HnRNP A1 et UP1 maturation, liaison aux séquences télomériques et modulation de la réplication des télomères in vitro

Des résultats antérieurs ont montré que la protéine hnRNP A1 est impliquée dans l'allongement des télomères. Le fragment N-terminal de A1, nommé UP1, est lui aussi en mesure de provoquer l'allongement des télomères daps [i.e. dans] une lignée cellulaire de souris. A1 et UP1 sont tous deux capables de lier spécifiquement des répétitions télomériques in vitro, mais seul UP1 possède la capacité d'interagir avec la télomérase. Donc, A1/UP1 semble être important pour la modulation de l'allongement des télomères. Malgré des évidences suggérant l'existence d'une activité protéolytique permettant de convertir A1 en UP1, mes résultats n'ont pas révélé une telle activité in vivo ni in vitro. De plus, la mutation des acides aminés au site de clivage présumé n'affecte pas l'activité de A1 sur les télomères. Ces résultats suggèrent que la conversion de A1 en UP1 n'est pas nécessaire à son activité sur les télomères. L'interaction spécifique de UP1 avec la télomérase pourrait refléter le besoin d'une modification post-traductionnelle influençant la structure du domaine riche en glycines (e.g., phosphorylation). Un modèle de la liaison de UP1 sur des répétitions télomériques simple-brin humaines a pu être établi. Ce modèle propose que UP1 pourrait se lier sous forme de dimère à deux séquences TAGGGT. Finalement, A1/UP1 est capable d'inhiber l'activité de deux enzymes répliquant les télomères, soit la télomérase et l'ADN polymérase a. UP1 inhibe aussi la déoxynucléotidyl transférase terminale lorsqu'un site de liaison pour UP1 est présent sur le substrat. Mes résultats suggèrent qu'A1/UP1 pourrait contribuer à la formation d'une structure capable de bloquer l'accès aux facteurs normalement chargés de reconnaître les bris d'ADN

Création sonore et cinéma contemporain : la pensée et la pratique du mixage

Notre thèse décrit et analyse les conditions esthétiques, matérielles et idéelles qui rendent possibles les agencements sonores du cinéma contemporain. Au cours des 30 dernières années, le raffinement des outils de manipulation du son, l’importance grandissante du concepteur sonore et le nouvel espace de cohabitation des sons (favorisé par le Dolby et la diffusion multicanal) sont des facteurs qui ont transformé la création et l’écoute du son au cinéma. Ces transformations révèlent un nouveau paradigme : le mixage s’est graduellement imposé comme le geste perceptif et créateur qui rend compte de la sensibilité contemporaine. Notre thèse explore les effets de la pensée du mixage (qui procède par résonance, simultanéité, dosage et modulation) sur notre écoute et notre compréhension de l'expérience cinématographique. À l'aide de paroles de concepteurs sonores (Murch, Beaugrand, Thom, Allard…), de textes théoriques sur le son filmique (Cardinal, Chion, Campan), de documentaires sur des musiciens improvisateurs (Lussier, Glennie, Frith), de films de fiction à la dimension sonore affirmée (Denis, Van Sant), de textes philosophiques sur la perception (Leibniz, James, Straus, Szendy…), d'analyses du dispositif sonore cinématographique, notre thèse rend audibles des tensions, des récurrences, de nouveaux agencements, des problèmes actuels et inactuels qui forgent et orientent l'écoute du théoricien, du créateur et de l'auditeur. En interrogeant la dimension sonore de la perception, de l’action, de l’espace et de la pensée, cette thèse a pour objectif de modifier la façon dont on écoute, crée et pense le son au cinéma.This thesis describes and analyzes the esthetic, material and conceptual conditions that make the acoustic structures of contemporary cinema possible. The refinement of tools used for manipulating sound, the growing importance the sound designer and the emergence of a new space for sounds to coexist in (brought on by Dolby and multichannel sound systems) are factors that, over the past 30 years, have transformed the way we work with and listen to sound in film. These transformations reveal a new paradigm: mixing gradually imposed itself as the creative and perceptual act capable of accounting for our contemporary sensibility. This thesis explores the effects of the “thought process of mixing” (which functions by resonance, simultaneity, dosage and modulation) on the way we hear and understand the cinematographic experience. Working from the accounts of sound designers (Murch, Beaugrand, Thom Allard…), theoretical texts on film sound (Cardinal, Chion, Campam), documentaries on improvisational musicians (Lussier, Glennie, Frith), fiction films with a acute acoustic sensibility (Denis, Van Sant), philosophical texts on perception (Leibniz, James, Straus, Szendy…) and analyses of the cinematographic sound apparatus, this thesis renders audible the tensions, the recurrences, the structural connections and the problems, old and new, that forge and direct the theoretician, the artist and the auditor’s way of listening. By questioning the auditory dimension of perception, action, space and thought, this thesis aims to change the way we hear, create and think cinema

