ATP Synthase is the fundamental means of cellular energy production in animals, plants, and almost all microorganisms. In order to understand the mechanism of ATP catalysis, critical amino acid residues involved in Pi binding have to be identified. The αVISIT-DG sequence at the interface of α/β subunits that contains residues from 345-351 is highly conserved and αAsp-350 has been chosen because of its negative charge side chain and its close proximity (~2.8 Å) to the known phosphate binding residue αArg-376. The mutant's αD350R, αD350Q, αD350A, αR376A/D, and αG351R/A/D were generated by site directed mutagenesis and several biochemical assays were performed on them to understand the role played by the amino acid residues in Pi binding. Biochemical results suggest that αD350 may be involved in catalysis of ATP synthase and play an important role in Pi binding, whereas αG351 may be involved only in the structural integrity.

Cette thèse explore la relation entre les catégories de modules sur les catégories différentielles graduées (abrégées DG) petites, d'une part, et les catégories triangulées bien engendrées d'autre part. Dans la première partie, on construit la catégorie dérivée $\alpha$-continue D_\alpha A d'une catégorie DG $\alpha$-cocomplète petite A, où $\alpha$ est un cardinal régulier. Cette construction jouit d'une propriété très intéressante, qui est la clef pour démontrer le théorème principal de la thèse. Les catégories D_\alpha A s'avèrent être les prototypes des catégories triangulées algébriques à engendrement $\alpha$-compact. On entend par algébrique, équivalente, en tant que catégorie triangulée à la catégorie stable d'une catégorie de Frobenius. Le résultat principal établit que les catégories algébriques bien engendrées sont précisément celles qui sont des localisations de la catégorie dérivée d'une catégorie DG petite. Ce résultat rappelle beaucoup un théorème de Gabriel et Popescu de 1964, qui caractérise les catégories abéliennes de Grothendieck comme des localisations de catégories de modules sur des anneaux. Il donne aussi une réponse positive à une question de Drinfeld qui demandait si toutes les catégories triangulées bien engendrées sont des localisations de catégories triangulées à engendrement compact, pour la classe des catégories triangulées algébriques. Dans la deuxième partie, on étudie les catégories DA et D_\alpha A en utilisant la structure projective de catégories de modèles de Quillen présente sur la catégorie des DG modules. On introduit la sous-catégorie des DG modules cofibrants homotopiquement $\alpha$-compacts et on montre que sa catégorie homotopique est précisément la catégorie dérivée $\alpha$-continue D_\alpha A. Cela nous permet de donner une deuxième preuve, complètement différente du résultat-clef de la première partie.

Pesticides are among the most pervasive environmental contaminants and they are an important potential risk for human health. Agricultural workers are constantly exposed to pesticide spray, drift and residues in the soil and foliage. Many agricultural pesticides are readily absorbed by the body, through contact with the skin, the respiratory track, the eyes, and the gastrointestinal system. Multiple studies have reported a strong association between pesticide exposure and various health outcomes including cancer. Oxidative stress and DNA damage have been proposed as mechanisms linking pesticide exposure to health effects and neurological diseases. The focus of the present translational study is to examine the relationship between human exposure to the organophosphate pesticide azinphos methyl (AZM) and oxidative stress by measuring biomarkers of oxidative stress in biological fluids (i.e., urine, serum) and peripheral blood lymphocytes (PBLs) of agricultural workers. The findings from these field studies will be validated in vitro by examining cultures of human lymphocytes treated with AZM for similar biomarkers of oxidative stress. Since the collection of PBLs from study participants is highly invasive and not suitable for studies involving younger subjects, we also examined buccal cells for biomarkers of oxidative stress (i.e., DNA damage) as a more universal source of human tissue to assess oxidative stress in pesticide exposed individuals. We demonstrated in this study that AZM induces oxidative stress and causes DNA damage in human tissues. Agricultural workers who had been exposed to AZM showed elevated serum levels of lipid peroxides, increased urinary