NCube/papyrus huggingface dataset:
Évaluation et modélisation de l’impact de la coexposition de composés organiques volatils sur l’excrétion de leurs biomarqueurs urinaires

Evaluation of volatile organic compounds (VOC) exposure commonly resorts to urinary metabolite analyses, assuming that no interaction occur between coexposed chemicals. However, previous studies have reported competitive inhibition between toluene (TOL), ethylbenzene (EBZ) and m-xylene (XYL). Chloroform, which is also metabolized by CYP2E1, is also often found in human biomonitoring samples along with the mentioned VOCs. The goal of the present study was to evaluate if chloroform (CHL) can interact with previous VOC and to evaluate those interactions at the urinary biomarker excretion level for corresponding metabolites, namely o-cresol, mandelic acid and m-methylhippuric acid for TOL, EBZ and XYL respectively. To obtain human data, five male volunteers were exposed by inhalation to different VOC combinations (single and binary or quaternary mixtures) where concentration of each chemical was equal to 1/4 or 1/8 of the threshold limit value (TLV) for 6h. Exhaled air blood and urine samples were collected. These data were then compared with existing physiologically based pharmacokinetic (PBPK) model predictions for adjustment for urinary excretion. Some differences were observed between single and mixed exposures but they may be mainly related to volunteer replacements throughout experiments. Vmax values for EBZ and CHL were optimized to better fit blood data. Except for EBZ model, all urinary excretion parameters were taken from the literature. Models adapted in the present study adequately simulated experimental data.

Keyphrases: Inhalation, PBPK modeling, Urinary biomarkers, Toluene, Ethylbenzene, m-Xylene, Inhalation
Validité et fiabilité d’un questionnaire de fréquence alimentaire visant à évaluer l’adhésion à la diète méditerranéenne

Validated dietary assessment methods are needed to conduct clinical trials evaluating the efficacy of the Mediterranean diet in primary and secondary prevention of cardiovascular disease. Aim: To assess the reproducibility and the validity of a semi-quantitative food frequency questionnaire (FFQ) to be used in clinical trials on the Mediterranean diet within the population of Quebec. Methods: Fifty-three participants were recruited. The FFQ was administered twice to assess reproducibility and was compared to a 12-day dietary record (DR) to assess validity. Results: For reproducibility, intraclass correlation coefficients (ICCs) for energy and nutrients ranged from 0.38 to 0.91. For validity, Pearson’s correlation coefficients (r) between the DR and the FFQ pre-DR ranged from 0.26 to 0.84 and ICCs ranged from 0.25 to 0.84. As for the DR and the FFQ post-DR, r ranged from 0.36 to 0.83 and ICCs ranged from 0.36 to 0.83. Conclusion: The FFQ demonstrates good reproducibility and validity for energy and most key nutrients of the Mediterranean diet.

Keyphrases: Food frequency questionnaire, Validity, Reproducibility, Mediterranean diet, Cardiovascular disease, Dietary record
Régulation de la kinase Ste20 Slik de Drosophila par phosphorylation de la boucle d'activation

Kinases constitute a major protein family which regulate diverse pathways through the phosphorylation of their substrates, but also through their non-catalytic activity. This kinase-independent role has been observed in a few proteins such as certain members of the Sterile-20 family. The Drosophila Ste20 kinase Slik helps to maintain epithelial integrity by phosphorylating the ERM Moesin and it can also drive non- autonomous cellular proliferation in a kinase-independent fashion. The mechanism of regulation of these two roles was unknown up until now. We have identified 19 phosphorylation sites in Slik by mass spectrometry. Using Slik mutants, we show that its two functions are regulated by the phosphorylation of at least 2 conserved residues of its activation segment by an auto- and/or trans-phosphorylation mechanism. This research brings a better understanding of the regulation of epithelial maintenance and growth, two key processes which are deregulated in cancer and certain genetic diseases.

Keyphrases: Slik, Moesin, kinase, phosphorylation, epithelium, proliferation, drosophile, Drosophila
L'épuisement professionnel des enseignants : l'indiscipline des élèves et le rôle modérateur du sentiment d'autoefficacité

The aim of this study was to identify misbehaviours that have significant relationships with professional burnout, as well as to determine the moderating role of teachers’ self-efficacy in these relationships. A self-reported questionnaire was administered at the beginning and at the end of the school year to 98 teachers from fifteen francophone public secondary schools of the region of Montréal (Canada). The results of multiple regressions indicated that acts of hostility directed towards teachers, and unpreparedness of students are positively associated with professional burnout, and that these two misbehaviours were less related to professional burnout when teachers reported a high level of self-efficacy The results of the qualitative analysis obtained with the help of QDA-Miner confirmed that the management of indiscipline is the most anxiety provoking aspect of the teaching profession, and that acts of hostility by students towards teachers are particularly stressful. The present study enhances our comprehension of the role of teachers’ self-efficacy: a high level of self-efficacy represents a factor of protection in the relationships between students’ indiscipline and professional burnout. Future research could deepen understanding of the impact of violent acts suffered by teachers on their professional fatigue, and of the role played by self-efficacy as a factor of protection.