Infections et exposition aux organo-chlorés chez les enfants du Nunavik

Les enfants inuits du Nunavik ont une exposition prénatale à certaines substances organochlorées immunotoxiques plusieurs fois supérieures à celle d’enfants du sud du Québec. Cette exposition tend à diminuer dans le temps mais demeure significative et pourrait altérer certaines fonctions de leur système immunitaire. Nous avons calculé que la concentration moyenne de biphenyls polychlorés (BPC) dans le sang de cordon ombilical des nouveau- nés inuits a diminué de près de 8 % par année entre 1994 et 2001. Plusieurs substances peuvent moduler les fonctions du système immunitaire et il existe une grande variété de méthodes pour en mesurer l’effet. Parmi celles-ci, une variation de l’incidence d’infections aiguës dans une population donnée constitue une mesure valide et cliniquement significative. Afin de mesurer l’impact de cette exposition prénatale sur l’incidence d’infections respiratoires aiguës, nous avons révisé les dossiers médicaux de deux cohortes d’enfants du Nunavik (n = 199 et n = 354). Un calcul de l’incidence d’infections respiratoires à partir de la revue des dossiers pendant les cinq premières années de vie a montré une fréquence d’otites moyenne aiguës (OMA), d’infections des voies respiratoires inférieures (IVRI) et d’hospitalisations pour infections respiratoires plus élevée au Nunavik comparativement à la majorité des populations caucasiennes nord-américaines. Afin de déterminer l’effet d’une exposition prénatale aux organochlorés sur l’incidence d’infections, nous avons calculé l’association statistique entre la concentration du congénère de BPC 153 dans le sang de cordon ombilical ou le sang de la mère lors de l’accouchement et l’incidence de diagnostics d’infections respiratoires en utilisant la régression de Poisson. Les résultats tirés d’une première cohorte d’enfants suivie de 0 à 12 mois ont montré une association positive entre l’exposition aux organochlorés et l’incidence d’infections respiratoires aiguës. Cependant, l’association n’était observable que chez les enfants de moins de 6 mois et la puissance statistique n’était pas suffisante pour obtenir une association significative. Les résultats de la deuxième cohorte ont quant à eux montré une association positive statistiquement significative entre l’exposition prénatale aux organochlorés et l’incidence d’OMA et d’IVRI. Une relation dose-réponse était observable pour les OMA. Globalement, les résultats de ces études montrent qu’une proportion significative d’infections respiratoires chez les enfants ii du Nunavik d’age préscolaire pourrait être due à leur exposition prénatale à des substances organochlorées.Inuit children from Nunavik are prenatally exposed to immunotoxic organochlorine substances (OCs) and display plasma concentrations several times higher than their counterparts from Southern Québec. This exposure tends to decrease over time but remains significantly high and could potentially alter certain immune functions. We calculated that the plasma concentration of polychlorinated biphenyls (PCB) decreased by almost 8% annually between 1994 and 2001 in Nunavik newborns. Several substances can modulate immune system functions and a wide variety of methods are available to evaluate their effects. Among them, variation in the incidence of acute respiratory infections in a given exposed population is a valid and clinically significant endpoint. To estimate the impact of exposure to OCs on the incidence of respiratory infections, we reviewed the medical charts of two cohorts of Nunavik children (n = 199 and n = 354). The calculated incidence of respiratory infections from the medical chart review during the first 5 years of life underlined a higher frequency of acute otitis media (AOM), of lower respiratory tract infections (LRTIs), and of admissions for respiratory infections, compared to most non- Inuit North-American populations. In order to determine the effect of prenatal exposure to OCs on the incidence of respiratory infections, we calculated the statistic association between plasma concentration of PCB congener 153 in umbilical cord blood or maternal blood at delivery and the incidence of diagnosed respiratory infections using Poisson regression. Results from the first cohort of children followed from 0 to 12 month of age showed a positive association between exposure to OCs and respiratory infections. However, the association was present only for children under 6 months of age and the statistical power was insufficient to reach statistical significance. Nevertheless, results from the second cohort showed a positive, statistically significant association between prenatal exposure to OCs and incidence of AOM and LRTIs. A dose-response relationship was present for AOM. Globally, these results support the hypothesis of a significant portion of respiratory infections in preschool children from Nunavik being due to prenatal exposure to OCs

