Dynamical mass estimates down to the planet-mass regime can help to understand planet formation. We present Atacama Large Millimeter/submillimeter Array (ALMA) 1.3 mm observations of FW Tau C, a proposed similar to 10M(Jup) planet-mass companion at similar to 330 au from the host binary FW Tau AB. We spatially and spectrally resolve the accretion disk of FWTau C in (CO)-C-12 (2-1). By modeling the Keplerian rotation of gas, we derive a dynamical mass of similar to 0.1 M-circle dot. Therefore, FW Tau C is unlikely a planet, but rather a low-mass star with a highly inclined disk. This also suggests that FW Tau is a triple system consisting of three similar to 0.1. M-circle dot stars.

Perdas embrionárias e alterações gestacionais são frequentemente observadas em prenhezes de embriões bovinos manipulados in vitro. Sabe-se que tais anormalidades são resultantes de alterações epigenéticas ocasionadas pela manipulação dos gametas e/ou do embrião durante as técnicas de reprodução assistida (ARTs), com destaque para as técnicas de fecundação in vitro (FIV) e da clonagem por transferência nuclear de células somáticas (SCNT). Tais alterações resultam em distúrbios no desenvolvimento do concepto em algum momento crítico entre a fertilização e o parto, fornecendo bons modelos de estudos sobre a fisiopatologia de perdas embrionárias e dos distúrbios de desenvolvimento. Caracterizam-se como momentos críticos após a transferência do embrião (TE) o desenvolvimento embrionário no útero, o reconhecimento materno da gestação, a placentação e o desenvolvimento da placenta e do feto, os quais tem de ser transpassados sem nenhuma falha, permitindo um desenvolvimento normal do concepto até o termo. Sendo assim, o presente trabalho abordou três fases distintas do amplo período gestacional em prenhezes por ARTs. O Estudo 1 foi realizado durante o período peri-reconhecimento materno da gestação e objetivou descrever a abundância de expressão de genes estimulados pelo interferon tau (ISGs) de células mononucleares do sangue periférico (PBMCs) maternas em gestações oriundas de ARTs no primeiro mês de gestação; o Estudo 2 compreendeu os primeiros 35 dias de gestação e objetivou descrever as mudanças morfológicas e vasculares do complexo útero-concepto-ovário e o estímulo à expressão de ISGs em PBMCs em gestações de conceptos clonados por SCNT com diferentes fenótipos de desenvolvimento, sendo esses denominados gestação anembrionada e CL persistente; e o Estudo 3 foi conduzido durante o período pré-parto e objetivou descrever as alterações na produção de esteroides sexuais e corticosteroides em gestações produzidas por ARTs. Três hipóteses foram testadas: (1) Gestações de conceptos clonados por SCNT apresentam uma baixa e mais tardia estimulação de ISGs em PBMCs maternas quando comparadas com gestações de conceptos produzidos por FIV e IA; (2) O concepto clonado por SCNT apresenta um menor estímulo sobre mudanças morfológicas e vasculares do complexo útero-ovário e ISGs em PBMCs maternas durante os primeiros 35 dias de gestação, quando comparado com conceptos oriundos de IA; e (3) Gestações de embriões oriundos de ARTs apresentam alterações na dinâmica esteroidogênica no pré-parto quando comparados com gestações de IA. No estudo 1 foram coletadas amostras de sangue de gestações produzidas por inseminação artificial (IA), FIV e clonagem por SCNT, nos dias 15, 18, 20, 22, 24, 26, 28 e 31 pós-ovulação e foi realizada mensuração da abundância de transcritos de ISGs (OAS1 e ISG15) em PBMCs maternas. No estudo 2, gestações produzidas por IA e clonagem por SCNT, foram submetidas a escaneamentos ultrassonográficos dos ovários, útero e concepto a cada 3 dias do dia 14 ao 35 (dia 0 = ovulação) e amostras de sangue foram coletadas nos dias 15, 18, 20, 22, 24, 26, 28 e 31 para mensuração da abundância de transcritos de ISGs (OAS1 e ISG15) em PBMCs maternas. No estudo 3, foram coletadas amostras de sangue no último mês em gestações naturais, oriundas de FIV e de clonagem por SCNT para análise hormonal de 10 esteroides utilizando o método de espectrometria de massas multi-hormonal de alta resolução LC-MS/MS. O primeiro estudo mostrou semelhanças na expressão de genes estimulados