus of my PhD was therefore to unravel the role of Rrd1 in response to rapamycin. First, we discovered that Rrd1 interacts with RNA polymerase II (RNAPII), more specifically with its C-terminal domain and we showed that in response to rapamycin, Rrd1 alters the structure of this C-terminal domain. This phenomenon was confirmed to be directly mediated by Rrd1 in vitro, presumably through its peptidyl prolyl isomerase activity. Further, we demonstrated that Rrd1 is capable of altering the occupancy of RNAPII on genes in vivo and in vitro. With the use of ChIP on chip technology, we show that Rrd1 is actually a transcription elongation factor that is associated with RNAPII on actively transcribed genes. In addition, we demonstrate that Rrd1 is indeed required to regulate the expression of a large subset of genes in response to rapamycin. This data let us propose a novel mechanism by which Rrd1 regulates RNAPII during transcription elongation. Finally, we provide evidence that Rrd1 is not only required for an efficient response towards rapamycin but to a larger variety of environmental stress conditions, thus establishing Rrd1 as a transcriptional elongation factor required to fine tune the transcriptional stress response of RNAPII.

Keyphrases: RNA polymerase II, rapamycin, peptidyl proly isomerase, chromatin immunoprecipitation and microarray, transcription elongation
Effet de l’insuffisance rénale chronique sur les enzymes du cytochrome P450 dans le cerveau de rat

Background: It has been shown that chronic renal failure (CRF) is associated with a downregulation of liver and intestinal cytochrome P450 (CYP450) in the rat. The present study aimed to investigate the repercussions of CRF on Brain. CYP450 isoenzymes mRNA and protein expression, as well as activity in different brain regions (cortex, cerebellum, hippocampus, and rest of brain parenchyma), have been studied in order to determine the effects of CRF on cerebral drug metabolism by CYP450.  Methods: The entire brain of CRF rats (induced by 5/6th nephrectomy) and control rats (sham laparotomy) was dissected into 4 parts (cortex, cerebellum, hippocampus, and rest of brain parenchyma). Protein and mRNA expression of CYP1A, CYP2C, CYP2D, CYP3A, and CYP4A were assessed by Western Blot assay and Real Time PCR, respectively. CYP3A activity was assessed using DFB metabolism into DFH in brain microsomal preparation. Protein and mRNA expression were also assessed in cultured astrocytes incubated with serum from CRF rats.  Results: In CRF rats, mRNA levels of CYP1A, CYP2C, and CYP3A were decreased significantly by at least 40% (p < 0.05) in almost all studied brain regions. Protein expression of these isoforms was decreased by at least 45% (p < 0.05) in almost all structures. A significant decrease in CYP3A activity was observed in the brain. The incubation of astrocytes with CRF sera induced a decrease in the protein and mRNA expression of the CYP2C11.  Conclusions: CRF is associated with a decrease in some major drug-metabolizing enzymes, which could explain an increase in bioavailability of drugs in the brain.

Keyphrases: Chronic renal failure, Drug metabolism, Cytochrome P450, Rat brain, Astrocytes de rat, Rat astrocytes, Nephrectomy
Synthèse de 4-désoxy hexopyrannoses, C-disaccharides et C-glycosides biologiquement actifs