levels of 8-OH-dG, and lymphocytes from these individuals showed increased DNA damage and associated changes in oxidative DNA repair enzymes. Biomarkers of oxidative stress were also elevated in human lymphocytes treated with physiologically relevant concentrations of AZM. In cultures of human lymphocytes, AZM caused a concentration-dependent loss of viability and associated increases in ROS and a reduction in intracellular GSH. We also demonstrated that viable leukocytes from the oral cavity can be readily obtained from humans and these buccal cells can be used to assess DNA damage following exposure to occupational and environmental genotoxicants. We also noted that oral leukocytes are especially sensitive to cryopreservation with DMSO and thus, these cells must be cryoprotected with 5% DMSO to preserve the viability of these cells for subsequent biochemical studies. In summary, these in vivo and in vitro studies demonstrated that AZM induces oxidative stress in a dose-dependent matter and that oral lymphocytes are a good source of human tissue for assessing DNA damage and possibly other biochemical changes. The possible health implications of the variations in these biomarkers of oxidative stress and DNA damage are undetermined. Yet the findings from these studies have provided a strong foundation for determining the mechanism by which pesticide induce oxidative stress, to explore the putative relationship between pesticide-induced oxidative stress and disease (e.g. cancer, neurodegenerative disorders) and determine whether tissue damage in humans is brought about by direct or by indirect action of organophosphate pesticides. / Graduation date: 2010

Dans les années à venir, l'industrie de la microélectronique doit développer de nouvelles filières technologiques qui pourront devenir des successeurs ou des compléments de la technologie CMOS ultime. Parmi ces technologies émergentes relevant du domaine ''Beyond CMOS'', ce travail de recherche porte sur les transistors mono-électroniques (SET) dont le fonctionnement est basé sur la quantification de la charge électrique, le transport quantique et la répulsion Coulombienne. Les SETs doivent être étudiés à trois niveaux : composants, circuits et système. Ces nouveaux composants, utilisent à leur profit le phénomène dit de blocage de Coulomb permettant le transit des électrons de manière séquentielle, afin de contrôler très précisément le courant véhiculé. Ainsi, le caractère granulaire de la charge électrique dans le transport des électrons par effet tunnel, permet d'envisager la réalisation de transistors et de cellules mémoires à haute densité d'intégration, basse consommation. L'objectif principal de ce travail de thèse est d'explorer et d'évaluer le potentiel des transistors mono-électroniques double-grille métalliques (DG-SETs) pour les circuits logiques numériques. De ce fait, les travaux de recherches proposés sont divisés en trois parties : i) le développement des outils de simulation et tout particulièrement un modèle analytique de DG-SET ; ii) la conception de circuits numériques à base de DGSETs dans une approche ''cellules standards'' ; et iii) l'exploration d'architectures logiques versatiles à base de DG-SETs en exploitant la double-grille du dispositif. Un modèle analytique pour les DG-SETs métalliques fonctionnant à température ambiante et au-delà est présenté. Ce modèle est basé sur des paramètres physiques et géométriques et implémenté en langage Verilog-A. Il est utilisable pour la conception de circuits analogiques ou numériques hybrides SET-CMOS. A l'aide de cet outil, nous avons conçu, simulé et évalué les performances de circuits logiques à base de DG-SETs afin de mettre en avant leur utilisation dans les futurs circuits ULSI. Une bibliothèque de cellules logiques, à base de DG-SETs, fonctionnant à haute température est présentée. Des résultats remarquables ont été atteints notamment en terme de consommation d'énergie. De plus, des architectures logiques telles que les blocs élémentaires pour le calcul (ALU, SRAM, etc.) ont été conçues entièrement à base de DG-SETs. La flexibilité offerte par la seconde grille du DG-SET a permis de concevoir une nouvelle famille de circuits logiques flexibles à base de portes de transmission. Une réduction du nombre de transistors par fonction et de consommation a été atteinte. Enfin, des analyses Monte-Carlo sont abordées afin de déterminer la robustesse des circuits logiques conçus à l'égard des dispersions technologiques.