pelo IFNT em gestações oriundas de ARTs e produzidas por IA. Entretanto, a estimulação nas gestações oriundas de ARTs aparentou ser quatro dias mais prolongada, sugerindo uma maior funcionalidade do trofectoderma em conceptos oriundos de ARTs. O segundo estudo demonstrou um aumento na expressão de ISGs em PBMCs maternas tanto em gestações de conceptos normais quanto em anormais, justificando a manutenção da função luteal mesmo na ausência de detecção do concepto por ultrasonografia. No terceiro estudo, demonstrou-se alterações na esteroidogênese nas gestações de embriões FIV e clonados no último mês de gestação, sendo essas compatíveis com a hiperativação da enzima aromatase durante todo o último mês de gestações oriundas de FIV e hiperativação das enzimas P450C11 e P450C21 trinta dias antes do parto em gestações oriundas de clonagem por SCNT. O presente estudo concluiu que conceptos oriundos de FIV e clonagem por SCNT apresentam um prolongamento no estímulo de ISGs pelo IFNT, conceptos clonados anormalos apresentam estímulo de ISGs, o que justifica a manutenção da função luteal, e, por fim, a cascata esteroidonênica que culmina com o parto apresenta-se alterada em gestações oriundas de FIV e clonagem por SCNT. / Pregnancy losses and gestational abnormalities are frequently observed in pregnancies from in vitro produced embryos in bovines. It is known that these abnormalities are due to epigenetic changes from the manipulation of gametes and/or embryo during the use of assisted reproduction techniques (ARTs), especially for the in vitro fertilization (IFV) and cloning by somatic cells nuclear transfer (SCNT). These changes results in disturbances of conceptus development in any critical stage between the fertilization and parturition, which provides good models for the study of physiopathology of embryo losses and disturbances of development. Critical stages after the embryo transfer (ET) to the uterus are characterized as the maternal recognition of pregnancy, placentation, and fetal-placental development, which needs to be surpassed without failures, in order to develop a normal conceptus until term. Therefore, the present work approached three distinct phases of the wide gestational period in pregnancies from ARTs. The Study 1 was conducted during the maternal peri-recongnition of pregnancy period and aimed to describe the expression of interferon stimulated genes (ISGs) in maternal peripheral blood mononuclear cells (PBMCs) in pregnancies derived of ARTs; the Study 2 comprise the first 35 days of pregnancy and aimed to describe morphological and vascular changes of the complex uterus-ovaries-conceptus, as well as the expression of ISGs in maternal PBMCs in pregnancies of conceptus cloned by SCNT with different phenotypes of development, denominated as anembryonic gestation and persistent CL; the Study 3 was conducted during the pre-partum period and aimed to describe changes in the production of sexual steroids and corticosteroids during the last month of pregnancies derived of ARTs. Three hypothesis were tested: (1) Pregnancies of conceptus cloned by SCNT presented a decrease and delay in the stimulation of ISGs in maternal PBMCs when compared with conceptuses produced by IFV and AI; (2) Stimulus from the conceptus for changes in the morphology and vasculature of the the uterus-ovarian complex, detected by ultrasonography in B and Doppler modes, and the stimulation of ISGs in maternal PBMCs during the first 35 days of pregnancy of conceptus cloned by SCNT are less intense when compared with conceptus derived from AI; and (3) Pregnancies derived of ARTs present changes in the steroidogenic dynamics in the pre-partum, when compared with pregnancies derived from AI. In Study 1 blood samples were collected from pregnancies produced by AI, IVF, and cloning by SCNT, at days 15, 18, 20, 22, 24, 26, 28, and 31 post-ovulation for the measurement of abundance of transcripts of ISGs (OAS1 and ISG15) in maternal PBMCs. In Study 2, pregnancies derived of AI and cloning by SCNT, were submitted to ultrasonographic scans for the evaluation and description of morphological and vascular changes in ovaries, uterus, and conceptus every 3 days