Carbohydrates represent a large family of organic molecules that play key roles in various biological processes. Due to their medicinal importance, preparation of deoxy-sugars, C-glycosides and C-disaccharides have become an important topic in organic synthesis. Mostly, this thesis presents a new de novo synthesis of 4-deoxy hexopyranoses, along with the preparation of biologically relevant C-glycosides. Moreover, a special attention has been focussed on the de novo synthesis of 4-deoxy-C-disaccharides. Firstly, Jacobsen Cr(III) catalyst and a binaphthol/titanium complex have been used to catalyze enantioselective hetero-Diels-Alder reactions. The dihydropyran thus formed has been transformed into naturally occurring 4-deoxy hexopyranoses. Therefore, the ezoaminuroic acid core, a desosamine precursor and neosidomycin have been prepared following a de novo approach. Moreover, as a comparative study, neosidomycin has also been synthesized using a chiron approach from methyl alpha-D-mannopyranoside. Finally, a preliminary biological evaluation of neosidomycin has been applied on concanavalin-A (Chapter 2). Secondly, homoallylic alcohols have been generated from a stereoselective allylation on aldehyde linked via C-C bonds to a mannoside residue. Then, the homoallylic alcohols have been transformed into 4-deoxy hexopyranoses in various configurations (D or L). Thereby, the syntheses of pseudo 4-deoxy-C-disaccharides, 4-deoxy-C-disaccharides and pseudo 4-deoxy aza-C-disaccharides have been easily performed. Determinations of the diastereoisomeric ratio of the allylation reactions along with the absolute configuration of the newly formed chiral center have been easily achieved. Various members of this new family have been deprotected for a preliminary biological evaluation on concanavalin-A (Chapter 3). Finally, the syntheses of relevant C-glycosides have been realized regarding two aspects: i) 3-C-mannopyranosyl coumarin synthesis and ii) synthesis of C-galactosides as PA-IL inhibitors. Methyl glycosyl cinnamates have been isolated using a Heck coupling on alpha,beta-insaturated ester linked to glycosidic moieties via C-C bonds. However, when 2-iodophenol is used as a Heck partner, the corresponding coumarins have been isolated. C-Galactosyl methyl cinnamate derivatives represent good monovalent inhibitors with Kd as low as 37 micro M against PA-IL (Chapter 4).

Keyphrases: C-glycoside, carbohydrate, 4-deoxy hexopyranose, de novo synthesis, hetero-Diels-Alder, stereoselective allylation, PA-IL inhibitor
Figures de la filiation littéraire dans Bourlinguer de Blaise Cendrars

The main objective of this thesis is to explain the intricacies of the representations of literary heritage in Blaise Cendrars’ Bourlinguer. The first chapter studies the intertextual relationships between Bourlinguer and a handful of texts (mainly Rudyard Kipling’s Kim) and thus shows how Cendrars uses knowledge as a tool to understand his identity and reality. The same chapter also sheds light on a peculiar process by which Cendrars simultaneously invokes and rejects literary influences, granting him prestige and impertinence at the same time. The second chapter analyses several types of libraries, the act of reading itself and Cendrars’ esthetic masters. Bourlinguer insists on experience and lucidity in reading, as well as on the importance of liberating oneself from authorities, paternal, literary or otherwise.

Keyphrases: Blaise Cendrars, Bourlinguer, Blaise Cendrars, Bourlinguer, intertextuality, library, reading
Charge virale intégrée du papillomavirus de type 16 dans la maladie anale préinvasive

The natural history of human papillomavirus type 16 (HPV-16) anal infection is undefined among HIV-seropositive men having sex with men (MSM). The aim of this study was to assess the association between HPV-16 episomal and integrated viral loads and the progression of anal intraepithelial neoplasia (AIN). HPV-16 episomal and integrated loads were measured on 665 specimens from 135 HPV-16-positive men participating in the prospective HIPVIRG (Human Immunodeficiency and Papilloma VIrus Research Group) study. AIN grade was evaluated on biopsies obtained during periodical high-resolution anoscopies. HPV-16 integration was confirmed by DIPS-PCR to demonstrate the presence of viral-cellular junctions. HPV-16 episomal loads [odds ratio (OR) 1.5, 95% confidence interval (CI)=1.1–2.1], burden of HPV infection [OR 1.4 (95% CI=1.1–1.8)] and current smoking [4.8 (95% CI=1.3–18.6)], but not integrated loads, were associated with high-grade lesions (AIN-2,3) after age and CD4 counts adjustment. A high HPV-16 episomal load was the only predictive factor of progression from low-grade AIN to high-grade AIN [OR 8.0 (95% CI=1.2–55.4)]. Specimens with higher HPV-16 episomal loads were less likely to contain integration [OR 0.5 (95% CI=0.3–0.8)]. HPV-16 integration was detected in the absence of AIN, in AIN-1 and in AIN-2,3. The analysis of the viral-cellular junctions did not allow identifying a specific site of integration.