The role of genetic selection on agonistic behavior and welfare of gestating sows housed in large semi-static groups

Confinement of gestating sows is becoming banished in favor of group-housing in countries worldwide, forcing breeding companies to develop genetic lines adapted for social living. This study aimed at assessing the influence of two genetic lines selected for high performance (HP1, HP2, derived from Landrace × Yorkshire) on welfare and reproductive performance of sows housed in large semi-static groups (20 groups of 46–91 animals) across several parities. To address this, agonistic behaviors were recorded on d0, d2, d27, and d29 post-mixing while body lesions were scored on d1, d26, and d84. Sows’ individual and reproductive performances were also recorded. HP2 sows were more aggressive than HP1 sows since they fought (p = 0.028) and bullied (p = 0.0009) pen-mates more frequently on d0–d2. HP2 sows had more total body lesions throughout gestation than HP1 sows at higher parities (p < 0.0001). Regarding reproductive performance, HP2 sows lost less piglets (p < 0.0001) and tended to wean more piglets (p = 0.067) than HP1 sows. In conclusion, while HP2 sows were the most aggressive, HP1 sows had piglets with lower survivability, which raises ethical issues in both cases and points to the need of considering social aspects when developing genetic lines for group-housing

Quantitative spectral quality assessment technique validated using intraoperative in vivo Raman spectroscopy measurements

Significance: Ensuring spectral quality is prerequisite to Raman spectroscopy applied to surgery. This is because the inclusion of poor-quality spectra in the training phase of Raman-based pathology detection models can compromise prediction robustness and generalizability to new data. Currently, there exists no quantitative spectral quality assessment technique that can be used to either reject low-quality data points in existing Raman datasets based on spectral morphology or, perhaps more importantly, to optimize the in vivo data acquisition process to ensure minimal spectral quality standards are met. Aim: To develop a quantitative method evaluating Raman signal quality based on the variance associated with stochastic noise in important tissue bands, including C─C stretch, CH2  /  CH3 deformation, and the amide bands. Approach: A single-point hand-held Raman spectroscopy probe system was used to acquire 315 spectra from 44 brain cancer patients. All measurements were classified as either high or low quality based on visual assessment (qualitative) and using a quantitative quality factor (QF) metric. Receiver-operator-characteristic (ROC) analyses were performed to evaluate the performance of the quantitative metric to assess spectral quality and improve cancer detection accuracy. Results: The method can separate high- and low-quality spectra with a sensitivity of 89% and a specificity of 90% which is shown to increase cancer detection sensitivity and specificity by up to 20% and 12%, respectively. Conclusions: The QF threshold is effective in stratifying spectra in terms of spectral quality and the observed false negatives and false positives can be linked to limitations of qualitative spectral quality assessment

