La thèse décrit une étude de l'état final en paire de leptons tau dans le mode de désintégration semi-leptonique en muons et hadrons en utilisant des données proton-proton collisions à une énergie de centre de masse de 7 TeV avec le détecteur CMS au CERN Large Hadron Collider. La performance de l'algorithme de reconstruction et d'identification des leptons tau est étudiée en utilisant un échantillon de données de collisions proton-proton à $ \ sqrt $ = 7 TeV, ce qui correspond à une luminosité intégrée de 36 pb $ ^ {-1} $. Les leptons tau qui se désintègrent en un seul hadron chargé, avec ou sans hadrons neutres sont reconstruits à l'aide de la technique dite du flot de particules pour la reconstruction des objets en utilisant un nouvel algorithme adapté aux leptons tau et appelé le Hadrons Plus Strips (HPS) qui utilise le trajectographe et le calorimètre électromagnétique de CMS. L'efficacité de l'algorithme de reconstruction est mesurée en utilisant les leptons taus produits lors de la désintégration de bosons Z. Le taux de mauvaise identification de leptons tau se désintégrant de manière hadronique pour les jets produits en association avec un boson W est également déterminé. La première mesure inclusive de production Z $ \ rightarrow \ tau \ tau $ dans les collisions pp au le LHC est présentée dans les états finals muon+jets en utilisant un échantillon de données de 36 pb $ ^ {-1} $. La section efficace mesurée est en bon accord avec les prédictions QCD à l'ordre doublement suivant l'ordre dominant (NNLO). Après avoir identifié le boson Z dans le mode de désintégration di-tau, une recherche inclusive de bosons de Higgs neutres du modèle supersymétrique standard minimal (MSSM) dans les collisions pp est réalisée à une énergie dans le centre de masse de 7 TeV. Les résultats sont basés sur un échantillon de données correspondant à une luminosité intégrée de 36 pb $ ^ {-1} $ et de 4,6 $ fb ^ {-1} $ enregistré par l'expérience CMS dans l'année 2010 et 2011 respectivement. La recherche utilise les désintégrations de bosons de Higgs en paire de leptons tau. Aucun excès n'est observée dans le spectre de masse invariante de paires de leptons tau. Les limites supérieures sur le produit de la section efficace de production de boson de Higgs par le rapport de branchement de la désintégration en paire de leptons tau en fonction de la masse du boson de Higgs pseudoscalaire permettent de donner des limites strictes dans l'espace des paramètres du MSSM. / The thesis describes a study of the tau-pair final state in the semi-leptonic decay mode into muon and hadrons using proton-proton collisions data at a center-of-mass energy of 7 TeV using the CMS detector at the CERN Large Hadron Collider. The performance of tau-lepton reconstruction and identification algorithm is studied using a data sample of proton-proton collisions at $\sqrt{s}$ = 7 TeV, corresponding to an integrated luminosity of 36 pb$^{-1}$. The tau leptons that decay into one charged hadron with or without the association of neutral hadrons is reconstructed using Particle-Flow object reconstruction technique with a novel tau identification algorithm called the Hadron Plus Strips (HPS) algorithm in the CMS tracker and electromagnetic calorimeter. The reconstruction efficiency of the algorithm is measured using $\tau$ leptons produced in Z-boson decays. The hadronically decaying tau lepton misidentification rate for jets produced in association with a W boson is also determined. The first measurement of inclusive Z$\rightarrow\tau\tau$ production in pp collisions at the LHC is presented in muon+hadrons final state using a data sample of 36 pb$^{-1}$. The measured cross-section is in good agreement with the next-to-next-to-leading order (NNLO) QCD prediction. After establishing the Z boson in di-tau decay mode, an inclusive search for neutral minimal supersymmetric standard model (MSSM) Higgs bosons in pp collisions is performed at a center-of-mass energy of 7 TeV. The results are based on a data sample corresponding to an integrated luminosity of 36 pb$^{-1}$ and 4.6 fb$^{-1}$ recorded by the CMS experiment in the year 2010 and 2011 respectively. The search uses decays of the Higgs bosons to tau pairs. No excess is observed in the tau-pair invariant-mass spectrum. The resulting upper limits on the Higgs boson production cross-section times the branching fraction to tau pairs, as a function of the pseudoscalar Higgs boson mass, yield stringent bounds in the MSSM parameter space.