Keyphrases: HPV-16, Natural history, Charge virale, Viral load, AIN, AIN, Integration, MSM, TAR, HAART
La perception des thérapeutes sur les difficultés d’intervenir auprès des adolescents atteints d’un trouble de personnalité limite (TPL) avec conduites suicidaires

In Quebec, suicide attempts in adolescents take a considerable extent in the public health sector and a high number of suicidal adolescents are often affected with a borderline personality disorder (BPD). These teens have many BDP seizures associated with suicidal behavior and self-injurious behaviors leading them to consult health professionals repeatedly due, among other things, to the premature abandonment of therapy. Considering these issues of concern, this study focused on factors involved in the complexity of representations of adolescents with BPD according to the perception of therapists. This qualitative exploratory project was conducted as semi-structured interviews with eleven therapists in third line child psychiatry. In the context of psychiatric care in Quebec, the results of this project confirms the complexity of working with these young people are emerging and several factors could explain the difficulties in the intervention process related, inter alia, the symptoms, the high suicide risk, the risk of premature abandonment, to their great emotional instability, relational and behavioral influences, for in so doing, the therapist in his know-how and life skills.

Keyphrases: Adolescent, Teenagers, BPD, Difficulties in the intervention, Therapist
The regulation of adult hippocampal neurogenesis by wheel running and environmental enrichment

Introduction: In mammals, new neurons continue to be produced throughout the adulthood in two brain regions: 1) the hippocampus and 2) the forebrain subventricular zone. Adult neurogenesis is not a stable process, and changes in response to diverse factors such as age and pathology. Furthermore, because changes in neurogenesis may in fact underlie pathogenesis, regulating or restoring neurogenesis is seen as an important therapeutic objective. In healthy and diseased mice, hippocampal neurogenesis can be robustly regulated by environmental enrichment. However, while physical activity and environmental enrichment are  potentially important in the treatment of some pathologies, comparatively little is known about the molecular and physiological mechanisms underlying activity/environment-dependent changes in neurogenesis.   Objectives and hypotheses: The primary objectives of this study are to characterize the neurogenesis-mediating effects of external stimuli and, in doing so, to elucidate the mechanisms that underlie observed changes. Using voluntary wheel running as a model, this study addresses two hypotheses: 1) that extended periods of physical activity can influence adult neurogenesis in the forebrain and the hippocampus and 2) that voluntary wheel running mediates neurogenesis through both running-dependent and running-independent stimuli.   Methods: To address the first hypothesis, we used a prolonged six-week voluntary paradigm and immunohistochemical analyses to characterize neural precursor activity in the subventricular zone and hippocampus. To address the second hypothesis, we used a modified version of the above paradigm, where an additional group of mice were housed in cages with a locked running wheel.    Results: With respect to the first hypothesis, prolonged voluntary wheel running was found to increase neural precursor proliferation and neurogenesis in the hippocampal dentate gyrus relative to control animals, confirming the results of previous studies. More importantly, in this paradigm, proliferation in the forebrain subventricular zone was also found to be increased. In keeping with the second hypothesis, mice that were housed in locked-running wheel cages showed an increase in hippocampal  neural precursor proliferation comparable to that of running animals. However, only running animals displayed increased hippocampal neurogenesis.   Conclusions: These results allow us to draw two novel conclusions regarding the effects of running on neurogenesis. First, proliferation in the forebrain subventricular zone, in addition to proliferation and neurogenesis in the hippocampus, is subject to regulation by wheel-running. Second, the wheel-running environment contains diverse stimuli which can influence some aspects of hippocampal neurogenesis in the absence of wheel running.