from day 14 to 35 (day 0 = ovulation) and blood samples were collected on days 15, 18, 20, 22, 24, 26, 28 e 31 for the measurement of the abundance of transcripts of ISGs (OAS1 and ISG15) in maternal PBMCs. In Study 3, blood samples were collected during the last month of pregnancies naturally conceived, derived of IVF, and cloned by SCNT for the analysis of 10 steroids using the method of mass spectrometry high resolution LC-MS/MS. The first study showed similarities in the ISGs expression stimulation in pregnancies derived of ARTs and AI. However, the stimulation in the ART derived pregnancies was apparently 4 days longer, suggesting a greater placental function in conceptus derived of ARTs. The second study showed an increase in ISG expression in both normal and abnormal conceptus development, which justifies the maintenance of CL in the absence of a conceptus structure detected by ultrasonography. In the third study, was detected changes in the steroidogenesis of pregnancies derived of IFV and cloning by SCNT during the last month of pregnancy, which are compatible with the hyperactivation of the aromatase enzyme during the last month of IFV derived pregnancies, and hyperactivation of the enzymes P450C11 and P450C21 thirty days before parturition in pregnancies derived of cloning by SCNT. The present study concludes that conceptus derived of IFV and cloning by SCNT present a prolonged stimulus of ISGs, cloned conceptus with anomalous development presents a stimulus of ISGs, which justifies the CL function maintenance, and, ultimately, the steroidogenic cascade that culminates with the term is altered in pregnancies derived from IFV and cloning by SCNT.

Fluorodeoxyglucose Positron Emission Tomography (FDG PET) and Magnetic Resonance Imaging (MRI) are commonly used in a clinical setting as an examination in Alzheimer’s Disease (AD) patients. FDG PET is an imaging tool to evaluate hypometabolism; meanwhile, the MRI observes the brain volume. However, it is still unclear which examination better reflects the tau tangles, which have been known as the hallmark’s pathology of AD. Therefore, this study was conducted to compare FDG PET and MRI in assessing tau pathology in AD, by utilizing a database from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). The presence of tau tangles was confirmed by using the Tau-PET images. In total, 275 cognitively impaired subjects were included as well as a subgroup of 147 subjects with positive amyloid status. Based on the analysis, it was observed that higher Tau-PET is significantly associated with FDG PET hypometabolism and MRI atrophy. A similar result was also seen in the amyloid positive subgroups. By comparing the spearman’s correlation coefficients, it was found that that the correlation was stronger between Tau PET and FDG PET (r=-0.414, p<0.001, and r=-0.475, p<0.001 in the positive amyloid subgroup) compared to Tau-PET and MRI (r=-0.331, p<0.001 and r=-0.440, p<0.001 in the positive amyloid subgroup). Inconclusion, FDG PET better reflects the tau pathology compared to MRI in AD.

Continuous time Markov chains are often used in the literature to model the dynamics of a system with low species count and uncertainty in transitions. In this paper, we investigate three particular algorithms that can be used to numerically simulate continuous time Markov chain models (a stochastic simulation algorithm, explicit and implicit tau-leaping algorithms). To compare these methods, we used them to analyze two stochastic infection models with different level of complexity. One of these models describes the dynamics of Vancomycin-Resistant Enterococcus (VRE) infection in a hospital, and the other is for the early infection of Human Immunodeficiency Virus (HIV) within a host. The relative efficiency of each algorithm is determined based on computational time and degree of precision required. The numerical results suggest that all three algorithms have similar computational efficiency for the VRE model due to the low number of species and small number of transitions. However, we found that with the larger and more complex HIV model, implementation and modification of tau-Leaping methods are preferred.