Keyphrases: high school teaching, student indiscipline, student hostility, teachers' self-efficacy
Effets des changements climatiques sur la santé et la sécurité des travailleurs au Québec

The impacts of climate change on human health are multiple and have been extensively studied in the general population, whereas these impacts on the working population have received little attention. In this perspective, the objective of this research is to document the negative effects of climate change on Occupational health and safety (OHS) in northern industrialized countries with a temperate climate, such as in Quebec. To achieve this goal, two approaches were used: a) exposure/hazards and potential effects of climate change on OHS were identified using a narrative review of the scientific literature validated by a working group of international and national experts and Quebec’s stakeholders, and research priorities applicable to the Quebec context were established by a consensus approach, b) statistical models, useful for quantifying the health impacts of climate change, were developed to estimate the associations between occupational illnesses, injuries and exposure to summer outdoor temperatures or tropospheric ozone, as these climate conditions are among the most preoccupying issues related to climate change in Quebec. The literature highlighted five categories of hazards that are likely to impact OHS in Quebec (heat waves/increased temperatures, air pollutants, UV radiation, extreme weather events, vector-borne/zoonotic diseases) and five conditions that could potentially affect the working environment and negatively impact the OHS (changes in agriculture/breeding methods, alterations in the fishing industry, disruptions of the forest ecosystem, deterioration of the built environment and emerging green industries). The modeled associations suggest that daily compensations for heat-related illnesses and work-related injury increase with ambient temperature, and that these relations vary according to workers age, industries and physical demand of the occupation (i.e. manual vs other type). Positive non-statistically significant associations were observed between acute respiratory problems compensations and levels of ozone. Overall, this work produced a list of twelve research topics for the Quebec context, all related to the knowledge acquisition, the surveillance of diseases or the development of adaptation strategies. According to this thesis, stakeholders and decision-makers should make effort to increase the protection of workers health and safety in the context of climate change.

Keyphrases: Ozone, Ambient temperature, Climate change, Compensation data, Heat related illnesses, Occupational health and safety, Workers, Northern industrialized country, Work-related injuries
Early adversity, brain development and emotion processing in monozygotic twins

There is now increasing evidence that both genetic and environmental factors interact together during specific periods of development to render an individual vulnerable to mental health disorders through multiple physiological adaptations. This thesis focuses on the impact of in utero adversity (indexed by low birth weight, BW) and early postnatal adversity (maternal depressive symptoms and negative maternal parenting behaviours) for brain development, particularly of fronto-limbic regions involved in emotion processing during childhood and adolescence. We utilize monozygotic (MZ) twins whenever possible to control for genetics. Chapters 1 and 2 present results of work testing the hypothesis that in utero and early postnatal adversity is associated with altered functioning of fronto-limbic regions including the amygdala, hippocampus, insula, anterior cingulate cortex and prefrontal cortex, in response to emotional stimuli in children and adolescents. We detect that greater maternal depressive symptomatology is associated with altered activation of fronto-limbic regions in their children in response to sadness. Results of the study in adolescents suggest that low BW, maternal depressive symptoms and negative maternal parenting behaviours are associated with altered function of fronto-limbic regions in response to emotional stimuli. In MZ twins we observe that within-pair discordance in BW and maternal parenting behaviours is associated with within-pair discordance in brain function, and that these alterations are sex-specific. Chapter 3 presents results of work testing the hypothesis that in utero and early postnatal adversity is associated with reduced total brain volume, and the hypothesis that maternal parenting habits may mediate or moderate the association between BW and brain volume. With MZ twins during adolescence, we observe that a) lower BW is indeed associated with decreased total brain volume and b) that within-pair discordance in BW is associated with within-pair discordance in brain volume. Together, this thesis presents a set of results that reinforce two important hypotheses to understand the effects of the environment on brain development: that the in utero and early postnatal environment impact brain development independent of genetics and that mechanisms involved may differ in boys and girls. Finally, these results are discussed in light of other research projects in this area and avenues for future research are proposed.