For the past 40 years, relentless focus on Moore’s Law transistor scaling has provided ever-increasing transistor performance and density. In order to continue the technology scaling beyond 22nm node, it is clear that conventional bulk-MOSFET needs to be replaced by new device architectures, most promising being the Multiple-Gate MOSFETs (MuGFET). Intel in mid 2011 announced the use of bulk Tri-Gate FinFETs in 22nm high volume logic process for its next-gen IvyBridge Microprocessor. It is expected that soon other semiconductor companies will also adopt the MuGFET devices. As like bulk-MOSFET, an accurate and physical compact model is important for MuGFET based circuit design. Compact modeling effort for MuGFET started in late nineties with planar double gate MOSFET(DGFET),as it is the simplest structure that one can conceive for MuGFET devices. The models so far proposed for DG MOSFETs are applicable for common gate symmetric DG (SDG) MOSFETs where both the gates have equal oxide thicknesses. However, for practical devices at nanoscale regime, there will always be some amount of asymmetry between the gate oxide thicknesses due to process variations and uncertainties, which can affect device performance significantly. At the same time, Independently controlled DG(IDG) MOSFETs have gained tremendous attention owing to its ability to modulate threshold voltage and transconductance dynamically. Due to the asymmetric nature of the electrostatic, developing efficient compact models for asymmetric/independent DG MOSFET is a daunting task. In this thesis effort has been put to provide some solutions to this challenge. We propose simple surface-potential based compact terminal charge models, applicable for Asymmetric Double gate MOSFETs (ADG) in two configurations1) Common-gate 2) Independent-gate. The charge model proposed for the common-gate ADG (CDG) MOSFET is seamless between the symmetric and asymmetric devices and utilizes the unique so-far-unexplored quasi-linear relationship between the surface potentials along the channel. In this model, the terminal charges could be computed by basic arithmetic operations from the surface potentials and applied biases, and can be easily implemented in any circuit simulator and extendable to short-channel devices. The charge model proposed for independent ADG(IDG)MOSFET is based on a novel piecewise linearization technique of surface potential along the channel. We show that the conventional “charge linearization techniques that have been used over the years in advanced compact models for bulk and double-gate(DG) MOSFETs are accurate only when the channel is fully hyperbolic in nature or the effective gate voltages are same. For other bias conditions, it leads to significant error in terminal charge computation. We demonstrate that the amount of nonlinearity that prevails between the surface potentials along the channel for a particular bias condition actually dictates if the conventional charge linearization technique could be applied or not. We propose a piecewise linearization technique that segments the channel into multiple sections where in each section, the assumption of quasi-linear relationship between the surface potentials remains valid. The cumulative sum of the terminal charges obtained for each of these channel sections yield terminal charges of the IDG device. We next present our work on modeling the non-ideal scenarios like presence of body doping in CDG devices and the non-planar devices like Tri-gate FinFETs. For a fully depleted channel, a simple technique to include body doping term in our charge model for CDG devices, using a perturbation on the effective gate voltage and correction to the coupling factor, is proposed. We present our study on the possibility of mapping a non-planar Tri-gate FinFET onto a planar DG model. In this framework, we demonstrate that, except for the case of large or tall devices, the generic mapping parameters become bias-dependent and an accurate bias-independent model valid for geometries is not possible. An efficient and robust “Root Bracketing Method” based algorithm for computation of surface potential in IDG MOSFET, where the conventional Newton-Raphson based techniques are inefficient due to the presence of singularity and discontinuity in input voltage equations, is presented. In case of small asymmetry for a CDG devices, a simple physics based perturbation technique to compute the surface potential with computational complexity of the same order of an SDG device is presented next. All the models proposed show excellent agreement with numerical and Technology Computer-Aided Design(TCAD) simulations for all wide range of bias conditions and geometries. The models are implemented in a professional circuit simulator through Verilog-A, and simulation examples for different circuits verify good model convergence.

