Interferon (IFN)τ is the luteotrophic signal in ruminants and is secreted by bovine blastocysts both in vivo and in vitro. IFNτ secretion is highly variable and its control is only partly understood. Most studies on the effects of environmental factors on IFNτ production have evaluated IFNτ production during the time of embryo elongation and attachment. There is less knowledge of how IFNτ production at the blastocyst stage is modulated. Therefore, the hypothesis of this thesis was that the amounts of IFNτ expressed and/or secreted by bovine blastocysts produced in vitro were modulated by environmental factors. In the first set of experiments, bovine embryos were incubated with a cytokine (granulocyte macrophage colony stimulating factor, GM-CSF). GM-CSF had been shown previously to promote embryo viability in a range of species and to modulate IFNτ secretion by ovine blastocysts and thus was classified as a beneficial environmental factor. Three experiments were conducted to test whether GM-CSF stimulated bovine blastocyst development and IFNτ secretion. Embryos were incubated with a range of different concentrations of GM-CSF (2, 5, 10 and 50 ng mL-1) and at different stages of development (1 to 3 and 1 to 9 days post-insemination). Bovine embryos were unresponsive to GM-CSF in terms of IFNτ secretion, pyruvate oxidation, rate of development, blastocyst yield, morphological quality and apoptotic index, irrespective of timing of exposure and/or concentration of GM-CSF. In the second part of the thesis, bovine blastocysts were exposed to a mild heat treatment (42°C for four h) to determine whether heat stress affected IFNτ expression by bovine blastocysts. A novel multiplex reverse-transcription polymerase chain reaction methodology was validated to detect IFNτ and heat shock protein (HSP)70 mRNA in individual bovine embryos relative to an endogenous gene (YWHAZ) and an exogenous mRNA (α-globin) and results were expressed both in absolute terms and in relation to the endogenous control. Heat treatment upregulated IFNτ mRNA expression, suggesting that detrimental environmental factors may influence IFNτ expression. Heat treatment also caused an increase in HSP70 mRNA expression but did not affect blastocyst morphology, suggesting that the level of stress caused by the heat treatment was great enough to activate the cellular stress response, but mild enough not to cause a change in morphology. In addition, the positive correlation between HSP70 and IFNτ transcript levels and the higher IFNτ expression by embryos which showed signs of degeneration and collapse compared to those which progressed in development suggested that IFNτ expression may be indicative of stress. The relationship between IFNτ expression and secretion in vitro with morphology, pyruvate metabolism, apoptotic index and cell number was inconsistent, suggesting that IFNτ production did not correlate with ‘quality’ (defined as an index of viability). Blastocyst yield, day of blastulation and change in morphology index did account for at least part of the variation in IFNτ production, suggesting that some intrinsic factors may regulate IFNτ secretion. These intrinsic factors, however, did not explain all the variation in IFNτ secretion between blastocysts. Therefore, the amount of IFNτ secreted by bovine blastocysts is modulated by both intrinsic and environmental factors. A model was proposed where different levels of stress affect survivability to different extents, and the ability to respond to mild levels of stress may be indicative of improved survivability.

The generation of vector boson mass via the Higgs mechanism in the Standard Model has been confirmed by the 2012 discovery of a candidate Higgs boson in the H&rarr;WW, H&rarr;ZZ, and H&rarr;&gamma;&gamma; decay channels. In contrast, the Yukawa couplings hypothesized to provide the mass of fermions in the Standard Model have yet to be observed. The H&rarr;&tau;&tau; decay channel currently provides the best opportunity for observing these couplings. This thesis describes two separate but related searches for Higgs boson decays in the H→&tau;&tau; decay channel using proton-proton collisions recorded by the ATLAS detector. The first analysis is a general search for all Higgs boson production mechanisms leading to a H&rarr;&tau;&tau; decay using 4.5 fb⁻¹ of 7 TeV and 20.3 fb⁻¹ of 8 TeV proton-proton collision data. A deviation from the background-only hypothesis is observed with a significance of 4.5&sigma; for a hypothetical Higgs boson mass of m_H = 125 GeV — a strong indication of a H&rarr;&tau;&tau; signal. For the same mass point, the best fit value for the signal strength is found to be 1.43 ^&plus;0.43<sub style='position: relative; left: -2.4em;'>−0.37</sub> x the Standard Model expectation. The second analysis is a search for Higgs boson production in association with a vector boson using 20.3 fb⁻¹ of 8 TeV proton-proton collision data. Results in the Z_llH&rarr;_&tau;l&tau;h channel indicate limits of 9.14 x the Standard Model expectation for VH signal production at m_H = 125 GeV. In addition, two studies on enhancement of computing performance in the ATLAS trigger and data analysis pipeline are presented.