L'objectif de ce projet est d'élaborer des composés capables d'interagir avec des processus biologiques impliquant des associations protéines-protéines, soit pour les inhiber, soit pour les marquer. Deux cibles protéiques impliquées dans la maladie d'Alzheimer et formant des fibres amylogènes sont envisagées : la protéine tau et le peptide Aβ40. Notre conception des inhibiteurs consiste à présenter de façon multimérique des composés biologiquement actifs (peptides et molécules organiques) sur un châssis moléculaire, la dicétopiperazine. L'activité biologique de nos composés est évaluée par des tests in vitro et in vivo. Un autre aspect du projet est la conception, la synthèse et la caractérisation d'un peptidomimétique des fibres de la protéine tau. / The aim of our project is to synthesize compounds able to interact with biological processes involved in protein-protein interactions. Two amyloidogenic proteins involved in Alzheimer's disease have been chosen: tau protein and Aβ40 peptide. Our approach is based on the multimeric presentation of biological compounds (peptides and organic compounds) and our inhibitors are designed from a diketopiperazine scaffold. The biological activity of our compounds is evaluated in vivo and in vitro. Other part of the project is the design, synthesis and characterization of compounds able to mimic Tau fibers.

Dans cette thèse, je présente ma contribution à la recherche du boson de Higgs du Modèle Standard dans son canal de désintégration en deux leptons taus dans le sous-canal τlepτhad. J’ai contribué aux différentes étapes de cette analyse. Premièrement, j’ai travaillé sur le développement du framework utilisé pour produire les fichiers d’analyse qui contiennent les informations nécessaires à cette étude. J’ai également participé au développement du framework utilisé pour introduire les prédictions des bruits de fond pour ce canal, tester l’accord entre ces prédictions et les données d’ATLAS, et à la production des fichiers utilisés dans l’étude statistique finale. J’ai également travaillé sur le modèle statistique, qui prend en compte les erreurs statistiques et systématiques, pour en extraire une mesure de la force du signal pour ce canal du couplage du Higgs aux leptons. Ma contribution à l’amélioration de la reconstruction d’un tau hadronique, à l’aide des algorithmes qui identifient les traces de conversion des photons provenant de la désintégration des pions neutres, est également détaillée. / In this thesis, I show my contribution to the search for the Standard Model Higgs Boson decaying into two tau leptons in the tlepthad sub-channel. I contributed to the different stages of this analysis. First, I worked on the development of the framework used to produce analysis files that contain the information necessary for this study. I also participated in the development of the framework used to introduce the predictions of the background for that channel, test the agreement between the predictionsand the ATLAS data, and on the production of files used in the final statistical analysis. I also worked on the statistical model, which takes into account the statistical and systematic errors to extract a measure of the signal strength for the Higgs coupling channel to leptons. My contribution to the improvement of reconstruction of a hadronic tau, using algorithms that identify photon conversion traces from the decay of neutral pions, is also detailed.

Previous studies showed that memantine inhibits tau hyperphosphorylation in vitro. In this study, phosphorylated tau (P-tau) and total tau (T-tau) were measured before and after 6 month treatment with memantine in 12 subjects ranging from normal cognition with subjective memory complaints, through mild cognitive impairment to mild Alzheimer's disease. Thirteen non-treated individuals served as controls. Treatment was associated with a reduction of P-tau in subjects with normal cognition. No treatment effects were seen among impaired individuals, suggesting that longer treatment time may be necessary to achieve biomarker effect in this group.

No description available.