Notre équipe a identifié le thé Labrador [Rhododendron groenlandicum L. (Ericaceae)] comme une plante potentiellement antidiabétique de la pharmacopée traditionnelle des Cris de la Baie James orientale. Dans la présente étude, nous avons évalué les effets néphroprotecteurs potentiels de la plante. De la microalbuminurie et de la fibrose rénale ont été développées chez des souris alimentées avec une diète grasse (DG). Le R. groenlandicum améliore d’une façon non-significative la microalbuminurie, avec des valeurs de l’aire sous la courbe (ACR) diminuant de 0.69 à 0.53. La valeur de la fibrose rénale qui était, à l’origine, de 4.85 unités arbitraires (UA) dans des souris alimentées à la DG, a chuté à 3.27 UA après avoir reçu un traitement de R. groenlandicum. Le R. groenlandicum a réduit la stéatose rénale de presque la moitié alors que l’expression du facteur de modification Bcl-2 (Bmf) a chuté de 13.96 UA à 9.43 UA. Dans leur ensemble les résultats suggèrent que le traitement avec R. groenlandicum peut améliorer la fonction rénale altérée par DG. Dans l’étude subséquente, notre équipe a identifié 17 espèces de la forêt boréale, de la pharmacopée traditionnelle des Cris de la Baie James orientale, qui ont présenté des activités biologiques prometteuses in vitro et in vivo dans le contexte du DT2. Nous avons maintenant examiné ces 17 extraits afin d’identifier lesquels possèdent un potentiel cytoprotecteur rénale en utilisant des cellules Madin Darby Canine Kidney (MDCK) mises à l’épreuve dans un médium hypertonique. Nous concluons que plusieurs plantes antidiabétiques Cris exercent une activité de protection rénale qui pourrait être pertinente dans le contexte de la néphropathie diabétique (ND) qui affecte une proportion importante des Cris. La G. hispidula et la A. balsamea sont parmi les plantes les plus puissantes dans ce contexte et elles semblent protectrices principalement en inhibant la caspase 9 dans la voie de signalisation apoptotique mitochondriale. Finalement, nous avons utilisé une approche de fractionnement guidée par un test biologique pour identifier les fractions actives et les composés de A. balsamea avec un potentiel de protection rénale in vitro dans des cellules MDCK mises au défi avec un médium hypertonique. La fraction d’hexane (Hex) possède le potentiel le plus élevé parmi toutes les fractions de solvant contre les dommages cellulaires induits par le stress hypertonique. Dans des études précédentes, trois composés purs ont été identifiés à partir de la fraction Hex, à savoir, l’acide abiétique, l’acide déhydroabiétique et le squalène. L’acide abiétique se distinguait par son effet puissant dans le maintien de la viabilité des cellules MDCK (AnnV-/PI-) à un niveau relativement élevé (augmentation de 25.48% relative au stress hypertonique, P<0.0001), ainsi qu’une réduction significative (diminution de 20.20% par rapport au stress hypertonique, P<0.0001) de l’apoptose de stade précoce (AnnV+/PI-). L’acide abiétique peut donc servir à normaliser les préparations traditionnelles d’A. balsamea et à trouver des applications potentielles dans le traitement de la néphropathie diabétique. Les trois études ont été intrinsèquement liées les unes aux autres, par conséquent, nous avons réussi à identifier R. groenlandicum ainsi que A. balsamea comme nouvelles plantes prometteuses contre la néphropathie diabétique. Nous croyons que ces résultats profiteront à la communauté crie pour la gestion des complications diabétiques, en