Les copules représentent un outil innovant pour modéliser la structure de dépendance de plusieurs variables aléatoires. Introduites par Sklar [1959] pour résoudre un problème de probabilité énoncé par Maurice Fréchet, les copules deviennent essentielles à l'appréhension de nombreux domaines d'application tels que l'hydrologie (Salvadori, De Michele, Kottegoda, et Rosso [2007]), les sciences actuarielles (Frees et Valdez [1998]), ou la finance (Cherubini, Vecchiato, et Luciano [2004]; Mc-Neil, Frey, et Embrechts [2005]). Le grand intérêt est qu'elles fournissent des expressions relativement simples des structures des dépendances liant les marges d'une loi multidimensionnelle. Plus précisément, pour le cas bidimensionnel, une copule C définie sur [0, 1] [indice supérieur 2], associée à une distribution F de marges uniformes F [indice inférieur 1] et F [indice inférieur 2], permet de représenter la fonction de répartition jointe F(x [indice inférieur 1], x [indice inférieur 2]) en fonction de ces marginales F [indice inférieur 1](x [indice inférieur 1]) et F [indice inférieur 2](x [indice inférieur 2]) par la relation : F(x [indice inférieur 1], x [indice inférieur 2]) = C(F [indice inférieur 1](x [indice inférieur 1]), F [indice inférieur 2](x [indice inférieur 2])). Cependant en pratique, la copule est inconnue, d'où l'utilité de l'estimer. Dans ce mémoire nous commençons par les définitions et les propriétés liées aux copules ainsi que les modèles paramétriques des copules. Ensuite nous présentons les différentes méthodes d'estimation: paramétriques, semi-paramétriques et non-paramétriques. Dans ce travail, on a étudié les propriétés asymptotiques d'un estimateur non-paramétrique basé sur les polynômes de Bernstein proposé par Sancetta & Satchell [2004]. Aussi, on a utilisé cet estimateur pour proposer un nouvel estimateur du tau de Kendall.

The aim of this thesis was to identify genetic factors involved in frontotemporal lobar degeneration (FTLD), a neurodegenerative disorder clinically characterised by a progressive change in personality, behaviour and language. FTLD is a genetically complex disorder and a positive family history is found in up to 40% of the cases. In 10-20% of the familial cases the disease can be explained by mutations in the gene encoding the microtubule associated protein tau (MAPT). In the first study we describe the clinical and neuropathological features of a Finnish family with FTLD caused by a mutation in MAPT. We also provide evidence that the pathogenic mechanism of this mutation is through altered splicing of MAPT transcripts. Recently, mutations in the gene encoding progranulin (PGRN) were identified as a major cause of FTLD. In the second study we describe a Swedish family with FTLD caused by a frameshift mutation in PGRN. We provide a clinical and neuropathological description of the family, as well as evidence that the pathogenicity of this mutation is through nonsense-mediated decay of the mutant mRNA transcripts and PGRN haploinsufficiency. In the third study we describe a novel PGRN splice site mutation and a previously described PGRN frameshift mutation, found in a mutation screen of 51 FTLD patients. We describe the clinical and neuropathological characteristics of the mutation carriers and demonstrate that haploinsufficiency is the pathogenic mechanism of the two mutations. In the fourth study we investigate the prevalence of PGRN and MAPT gene dosage alterations in 39 patients with FTLD. No gene dosage alterations were identified, indicating that variations in copy number of the PGRN and MAPT genes are not a common cause of disease, at least not in this FTLD patient collection.