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

Bakgrund: Alzheimers sjukdom (AD) är neurodegenerativ och kännetecknas framför allt av det tidiga symtomet minnesförlust. De patologiska skadorna i hjärnan utmärks av senila plack och neurofibrillära nystan (NFTs). Senila plack består av peptiden amyloid-b (Ab) och NFTs innehåller proteinet tau. Ab har länge stått i fokus när det kommer till patogenesen vid AD och forskning kring behandlingsstrategier mot sjukdomen har länge riktat sig mot denna peptid, men än så länge utan lyckade resultat. Mer fokus har riktats till tau och i nuläget finns det ett antal tau-riktade behandlingsstrategier under utveckling och tau-immunoterapi är en av dessa. Syfte: Idag finns det inte någon behandling som botar AD vilket betyder att det är viktigt att hitta nya behandlingsstrategier mot sjukdomen. Tidigare studier tyder på att tau är ett potentiellt mål för behandling mot AD och syftet med detta arbete var därför att undersöka om tau-immunoterapi är en möjlig behandlingsstrategi vid AD. Metod: Sekundärdata samlades in från databasen PubMed. Datan granskades och bedömdes som användbar eller inte. Detta resulterade i att sju orginalartiklar valdes till arbetet, sex studier i djurmodeller och en klinisk studie.  Resultat: Studierna i djurmodellerna visade att tau-immunoterapi reducerade patologiskt tau och i hälften av studierna observerades även en förbättring av de kliniska symtomen. Den kliniska studien visade att AADvac1 är säkert och ansågs vara en lovande kandidat för vidare studier. Slutsats: Resultaten från studierna visar att tau-immunoterapi är en lovande behandlingsstrategi vid AD. Trots detta krävs det fler kliniska studier som undersöker tau-immunoterapi för att säkerställa om behandlingen har någon klinisk effekt på patienter med AD eller inte.

Questa tesi presenta la misura della produzione del bosone di Higgs all’interno del Modello Standard nel decadimento H → ττ con particolare enfasi allo stato finale in cui uno dei due τ decade adronicamente e l’altro decade leptonicamente (canale H → ττ → τlepτhad). L’analisi utilizza un campione di dati corrispondenti a 36.1 fb−1 registrati dal rivelatore ATLAS durante il Run 2 nel periodo di presa dati 2015 e 2016 ad un’energia nel centro di massa √s = 13 TeV. Il decadimento del bosone di Higgs in una coppia di leptoni τ `e attualmente l’unico modo possibile per misurare l’accoppiamento di Yukawa tra il bosone di Higgs ed i lep- toni. In questo contesto, lo stato finale H → ττ → τlepτhad ha un ruolo importante dovuto all’alta frazione di decadimento e ad un fondo moderato. L’analisi `e basata su una selezione ottimizzata per aumentare la sensitivit`a del segnale considerando le caratteristiche cinematiche dei principali canali di produzione del bosone di Higgs: la fusione di gluoni e la fusione di bosoni vettori. I risultati sono stati estratti da un profile likelihood fit sulla massa della coppia di τ e saranno presentati considerando prima solamente lo stato finale τlepτhad e poi con- siderando tutti i possibili stati finali derivanti dai decadimenti dei due τ. Considerando il fit combinato, sono stati misurati la signal strength μ = 1.08+0.175(stat.)+0.265(syst.) ed il −0.171 −0.222 prodottodellesezionid’urtoperlefrazionididecadimentoσHττ(VBF) = 0.28+0.09(stat.) −0.09 +0.10(syst.) pb, σHττ(ggH) = 2.97+1.03(stat.)+1.67(syst.) pb. I risultati sono in buon ac- −0.09 −1.01 −1.23 cordo con le previsioni del Modello Standard all’interno delle incertezze stimate. La significativit`a osservata (attesa), considerando solo i dati raccolti nel Run 2, `e 4.36 (4.13) deviazioni standard rispetto all’ipotesi di solo fondo. Dalla combinazione dei dati raccolti nel Run 1 e nel Run 2 si ottiene una significativita` di 6.37 (5.43), che `e superiore alla soglia di 5 deviazioni standard stabilita per l’osservazione di un nuovo processo.