particulier la néphropathie diabétique. En parallèle, nos données pourraient faire avancer l'essai clinique de certaines plantes médicinales de la pharmacopée traditionnelle des Cris de la Baie James orientale du Canada. / Our team has identified Labrador tea [Rhododendron groenlandicum L. (Ericaceae)] as a potential antidiabetic plant from the traditional pharmacopeia of the Eastern James Bay Cree. In the present study, we assessed the plant’s potential renoprotective effects. Microalbuminuria and renal fibrosis was developed in high fat diet (HFD)-fed mice. Meanwhile, there was a tendency for R. groenlandicum to improve microalbuminuria, with the values of area under the curve (ACR) reducing from 0.69 to 0.53. Renal fibrosis value was originally 4.85 arbitrary units (AU) in HFD-fed mice, dropped to 3.27 AU after receiving R. groenlandicum treatment. R. groenlandicum reduced renal steatosis by nearly one half whereas the expression of Bcl-2-modifying factor (Bmf) diminished from 13.96 AU to 9.43 AU. Taken altogether, the results suggest that R. groenlandicum treatment can improve renal function impaired by HFD. In the following study, our team has identified 17 Boreal forest species from the traditional pharmacopeia of the Eastern James Bay Cree that presented promising in vitro and in vivo biological activities in the context of type 2 diabetes (T2D). We now screened the 17 plants extracts for potential renal protective activity using Madin Darby Canine Kidney (MDCK) cells challenged with hypertonic medium. Cytoprotective potential as well as underlying mechanisms were investigated. We conclude that several Cree antidiabetic plants exert renal protective activity that may be relevant in the context of diabetic nephropathy that affects a significant proportion of Cree diabetics. G. hispidula and A. balsamea are amongst the most powerful plants in this context and they appear to exert their modulatory effect primarily by inhibiting caspase 9 in the mitochondrial apoptotic signaling pathway. We used a bioassay-guided fractionation approach to identify active fractions and compounds of A. balsamea with renal protective potential in vitro in MDCK cells challenged with hypertonic medium. The hexane (Hex) fraction possessed the highest potential among all solvent fractions against cell damage induced by hypertonic stress. In previous studies, three pure compounds were identified from the Hex fraction, namely, abietic acid, dehydroabietic acid and squalene. Abietic acid stood out by its strongest effect in maintaining MDCK cell viability (AnnV-/PI-) at a relatively high level (25.48% increase relative to hypertonic stress, P<0.0001) as well as a significant reduction (20.20% decrease relative to hypertonic stress, P<0.0001) of early stage apoptosis (AnnV+/PI-). Abietic acid may thus serve to standardize A. balsamea traditional preparations and find potential applications in the treatment of diabetic nephropathy. The three studies were inherently associated with each other, as a result we had successfully identified R. groenlandicum as well as A. balsamea as novel medicinal plants against diabetic nephropathy. We believe such findings will benefit the Cree community for the management of diabetic related complications, especially diabetic nephropathy. Meanwhile, our data might advance the clinical trial of certain medicinal plants from the traditional pharmacopeia of the Canadian Eastern James Bay Cree.

No description available.