Keyphrases: Early adversity, Brain function, Monozygotic twins, Environment, Emotion processing, Neuroimaging
Feedback regulation of Gab2-dependent signaling by the Ras/MAPK pathway

Receptor tyrosine kinase (RTK) signaling plays an essential role in modulating cell growth, proliferation, differentiation and motility. Abnormal regulation of RTKs results in many human diseases, including breast cancer, the second leading cause of cancer mortality in women by the frequent amplification and mutation of the HER2 (ERBB2) tyrosine kinase. The Grb2-associated binder (Gab) 2 is an adaptor protein that acts downstream of several RTKs, including HER2, to regulate multiple signaling pathways. In response to the stimulation of a number of growth factors and cytokines, Gab2 is recruited to the plasma membrane, where it potentiates the activation of the Ras/mitogen-activated protein kinase (MAPK) and PI3K (phosphatidylinositol-3-kinase)/Akt (protein kinase B) pathways. In addition to playing an important role in the hematopoietic system during development, GAB2 is often amplified in cancers including breast cancer and melanoma, however, little is known about the molecular mechanisms that regulate Gab2 function. It has been well established that upon RTKs activation, Gab2 becomes phosphorylated on several Tyr residues leading to diverse adaptor protein associations, such as p85 and Shp2. Aside from the tyrosine phosphorylation, our lab and other groups noticed that Gab2 is also phosphorylated on Ser/Thr residues upon activation of MAPK signaling. However, less is known about this post-translational modification in the regulation of Gab2 functions. In order to understand how Gab2 is regulated by the MAPK pathway, we used different approaches. In the first part of my thesis, we determined a new mechanism by which the Ras/MAPK pathway through RSK (p90 ribosomal S6 kinase) phosphorylated Gab2 on three conserved Ser/Thr residues, both in vivo and in vitro. Mutation of these phosphorylation sites promoted Shp2 recruitment leading to increased cell motility, suggesting that RSK restricts Gab2-dependent functions as a result of participation in the negative feedback loop of MAPK signaling. In the second part of the thesis, we found that ERK1/2 phosphorylated Gab2 on several potential pS/T-P residues, both in vivo and in vitro, resulting in inhibited p85 recruitment. In addition, to the best of our knowledge, we established for the first time that Gab2 physically interacted with ERK1/2 in cells upon activation of the MAPK pathway. Furthermore, we revealed a novel ERK1/2 docking domain in Gab2. Mutation of the essential residues in this docking domain not only disrupted ERK1/2-Gab2 interaction, but also diminished ERK1/2-dependent phosphorylation on Gab2. Taken together, our data showed that the MAPK pathway regulates Gab2 functions through both RSK- and ERK1/2-dependent manners. Given that Gab2 is overexpressed in several cancers, this thesis decodes a complete figure of modulating actions of Gab2 by MAPK signaling in cancer development.

Keyphrases: Gab2, MAPK, RSK, ERK1/2, D-domain, phosphorylation, Shp2, p85
Caractérisation fonctionnelle du suppresseur de tumeurs BAP1

The deubiquitinase BAP1 (BRCA1-Associated Protein1) is a nuclear member of the ubiquitin C-terminal hydrolase (UCH) family, previously isolated for promoting the function of the tumor suppressor BRCA1. Importantly, homozygous inactivating mutations of BAP1 have been found in mesothelioma, renal, melanoma and breast cancers strongly suggesting that this deubiquitinase is a tumor suppressor. Indeed BAP1 overexpression reduces cell proliferation and tumor growth in xenograft models. Nonetheless, the biological function and the mechanism of action of this deubiquitinase remain poorly defined. The goals of this thesis are to characterize the biological function of BAP1 and to reveal the molecular basis of its tumor suppressive function.   To provide insights into BAP1 biological function, we conducted a tandem affinity immunopurification of BAP1-associated proteins and found that most interacting partners are transcription factors and cofactors. Next, we demonstrated that BAP1 is indeed a transcription regulator. Concomitantly, another group showed that the drosophila BAP1, Calypso, is a Polycomb Group protein that regulates the ubiquitination levels of H2A and gene expression. Indeed, our global gene expression analysis suggests that BAP1 plays important role in DNA damage response. Consistently, loss- and gain- of function experiments (RNAi approach, DT40 chicken B cells KO model and re-introduction of BAP1 in BAP1 null-cells) revealed that BAP1 promotes homologous recombination-mediated DNA double strand break repair.   Our data suggest that BAP1 exerts its tumor suppressor function by controlling error-free DNA repair by homologous recombination. Thus, in a situation of BAP1 inactivation, cells might become more reliant on non-homologous end joining, an error-prone DNA repair mechanism, which would result in the accumulation of mutations and chromosomal aberrations, causing genomic instability. Further studies are required to delineate the exact role of BAP1 in transcription and to define how deregulation of H2A ubiquitination pathway contributes to cancer. Defining the mechanisms of tumor suppression is of great interest, not only for understanding cancer development, but also for designing rational cancer therapies.