Effect of Prenatal Exposure to Polychlorinated Biphenyls on Incidence of Acute Respiratory Infections in Preschool Inuit Children

OBJECTIVE: We set out to assess whether environmental prenatal exposure to polychlorinated biphenyls (PCBs) is associated with incidence of acute respiratory infections in preschool Inuit children. STUDY DESIGN: We reviewed the medical charts of 343 children from 0 to 5 years of age and evaluated the associations between PCB-153 concentration in umbilical cord plasma and the incidence rates of acute otitis media (AOM) and of upper and lower respiratory tract infections (URTIs and LRTIs, respectively). RESULTS: The incidence rates of AOM and LRTIs were positively associated with prenatal exposure to PCBs. Compared with children in the first quartile of exposure (least exposed), children in fourth quartile (most exposed) had rate ratios of 1.25 (p < 0.001) and 1.40 (p < 0.001) for AOM and LRTIs, respectively. There was no association between prenatal PCB exposure and incidence rate of URTIs or hospitalization. CONCLUSION: Prenatal exposure to PCBs could be responsible for a significant portion of respiratory infections in children of this population

Evaluation of intensive versus standard blood pressure reduction and association with cognitive decline and dementia : a systematic review and metaAnalysis

Importance: Optimal blood pressure (BP) targets for the prevention of cognitive impairment remain uncertain. Objective: To explore the association of intensive (i.e. lower than usual) BP reduction compared to guidelines on the incidence of cognitive decline and dementia in adults with hypertension. Data Sources and Study Selection: We conducted a systematic review and meta-analysis of randomized controlled trials that evaluated the association of intensive systolic BP lowering on cognitive outcomes by searching MEDLINE, Embase, CENTRAL, Web of Science, CINAHL, PsycINFO, ICTRP and ClinicalTrials.gov for data up to October 27, 2020. Data Extraction and Synthesis: Data screening and extraction were performed independently by two reviewers based on PRISMA guidelines. The risk of bias was assessed using the Cochrane risk-of-bias 2 tool. We used random-effects models using the inverse variance method for our pooled analyses. We evaluated the presence of potential heterogeneity with the I2 index. Main Outcomes and Measures: Our primary outcome was cognitive decline. Secondary outcomes included the incidence of dementia, mild cognitive impairment (MCI), cerebrovascular events, serious adverse events, and all-cause mortality. Results: From 7,755 citations, we identified sixteen publications from five trials (17,396 participants, mean age 65.7 years, 60.5% males) and two additional ongoing trials. All five trials included in quantitative analyses were considered at unclear to high risk of bias. The mean followup duration was 3.3 years (range 2.0 to 4.7 years). Intensive BP reduction was not significantly associated with global cognitive performance (SMD 0.01, 95% CI -0.04 to 0.06, I2 = 0%, four trials, 5,246 patients), incidence of dementia (RR 1.09, 95% CI 0.32 to 3.67, I2 = 27%, two trials, 9,444 patients) or incidence of MCI (RR 0.91, 95% CI 0.73 to 1.14, I2 = 74%, two trials, 10,774 patients) when compared to standard treatment. However, we found a reduction of cerebrovascular events in the intensive arm (RR 0.79, 95% CI 0.67-0.93, I2 = 0%, five trials, 17,396 patients) without an increased risk of serious adverse events or mortality. Conclusions and Relevance: We did not detect a significant association between BP reduction and lower risk of cognitive decline, dementia or MCI. The certainty of this evidence is low due to the limited sample size, the risk of bias of included trials and the observed statistical heterogeneity. Hence, current available evidence does not justify the use of lower BP targets for the prevention of cognitive decline and dementi