<p> G93A SODI mice (G93A mice) are a transgenic model over-expressing a mutant human Cu/Zn-SOD gene, and are a model for amyotrophic lateral sclerosis (ALS), a predominantly motor neurodegenerative disease. Hippocampal neurogenesis in the subgranular zone (SGZ) of dentate gyms (DG) occurs throughout the life. It is regulated by many pathological and physiological processes. There is controversy with respect to the basal level of hippocampal neurogenesis and its response to exercise in neurodegenerative diseases and their mouse models. Little information regarding hippocampal neurogenesis is available in G93A mice. The present study was designed to study the impact of treadmill exercise and sex differences on hippocampal neurogenesis in this model. In addition, potential molecular mechanisms regulating hippocampal neurogenesis including growth factors (BDNF and IGFl) and oxidative stress (SOD2, catalase, 8-0Hdg, and 3-NT) were also addressed in the study. Bromodeoxyuridine (BrdU) was used to label newly generated cells. G93A and wild type (WT) mice were subjected to treadmill exercise (EX) or a sedentary (SEO) lifestyle. Immunohistochemistry was used to detect BrdU labeled newly proliferating cells, surviving cells, and their phenotype, as well as for determination of oxidative stress. BDNF and IGFl mRNA expression was assessed by in situ hybridization. Results showed that (1) G93A mice had an elevated basal level of hippocampal neurogenesis for both cell survival and neuronal differentiation, a growth factor (BDNF mRNA), and an oxidative stress marker (NT), as compared to wild type sedentary mice. (2) Treadmill running did not show any further effect on hippocampal neurogenesis, growth factors, oxidative stress, and antioxidant enzymes in G93A mice, while treadmill running promoted hippocampal neurogenes1s and expression of the growth factor (BDNF mRNA), and lowered oxidative stress (8-0Hdg) in WT mice. (3) There also were sex differences in hippocampal neurogenesis in G93A mice, whereby male G93A mice had a significant higher level of cell proliferation but a lower level of survival than female G93A mice. (4) The DG BDNF mRNA was associated with cell survival and neuronal differentiation in sedentary G93A mice, suggesting that BDNF is associated with a higher basal level of hippocampal neurogenesis in G93A mice. We conclude that G93A mice are more permissive in the context of hippocampal neurogenesis, which is associated with elevated DG BDNF mRNA expression. Running did not have impact on hippocampal neurogenesis and BDNF mRNA expression in G93A mice, probably due to a 'ceiling effect' of the already heightened basal levels of hippocampal neurogenesis and BDNF mRNA in this model. In addition, sex differences also affect hippocampal neurogenes1s, but the further study is needed to clarify the underlying molecular mechanisms. </p> / Thesis / Doctor of Philosophy (PhD)

No description available.

Nous présentons dans cette thèse les évolutions apportées au solveur Galerkin Discontinu Teta-CLAC, issu de la collaboration IRMA-AxesSim, au cours du projet HOROCH (2015-2018). Ce solveur permet de résoudre les équations de Maxwell en 3D, en parallèle sur un grand nombre d'accélérateurs OpenCL. L'objectif du projet HOROCH était d'effectuer des simulations de grande envergure sur un modèle numérique complet de corps humain. Ce modèle comporte 24 millions de mailles hexaédriques pour des calculs dans la bande de fréquences des objets connectés allant de 1 à 3 GHz (Bluetooth). Les applications sont nombreuses : téléphonie et accessoires, sport (maillots connectés), médecine (sondes : gélules, patchs), etc. Les évolutions ainsi apportées comprennent, entre autres : l'optimisation des kernels OpenCL à destination des CPU dans le but d'utiliser au mieux les architectures hybrides ; l'expérimentation du runtime StarPU ; le design d'un schéma d'intégration à pas de temps local ; et bon nombre d'optimisations permettant au solveur de traiter des simulations de plusieurs millions de mailles. / In this thesis, we present the evolutions made to the Discontinuous Galerkin solver Teta-CLAC – resulting from the IRMA-AxesSim collaboration – during the HOROCH project (2015-2018). This solver allows to solve the Maxwell equations in 3D and in parallel on a large amount of OpenCL accelerators. The goal of the HOROCH project was to perform large-scale simulations on a complete digital human body model. This model is composed of 24 million hexahedral cells in order to perform calculations in the frequency band of connected objects going from 1 to 3 GHz (Bluetooth). The applications are numerous: telephony and accessories, sport (connected shirts), medicine (probes: capsules, patches), etc. The changes thus made include, among others: optimization of OpenCL kernels for CPUs in order to make the best use of hybrid architectures; StarPU runtime experimentation; the design of an integration scheme using local time steps; and many optimizations allowing the solver to process simulations of several millions of cells.