Les Tauopathies sont un ensemble de maladies neurodégénératives caractérisées par l’agrégation de la protéine Tau dans les neurones, astrocytes et autres types cellulaires. Toutefois, les mécanismes sous-tendant la présence de Tau dans les astrocytes et les conséquences de Tau sur les astrocytes restent peu connus. L’objectif de ce projet a été d’étudier l’interaction entre les neurones porteurs de Tau soluble et/ou agrégée et les astrocytes avoisinants. Nous avons généré trois modèles de Tauopathie par transfert de gènes et avons caractérisé la pathologie Tau neuronale et astrocytaire par histologie et biologie moléculaire. Dans l’hippocampe, la surexpression de l’isoforme mutante hTAUP301L ou d’une forme pro-agrégeante hTAUProAggr, mais pas celle de la protéine sauvage hTAUWT, a entraîné la formation progressive d’agrégats aussi bien dans les neurones que dans les astrocytes. Nous avons montré que les inclusions astrocytaires de Tau étaient secondaires à une pathologie neuronale par différents schémas expérimentaux. En utilisant des vecteurs spécifiques de types cellulaires, nous avons également démontré le transfert bi-directionnel d’espèces de Tau entre neurones et astrocytes. Curieusement, nous avons observé une perte astrocytaire uniquement dans le subiculum du groupe hTAUWT qui ne présente pas d’inclusions astrocytaires de Tau. Nos données ont montré que, dans nos modèles, la tauopathie astrocytaire est secondaire à la présence de dégénérescences neurofibrillaires et ne résulte pas d’une agrégation liée à une surexpression réactionnelle de Tau endogène dans l’astrocyte. De plus, des amorces de Tau neuronales peuvent promouvoir l’agrégation de Tau astrocytaire et la Tau astrocytaire peut être transférée aux neurones. Par ailleurs, si les agrégats de Tau paraissent plutôt bénins pour les astrocytes, les conséquences fonctionnelles d’une telle astrogliopathie restent encore à évaluer. / Tauopathies are neurodegenerative diseases characterized by the aggregation of Tau protein in neurons, astrocytes and other cell types. However, the mechanisms leading to the presence of Tau aggregates in astrocytes and the consequences of Tau on astrocytes are poorly understood. The aim of this project was to study the relationship between neurons bearing soluble and/or aggregated Tau species and their neighboring astrocytes.We thus generated three gene transfer-based Tauopathy models and used immunohistological and molecular biology methods to characterize Tau pathology in neurons and astrocytes.In the hippocampus, overexpression of mutant hTAUP301L or that of a pro-aggregating variant hTAUProAggr, but not that of wild-type Tau hTAUWT, led to a gradual increase in the formation of aggregates not only in neurons but also in astrocytes. Using different experimental paradigms, we showed that astrocytic Tau was secondary to neuronal pathology. Using cell type-specific AAV- Tau vectors, we further demonstrated the bi-directional transfer of Tau species between neurons and astrocytes. Interestingly, we observed astrocyte loss in the subiculum only in the hTauWT group in the absence of any astrocytic Tau inclusions.Our data show that astroglial tauopathy is secondary to the presence of neurofibrillary tangles in our models and does not result from aggregation of overexpressed endogenous Tau in astrocytes. In addition, neuronal Tau seeds can promote the aggregation of astrocytic Tau and astrocytic Tau can be transferred to neurons. Furthermore, if Tau aggregates appear fairly innocuous for astrocytes, the functional consequences of such astroglial tauopathy still remain to be further assessed.

Le modèle standard des interactions entre particules élémentaires est la réalisation exceptionnelle des quarante dernières années d'activité expérimentale et théorique en physique des particules. Depuis la découverte du boson de Higgs en 2012 par les expériences du Large Hadron Collider (LHC), la mesure précise est devenue le défi dans les expériences de physique des hautes énergies.De nombreuses usines de Higgs électron-positon avec une précision améliorée sur les mesures de largeur totale de Higgs ont été proposées, y compris le collisionneur linéaire international (ILC) et le collisionneur à électrons positrons circulaires (CEPC).Le programme de physique de Higgs à réaliser dans les futurs collisionneurs $ e^{+}e^{-} $ a été évalué et son degré de précision de nombreux couplages est estimé à des niveaux de pourcentage ou de sous-pourcentage.Afin d'atteindre cette précision, l'utilisation de l'algorithme de flux de particules (PFA) est devenue le paradigme de la conception de détecteurs pour la frontière à haute énergie. L'idée clé est de reconstruire chaque particule d'état finale dans les sous-détecteurs les plus adaptés, et de reconstruire tous les objets physiques au-dessus des particules