Tau est une protéine associée aux microtubules enrichie dans l’axone. Dans la maladie d’Alzheimer, Tau devient anormalement hyperphosphorylée, s’accumule dans le compartiment somato-dendritique et s’agrège pour former des enchevêtrements neurofibrillaires (NFTs). Ces NFTs se propagent dans le cerveau dans un ordre bien précis. Ils apparaissent d’abord dans le cortex transenthorinal pour ensuite se propager là où ces neurones projettent, c’est-à-dire au cortex entorhinal. Les NFTs s’étendent ensuite à l’hippocampe puis à différentes régions du cortex et néocortex. De plus, des études récentes ont démontré que la protéine Tau peut être sécrétée par des lignées neuronales et que lorsqu’on injecte des agrégats de Tau dans un cerveau de souris, ceux-ci peuvent pénétrer dans les neurones et induire la pathologie de Tau dans le cerveau. Ces observations ont mené à l’hypothèse que la protéine Tau pathologique pourrait être sécrétée par les neurones, pour ensuite être endocytée par les cellules avoisinantes et ainsi propager la maladie. L’objectif de la présente étude était donc de prouver la sécrétion de la protéine Tau par les neurones et d’identifier par quelle voie elle est secrétée. Nos résultats ont permis de démontrer que la protéine Tau est sécrétée par des neurones corticaux de souris de type sauvage ainsi que dans un modèle de surexpression dans des cellules HeLa et PC12. Nos résultats indiquent que la sécrétion de Tau se ferait par les autophagosomes. Finalement, nous avons démontré que la protéine Tau sécrétée est déphosphorylée et clivée par rapport à la protéine Tau intracellulaire non sécrétée. / Tau, a microtubule-associated protein, is enriched in the axon. In Alzheimer’s disease, Tau becomes hyperphosphorylated, redistributes to the somato-dendritic compartment and forms aggregates called neurofibrillary tangles (NFTs). The NFTs propagates in a predictable manner in particular neuronal networks. Indeed, they appear in the trans-entorhinal region and then propagate to the entorhinal cortex where the trans-entorhinal cortex projects. Then, the NFTs propagate to the hippocampus and to different regions of the cortex and neocortex. Recent studies have reported that Tau can be secreted by neuronal cell lines. Besides, when aggregates of Tau protein were injected in mouse brain, they could enter neurons and induced Tau pathology. Based on those observations, it was speculated that Tau could be secreted by neurons and then captured by neighbouring cells to propagate Tau pathology in the brain. The goal of the present study was to prove that Tau can be secreted by neurons and to find the secretory pathway involved in Tau secretion. Moreover, the phosphorylation state of Tau protein was examined and compared to intracellular non-secreted Tau. Our results showed that Tau is secreted by cortical neurons isolated from wild-type mice and by HeLa and PC12 cells overexpressing human Tau. Our results also indicated that autophagosomes would be involved in Tau secretion. Finally, we found that secreted Tau was dephosphorylated and cleaved compared to the non-secreted intracellular Tau.

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

The Standard Model predicts existence of one Higgs boson with combined parity CP = +1. In MSSM there exist Higgs boson with CP = −1 in addition. The work develops one method of Higgs boson CP determination on the basis of angular correlations of pions and ρ-mesons born in cascade decay H/A → τ− τ+ → ρ− /π− ντ ρ+ /π+ ¯ντ . The calculations are done in the leading order of perturbation theory. Further, the possibility of signal (Higgs boson decay) and background (Z boson decay) differentiation is studied. The processes in question are simulated using Monte Carlo generators Pythia and Tauola. Simulation outputs are compared with calculated theoretical results. 1

The eukaryotic stress response involves translational suppression of non-housekeeping proteins, and the sequestration of unnecessary mRNA transcripts into stress granules (SGs). This process is dependent on mRNA binding proteins (RBPs), such as T- cell intracellular antigen (TIA-1). RBPs interact with unnecessary mRNA transcripts through prion and poly-glutamine like domains, and their aggregation mirrors proteins linked to neurodegenerative diseases. Recent advances in molecular genetics emphasize the importance of SG biology in disease by associating multiple RBPs linked to SGs with neurodegenerative disease. The major difference between SG proteins and aggregation prone proteins in neurodegeneration is that aggregation of SGs is transient and rapidly reverses when the stress is removed. In contrast, aggregates associated with disease are stable and accumulate over time. This study identifies overabundant SGs as a novel pathology in Alzheimer's disease and related tauopathies. The data suggest that TIA-1 is intimately linked to tau pathogenesis, acting as a modifier of tau aggregation and associated toxicity. TIA-1 is present in a protein complex with tau protein including hyper-phosphorylated and misfolded tau. The expression of WT or P301L mutant tau increases the formation and size of TIA-1 positive SGs, and the localization and dynamics of these SGs are altered. Conversely, the expression of TIA-1 increases the formation and stabilization of phospho- and misfolded tau inclusions, as well as visible alterations in microtubule morphology, perhaps reflecting a loss of tau function. The data further show that co-expression of TIA-1 and tau leads to dendrite shortening, increases in caspase cleavage, and apoptosis in primary neurons, suggesting that an interaction between TIA-1 and tau results in neurotoxicity. This toxicity is SG-dependent and is rescued by microtubule stabilizing drugs. The results of this thesis research suggest that the aggregation of tau may proceed through the SG pathway, with SG formation accelerating the pathophysiology of tau aggregation. These studies propose that these tau aggregates serve as a nidus for further accelerated aggregation of SGs, leading to formation of long-lived pathological SG.