Keyphrases: Chromatine, Ubiquitine, H2A, Transcription, Deubiquitinase, Ubiquitin, Chromatin, DNA damage, Double strand break, Homologous recombination
Rôles physiologiques du transporteur vésiculaire du glutamate VGLUT2 dans les neurones dopaminergiques

A subset of midbrain dopamine (DA) neurons has been shown to express the type 2 vesicular glutamate transporter (VGLUT2) supporting their capacity for glutamate co-release from some of their axon terminals. However, the physiological significance of this phenomenon is presently unknown. VGLUT2 expression by DA neurons occurs early during their development and is mainly found in DA neurons localized to the ventral tegmental area (VTA). Glutamate release by DA neurons can be detected at terminals contacting ventral but not dorsal striatal neurons. Together, these findings suggest the possibility glutamate co-release by DA neurons plays a developmental role and that target-derived signals regulate the neurotransmitter phenotype of DA neurons. Whether glutamate can be released from the same terminals that release DA or from a special subset of axon terminals is undetermined. Moreover, the physiological role of glutamate release by DA neurons is essentially unknown. Using a conditional gene knock-out approach to selectively disrupt the Vglut2 gene in mouse DA neurons, we obtained in vitro and in vivo evidence demonstrating reduced growth and survival of mesencephalic DA neurons, associated with a decrease in the density of DA innervation in the nucleus accumbens, reduced activity-dependent DA release, decreased motor coordination and impaired locomotor activation induced by drugs of abuse. In this study we also provide in vitro and in vivo data supporting the hypothesis that DA and glutamate-releasing terminals are mostly segregated and that striatal neurons regulate the co-phenotype of midbrain DA neurons and the segregation of release sites. These findings provide strong evidence for a functional role of the glutamatergic cophenotype in the development of mesencephalic DA neurons, unveils a fundamental feature of dual neurotransmission and plasticity of the DA system and open new perspectives into the pathophysiology of brain diseases implicatingthe DA system.

Keyphrases: Dopamine, Dopamine, Glutamate, Glutamate, Vglut2, Vglut2, Co-release, Survival, Growth, Heterogeneity, Segregation
Mesures subjectives et épidémiologie : problèmes méthodologiques liés à l'utilisation des techniques psychométriques

Recently, subjective measurements have increasingly been used in epidemiology, alongside the growing will to integrate individuals’ point of view on their health in studies on diseases or health interventions. Psychometrics includes statistical methods used to develop questionnaires and to analyze questionnaire data. This doctoral dissertation aimed to explore methodological issues raised by the use of psychometric techniques in epidemiology. Three empirical studies are presented and cover 1 / the validation stage of a questionnaire: the objective was to develop, using simulated data, a tool to determine sample size for internal validity studies on psychiatric scale; 2 / the mathematical properties of the subjective measurement: the objective was to compare the performances of the minimal clinically important difference of a questionnaire, assessed on data from a cohort study, computed using the classical test theory (CTT) framework or the item response theory framework (IRT); 3 / its use in a longitudinal design: the objective was to compare, using simulated data, the performances of a statistical method aimed to analyze the longitudinal course of a subjective phenomenon measured using the CTT or IRT framework, especially when some of the available items used for its measurement differ at each time of data collection. Finally, directed acyclic graphs were used to discuss the results from these three studies and the concept of information bias when subjective measurements are used in epidemiology.

Keyphrases: Questionnaire, Variable latente, Longitudinal, Subjective measurement, Psychometrics, Latent variable, Epidemiology, Longitudinal design, Information bias, Directed acyclic graphs
Pérennisation des changements et des résultats des interventions sanitaires dans les pays en développement (étude de cas du PNMLS)

Background : For health programs made in developing countries, non-sustainability of the changes and progress is an important phenomenon (Pluyer, Potvin, & Denis, 2004). However, few studies have been conducted to present solutions to this problem. To find possible answers to the issue, we have decided to do a case study on the national program of multi-sectoral fights against HIV/AIDS (PNMLS) in the Democratic Republic of Congo. In 2004, the program was implemented with the help of the World Bank through the MAP (Multi Aids Program). In 2010, MAP stopped its involvement in the program. Objectives : The goal of our research was to determine, three years after MAP stopped its involvement, what was the level of sustainability of the results achieved by the program back in 2010. Our other goal was to detect what were the factors that influenced the sustainability of those results. Methods: We did a review of existing literature on sustainability and developed a theoretical framework that shows the dynamic between factors that could influence the sustainability of results. We have observed the PNLMS in its ecosystem to in order to identify what factors had an influence on the sustainability of results. We had interviews with key players and did a review of all publications that were made on the PNMLS. This method helped us so to find answers to our research questions. Result: our research supports the concept that a multisectoral approach can have a positive impact on the sustainability of results. However, it is important to adapt the multi-sectoral approach to the environment and the ecosystem in which the program operates. This adjustment must be made from the implementation stage of the program.

Keyphrases: Structure, Processus, Mono sectoriel, PNMLS, MAP, Process, Objectives, Actors, Environment, Multisectoral, Mono sectoral, Sustainability