d'état finales. Les détecteurs orientés à PFA ont une grande efficacité dans la reconstruction d'objets physiques tels que les leptons, les jets et l'énergie manquante.L'identification du lepton est essentielle pour les programmes de physique, en particulier pour la mesure précise du boson de Higgs.Dans cette thèse, une identification par lepton basée sur PFA (Lepton Identification pour calorimètre à haute granularité) a été développée pour des détecteurs utilisant des calorimètres à haute granularité.Utilisation de la géométrie du détecteur conceptuel pour le CEPC avec granularité calorimétrique typique de 1000 et 400 cellules / dm³ pour les parties électromagnétiques et hadroniques respectivement, et les échantillons de particules chargées uniques d'énergie supérieure à 2 GeV, LICH identifie les électrons ou les muons avec des rendements supérieurs à 99,5% et contrôle le taux de désinscription du hadron aux muons ou aux électrons 1% ou 0.5 %. Réduisant la granularité du calorimètre de 1 ou 2 ordres de grandeur, la performance d'identification du lepton est stable pour les particules avec E > 2 GeV Appliquée à des événements $eeH$ ou $ mumu H$ simulés à $ sqrt{s} = 250 $ GeV, la performance d'identification du lepton est cohérente avec le cas d'une seule particule: l'efficacité d'identifier tous les leptons de haute énergie dans un événement est de 95,5 $ sim $ 98,5 %. Contrairement aux muons et aux électrons, les $ au $ 's sont des objets de physique extrêmement intrigants car leur couplage de Yukawa au boson de Higgs est relativement important. En raison de leurs riches produits de désintégration, des propriétés telles que les paramètres Higgs CP et EW dans une Z-factory. Les produits $ au $-decay dans les collisionneurs de haute énergie sont étroitement collimatés et ont une faible multiplicité, fournissant d'excellentes signatures à sonder. Dans cette thèse, les canaux H $ightarrow $ $ au au $ sont analysés dans différents modes de désintégration Z avec le contexte SM pris en compte. La précision finale combinée de $ sigma imes Br (Hightarrow au au) $ devrait être de 0.89 %. / The Standard Model of elementary particle interactions is the outstanding achievement of the past forty years of experimental and theoretical activity in particle physics. Since the discovery of the Higgs boson in 2012 by the experiments at the Large Hadron Collider (LHC), the precise measurement has become the issue in high energy physics experiments.Many electron-positron Higgs factories with better accuracy on the Higgs total width measurements have been proposed, including the International Linear Collider (ILC) and the Circular Electron Positron Collider (CEPC).The Higgs physics program to be carried out at the future $e^{+}e^{-}$ colliders have been be evaluated and its extent of the precision of many of couplings are estimated to percent or sub-percent levels.In order to achieve this precision, the Particle Flow Algorithm (PFA) has become the paradigm of detector design for the high energy frontier. The key idea is to reconstruct every final state particle in the most suited sub-detectors, and reconstruct all the physics objects on top of the final state particles. The PFA oriented detectors have high efficiency in reconstructing physics objects such as leptons, jets, and missing energy.The lepton identification is essential for the physics programs, especially for the precise measurement of the Higgs boson.In this thesis, a PFA based lepton identification (Lepton Identification for Calorimeter with High granularity) has been developed for detectors using high granularity calorimeters. Using the conceptual detector geometry for the CEPC and single charged particle samples with energy larger than 2 GeV, LICH identifies electrons/muons with efficiencies higher than 99.5% and controls the mis-identification rate of hadron to muons/electrons to better than 1%/0.5%. Reducing the calorimeter granularity by 1-2 orders of magnitude, the lepton identification performance is stable for particles with E > 2 GeV. Applied to fully simulated eeH/$mumu$ H events, the lepton identification performance is consistent with the single particle case: the efficiency of identifying all the high energy leptons in an event, is 95.5-98.5%.Except for e and $mu$, $tau$s are extremely intriguing physics objects as its Yukawa coupling to the Higgs boson is relatively large. Due to its rich decay products, properties such as the Higgs CP and EW parameters at the Z-factory can be precisely measured. The $tau$ decay in high energy colliders is tightly collimated and low multiplicity, which provide excellent signatures to probe. In this thesis, the H$rightarrow$ $tautau$ channels are analyzed in different Z decay modes with SM background taken into account and the combine final accuracy is expected to be 1.3%.