Keyphrases: Neurogenesis, Hippocampus, Subventricular Zone, Exercise, Environmental Enrichment, exercice
Polyconsommation  d’alcool et de cannabis et comportements à risque chez les étudiants universitaires canadiens : une analyse situationnelle

Alcohol and cannabis polydrug use is a common consumption pattern among Canadian young adults (Flight, 2007). Moreover, epidemiological studies suggest that alcohol and cannabis use is associated with other risky behaviours such as binge drinking and driving a vehicle under the influence of both substances (Jones et al. 2001; Mohler-Kuo et al. 2003; Shillington & Clapp, 2006). Studies which have reported an increased risk for polydrug users focus on substance use. The present study propose a situational approach, in which the effect of poly drug use, as well as the effect of simultaneous use on these risky behaviours are investigated while considering the context in which the consumption takes place.  The probability of driving under the influence of alcohol, and the probability of binge drinking are examined among a sample of university students. The respective contribution of substance use, university life experience and drinking situations is examined.   The methodology used to perform this study is based on multilevel logistic regression models, among drinkers (10 747 occasions, nested within 4396 drinkers) as well as among the polydrug users subsample (2311 drinking occasions, nested within 880 individuals). The data are drawn from the Canadian Campus Survey conducted in 2004 with a random nationally representative sample of 6282 students from 40 universities. Polydrug status is positively associated with episodic binge drinking, but not with driving under the influence of alcohol. However, cannabis use is not associated with binge drinking, among polydrug users. Moreover, for this specific population, cannabis smoking is negatively associated with driving under the influence of alcohol. Several situational characteristics are associated with either one or both studied behaviours and partially explain the relationship between those behaviours and polydrug use.

Keyphrases: cannabis, alcohol, cannabis, context, multilevel analysis
Le processus de production de savoirs dans la pratique infirmière au moyen de la réflexivité

A new theoretical framework for designing the process of knowledge production within nursing practice is necessary to take into account the individual and the collective process of knowledge production as well as the influence of the context on this production. The theory of reflexivity of Giddens seems to be most relevant. This study aimed to describe and understand the process of knowledge production within nursing practice through reflexivity. More specifically, it was important to uncover the conditions and dynamics of the institutional, professional and practice context which influence the process of knowledge production within nursing practice and to identify the steps of this process. Projective constructivism was the paradigm that has guided the study. The research design was a secondary analysis of qualitative data. The study context was a critical care unit of a general and university hospital in Barcelona. Data were collected through systematic observation, six structured interviews, seven focus groups, and documents analysis. Data were analysed according to the mixed approach of Miles and Huberman, the qualitative analysis of Morse, and recommendations from various authors on secondary analysis. The rigor criteria were used and the ethical aspects were covered. The study results suggest that the conditions and dynamics of institutional, practical and professional contexts impact profoundly the nursing action and knowledge production. These conditions and dynamics are internalized in the working lives of nurses and provide “normal” ways of nursing practice. However, although there is an acceptance of the status quo, the conflicting feelings and suffering emerge easily. These conditions and dynamics cause incapacity among nurses to act fairly, ethically and responsibly and limit their exploration of new possibilities, formulations and demonstrations of practice. The results propose also the stages of knowledge production through four major themes: the recognition of daily reflexivity, systematic review of practices, the construction of new knowledge and the re-construction of emancipatory knowledge. Finally, this thesis suggests the importance of Giddens' theory for the study of knowledge production and the relationship between the nurse and the context, as well as the use of secondary analysis of qualitative data for the nursing discipline.

Keyphrases: Knowledge production, Institutional context, Structuration theory, Practical context, Critical care, Nursing, Secondary analysis, Professional context, Reflective practice, Reflexivity
Rôle des kinines dans la physiopathologie des effets secondaires causés par
les héparines contaminées d’origine chinoise : approche expérimentale