"Alzheimer’s disease (AD) is the most widespread neurodegenerative disorder, affecting approximately 20 million people worldwide. AD pathology is primarily characterized by the formation of extracellular amyloid plaques resulting from the aggregation of insoluble amyloid-beta 1-42 (A-beta), and neurofibrillary tangles (NFT’s) resulting from intracellular aggregation of hyperphosphorylated tau protein. The current FDA-approved AD treatments do not stop or reverse neurodegeneration, but only treat the symptoms by increasing acetylcholine neurotransmitter. Our laboratory is attempting to provide an additional therapeutic approach by using neurotrophic factors to block apoptosis or to restore neurons. We previously demonstrated that, in an in vitro model for AD, hEPN-1 neurotrophic factor mimetics can block synthetic A-beta-induced neuronal cell death when added to cultures, presumably by blocking caspase activation. In this thesis, we extended these findings to study the effect of A-beta and hEPN-1 on tau hyperphosphorylation (as measured by immunoblots with phospho-specific antibodies) and nuclear DNA fragmentation (as measured by TUNEL staining), both in vitro and in vivo in AD transgenic mice. We found that A-beta induces the hyperphosphorylation of tau in both mouse N2a and human SHSY neuronal cells, and that hEPN-1 may lower this phosphorylation in N2a cells. Furthermore, we discovered that hEPN-1 can reduce nuclear DNA fragmentation when added both simultaneously to A-beta and 3 and 6 hours post A-beta addition. Finally, in vivo hEPN-1 may lower both tau hyperphosphorylation and caspase-7 related protein (C7RP) in AD transgenic (Tg) mice. The overall results validate our in vitro AD model, show the efficacy of hEPN-1 at blocking A-beta-induced DNA fragmentation even when added post-insult, and show that hEPN-1 may work in an AD mouse model. However, more studies must be conducted to confirm these findings. "

Neurons are among the most highly polarized cells in the human body. This polarization allows the neuron to participate in the transfer of chemical and electrical signals which are crucial to the survival of the organism. As part of polarization, each neuron develops a dendritic arbor and an axon. To ensure the survival of the cell, materials synthesized in the cell body must be trafficked through the axon for delivery throughout ultimately ending at the synaptic termini. The bulk of this cargo transport is microtubule-based fast axonal transport which is molecular motor mediated and tightly regulated though many pathways. Motor based transport is established early in development and maintained for the life of the cell. The kinesin motor protein family plays an integral role in fast axonal transport and the regulation of these motors is essential to proper cargo delivery. Regulation occurs through auto-inhibition, motor interactions with microtubule associated proteins (MAPs) and complex signaling pathways which control the post-translational modification of MAPs, the microtubule track and the motors. The disruption of cargo transport is linked to neurodegeneration and disease state development. Of particular interest in this process is the MAP Tau which has been implicated in a number of neurodegenerative diseases including Alzheimer’s Disease. Tau is expressed at all stages of neural development and has been shown to participate in signaling cascades, modulate microtubule dynamics and preferentially inhibit kinesin-1 motility. Though Tau is involved in these processes, the non-disease state regulation of this MAP and it’s inhibition of kinesin-1 is not well understood. Tau has been shown to bind the microtubule surface in a static-diffusive state equilibrium which differs with isoform and lattice. Previous work demonstrates that the static state is more inhibitory to kinesin-1 than the diffusive state. These different binding behaviors with their different effects on kinesin-1 motility, suggest that cellular regulation of Tau’s static-diffusive binding equilibrium may control inhibition of kinesin-1 and that structural changes may underlie Tau binding to the microtubule surface. Cellular regulation of Tau’s structure and therefore its behavior on the microtubule surface points to a means by which Tau is regulated in the non-disease state. Additionally, this would highlight how early changes lead to disease state development. Using a combination of molecular biology, biochemical techniques and imaging strategies including Total Internal Reflection Fluorescence, single molecule Fluorescence Resonance Energy Transfer (smFRET) and Alternating Laser Excitation, we show that Tau’s static-diffusive state equilibrium is regulated by non-disease state phosphorylation at tyrosine 18. Phospho-mimetics are shifted towards diffusive binding and have decreased affinity for the microtubule surface which in turn reduces inhibition of kinesin-1 motility. These results further demonstrate that Tau undergoes long range structural change while bound to the microtubule surface. We performed smFRET assays and found that Tau binds the microtubule surface in distinct conformations which underlie static and diffusive binding. This work ties the regulation of Tau’s structure and binding behavior to its function and paves the way for our understanding of how cellular regulation acts on multiple levels to fine tune axonal transport.