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

<p>Hyperphosphorylation of the microtubule-associated protein Tau is a major hallmark of Alzheimer’s disease (AD) and other tauopathies. Understanding the protein kinases that phosphorylate Tau is critical for the development of new drugs that target Tau phosphorylation. At present, the repertoire of the Tau kinases remains incomplete, and methods to uncover novel upstream protein kinases are still limited. Here, I apply our newly developed proteomic strategy, fluorescence complementation mass spectrometry (FCMS), to identify novel kinase candidates of Tau. By constructing Tau- and kinase-fluorescent fragment library, I detected 59 Tau-associated kinases, including 23 known kinases of Tau and 36 novel candidate kinases. In the validation phase using in vitro phosphorylation, 15 candidate kinases were successfully expressed and purified, and four candidate kinases, OXSR1, DAPK2, CSK, and ZAP70, displayed the ability to phosphorylate Tau. Furthermore, co-expression of these four kinases along with Tau increased the phosphorylation of Tau in human neuroglioma H4 cells. I demonstrate that FCMS is a powerful proteomic strategy to systematically identify potential kinases that can phosphorylate Tau in cells. Our discovery of new candidate kinases of Tau can present new opportunities for developing AD therapeutic strategies.</p>

Understanding the origin or Electroweak symmetry breaking within the Standard Model was a key motivation for the construction of the Large Hadron Collider (LHC) experiment at CERN. This thesis presents a search for evidence of Higgs boson production in the 4.7 fb−1 of collision data recorded at a centre-of-mass energy of 7 TeV at the ATLAS detector during 2011. This search is focused on signal events in which a Higgs boson is produced in the mass range 100 < mH < 180 GeV/c2 and subsequently decays to a pair of W bosons or a pair of tau leptons to final states with one hadronically decaying tau lepton and one light lepton. After an event selection criteria has been applied, the number of events in this data sample is consistent with the total background estimate and an upper limit is placed on the SM Higgs boson production rate at 95% confidence level. In addition, the prospects for measuring the SM Higgs coupling strength to tau leptons with the associated Higgs production channels and the full LHC dataset are also presented.

Senile plaques (Aβ) and neurofibrillary tangles (tau) are pathological hallmarks of Alzheimer’s disease (AD). If and how the formation of these deposits are mechanistically linked remains mainly unknown. In recent years, the focus has shifted from insoluble protein deposits to soluble aggregates of Aβ and tau. Protofibrils are large soluble Aβ oligomers which were linked to AD by the discovery of the Arctic AβPP mutation. Treatment of young tg-ArcSwe mice with an Aβ protofibril-selective antibody, mAb158, cleared protofibrils, prevented amyloid plaque deposition and protected cultured cells from protofibril-mediated toxicity. This suggests that Aβ protofibrils are necessary for the formation of Aβ deposits. Functional assessment of tg-ArcSwe mice in IntelliCage demonstrated hippocampal-dependent behavioral deficits such as memory/learning impairments, hyperactivity and perseverance behavior. Learning impairments did not correlate to Aβ-measures but to calbindin, which might be a good marker for Aβ-mediated neuronal dysfunction. Splicing of exon 10 in the tau gene differs between human and mouse brain. Exon 10 is part of the microtubule-binding domains which helps to maintain microtubule stability and axonal transport, functions vital to neuronal viability. Axonal transport dysfunction has been proposed as a common pathway of Aβ and tau pathogenesis in AD. Generation of a novel tau mouse model with absence of exon 10 led to age-dependent sensorimotor impairments which may relate to dysfunctions in cerebellum. No tau pathology was evident suggesting that a trigger of tau fibrillization e.g. a human Aβ or tau aggregate is needed. Generation of AβPPxE10 bitransgenic mice with no exon 10 showed lower Aβ plaque burden. Possibly changes in microtubule function lead to altered intracellular AβPP transport and Aβ production. Initiation of tau pathology in AβPPxE10 mice might require a certain type of Aβ-aggregates which is not produced or exist at too low concentration in transgenic mouse brain. In summary, the Aβ protofibril-selective antibody was found to be a promising treatment for AD. The IntelliCage system was proven to be useful for functional evaluation of AβPP mice. Exon 10 in tau was shown to affect sensorimotor functions and Aβ pathology in bitransgenic mice by mechanisms that deserve further investigation.