In January 2008, fatal anaphylactoid reaction (AR) has been associated to oversulfated chondroitin sulphate (OSCS) contaminated heparin. Although attributed to bradykinin (BK) released during contact system activation by OSCS, no definitive evidence exists until now for a BK release during incubation of contaminated heparin with human plasma. While looking at the number of death associated with OSCS (>150 worldwide) and at the epidemiologic fact, who state that 25% of the cases of AR associated to OSCS in United-States were treated with an angiotensin converting enzyme inhibitor (ACEi), we hypothesis that: AR associated with bolus injection of OSCS contaminated heparin are bind to a complex and multi-factorial aspect. The first objective of our study is to measure the kinetics of BK release in human plasma incubated with OSCS in presence of an ACEi and to compare it to the kinetics profile of the reference activator dextran sulfate. As the AR associated with OSCS contaminated heparin occurred mainly in the first minutes of dialysis session, we also studied the effect of the plasma dilution on the amount of BK released when treated or not with an ACEi. We also quantify the BK forming capacity of different batches of OSCS contaminated heparin responsible for AR and we compare this effect with reference heparin spiked or not with increasing concentrations of synthetic OSCS. Finally, we measure the kinetics of BK and des- Arg9-BK, its active metabolite, release in human plasma collected from patients who developed an AR associated to negatively charged dialysis membrane. The application of experimental method developed in our laboratory show, for the first time, that OSCS contaminated heparin incubated with human plasma has the capacity to liberate BK at a concentration that could explain the role of this inflammatory peptide in the pathophysiology of AR associated with OSCS contaminated Chinese heparins.

Keyphrases: Des-Arg9-bradykinine, Chinese heparin, Oversulfated chondroitin sulphate, bradykinin, Anaphylactoid reaction
Les déterminants organisationnels et sociaux des trois dimensions de l'épuisement professionnel

Conducted with a sample of 410 civilians and police officers of the Service de police de la Ville de Montréal (SPVM) consulted in February 2009, this study aims to increase knowledge regarding the influence of skill utilization, decision authority, social support in the workplace, abusive supervision and social support outside the workplace on the three dimensions of the burnout syndrome (emotional exhaustion, cynicism, professional efficiency). This study also aims to establish if the relations between these organizational and social factors and the three dimensions of the burnout syndrome vary according to the civilian or police nature of the workforce.  Results of the multivariate analysis show the distinctive influence of explicative variables on the three dimensions of the burnout. Results also emphasize the distinction between the concept of skill utilization and decision authority as well as increase knowledge regarding the influence of abusive supervision, social support outside the workplace and the role of the profession as a moderator on the three dimensions of the burnout syndrom.

Keyphrases: Profession, Burnout, Emotional exhaustion, Cynicism, Professional efficiency, Skill utilization, Decision authority, Social support, Abusive supervision, Profession, Police officers
The role of transcription factor Pitx1 and its regulation by hypoxia in Adolescent Idiopathic Scoliosis

Adolescent Idiopathic Scoliosis is a lateral curvature of the spine greater than 10 degrees, with an unknown cause, affecting primarily adolescents. Previous mouse model studies showed that partial inactivation of Pitx1 gene resulted in the development of severe spinal deformities in Pitx1 +/- mice, which is strikingly similar to the AIS phenotype. Based on this observation, we postulated that loss of Pitx1 function might have a role in AIS and could be regulated through specific molecular mechanisms. Indeed, expression studies revealed a loss of Pitx1 expression in osteoblasts derived from AIS patients, at the mRNA level. We hypothesized that the loss of Pitx1 in AIS could be triggered by hypoxic factors, since Pitx1 is known to be repressed by hypoxia and that HIF-2 alpha was up regulated in AIS osteoblasts even under normoxic conditions. Also, we found a mutation in the ODD domain of HIF-1 alpha in some AIS patients (3.1%), which is known to stabilize and enhance HIF-1 alpha transcriptional activity in normoxic conditions. We confirmed through EMSA the existence of a functional hypoxia response element on Pitx1 promoter. However, co-transfection assays with HIF-1 alpha and HIF-2 alpha expression vectors in the presence of their beta subunit ARNT led to the activation of Pitx1 promoter in human osteoblast cell line MG-63 cells and osteoblasts from control subjects. Interestingly, no Pitx1 promoter activity was observed in AIS osteoblasts, even after the co expression of HIF2 alpha and ARNT, consolidating the fact that Pitx1 expression is abrogated in AIS. Taken together, our findings show an important role for Pitx1 in AIS and hypoxic factors could be one of its regulators.

Keyphrases: Pitx1, HIF-1a, HIF-2, ARNT, ODDD, AIS, Hypoxia, Osteoblasts, Hypoxia response element