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

Abstract Academic Leadership and Development Academy (ALDA) was instituted by the Tau Lambda-at-Large Chapter Sigma Theta Tau International (STTI). In 2011-2012 ALDA intended goal was to emancipate participants to be able to take professional leadership positions, generate a funded research project, professional networking muscle and collaboration, including publishing in an accredited journal. The purpose of the study was to explore and describe the needs of the fellows enrolled for the 2011-2012 ALDA leadership programme. The word ‘fellow’ refers to all candidates who were selected to participate in the ALDA programme. The programme was tailor-made to develop and prepare professional nurses for middle or high level leadership positions within the academic environment. Four African universities and colleges were involved. The research design was qualitative, exploratory, and descriptive in nature. The target population included all 2011-2012 fellows of the ALDA of the Sigma Theta Tau Lambda-at-Large Chapter Africa. The sample consisted of all 14 fellows of the 2011-2012 ALDA who were involved in programme. This programme was the first of its kind in Africa engineered by ALDA in Africa in 2011. Data gathering was a self-report through naïve sketches. Tesch’s eight steps of data analysis were applied. An independent coder was engaged to improve trustworthiness of the data. The results showed that fellows needed professionalism and recognition; communication and setting the stage; and more collaboration with research expects. At first the programme did not have a clear curriculum content outlined and as such fellows were dissatisfied for some time which affected the progress as expected by both the fellows and the faculty. Faculty refers to experts involved in the programme. However, fellows managed to work cooperatively with one another, thus promoting a social learning environment and providing opportunities of collaborative research studies in the future.

This thesis presents a cross-section measurement of the Z -+ TeTh process performed using the ATLAS detector at the Large Hadron Collider at CERN. The data used were collected at a centre-of-mass energy of 7 TeV during 2010 and corresponds to an integrated luminosity of 36 pb-I. This measurement uses the final state where one T lepton decays leptonically, to an electron or muon, plus neutrinos, and the other T lepton decays hadronically. The "(* / Z -+ a, It and di-boson background processes are estimated using Monte Carlo simulation, the W -+ TV Monte Carlo background prediction is estimated using a semi data-driven method. The multijet background is estimated with a fully data-driven 'ABCD' method using three exclusive control regions built by inverting uncorrelated requirements on the isolation of the electron or muon and the product of the electric charge of the identified electron or muon and hadronically decayed T lepton. The measured cross-sections in each channel are corrected for the individual branching ratios and yield the total cross-section a(Z -+ TT, minv 66 - 116 GeV) = 1142 ± 135.5(stat.) ± 206.2(syst.) ± 40. 19(1umi.) ± 3.6(theo.) pb for the electron channel and a(Z -+ TT, minv 66 - 116 GeV) = 857.6 ± 81.4(stat.) ± 132.5(syst.) ± 30.19(lumi.) ± 2.8(theo.) pb for the muon channel, where the invariant mass of the Z boson is between 66 and 116 GeV. These are in good agreement with the theoretical prediction of960 ± 49.5 pb. Performing a measurement of a well-known Standard Model process using the ATLAS de- tector in this new high energy regime is essential for validating the T lepton identification in particular, which is essential for any new physics search such as H -+ TeTh' A cut-based analysis for the Vector Boson Fusion produced Higgs boson decaying to two T leptons channel is introduced and the possibility of using the more complex analysis technique, the Matrix Element method, to increase sensitivity is discussed.

La Maladie d’Alzheimer est caractérisée par la formation de dégénérescences neurofibrillaires, constituées de protéine Tau anormalement hyperphosphorylée et agrégée. De nombreuses études traitent de possibles stratégies thérapeutiques basées sur l’inhibition de cette polymérisation, et présentent les effets bénéfiques de certaines molécules dont les polyphénols, mais les résultats obtenus jusque là, manquent de données au niveau moléculaire. Ainsi, après avoir synthétisé, une banque de polyphénols de structures différentes, et 3 peptides représentatifs de la région P de phosphorylation de Tau, c’est en suivant une stratégie combinant la RMN et la modélisation moléculaire, que nous avons évalué les paramètres dynamiques du complexe formé. Ce projet nous a apporté des informations en termes d’affinité, et de relations structure/activité et ainsi, de mieux appréhender les mécanismes d’interactions intervenant dans l’agrégation de Tau par les polyphénols. / Alzheimer's disease is characterized by the formation of neurofibrillary tangles constituted by abnormally hyperphosphorylated and aggregated Tau protein. Many studies deal with potential therapeutic strategies based on the inhibition of this polymerization, and show the beneficial effects of some molecules like polyphenols, but the obtained so far results show a lack of data at the molecular level. Thus, after the synthesis of, a library of polyphenols with different structures, and 3 representative peptides of the P2 phosphorylation Tau region, by following a strategy combining NMR and molecular modeling, we have evaluated dynamic parameters of the formed complex. This project has provided us informations in terms of affinity, and structure / activity relationships, and leading us to a better understanding of the mechanisms led to better understand the mechanisms involved in the aggregation Tau inhibition phenomena by polyphenols.

This thesis describes a measurement of the Standard Model Higgs boson coupling to fermions in decays to two τ-leptons, a search for charged Higgs bosons in decays to a τ-lepton and a neutrino, as well as the reconstruction, identification and triggering of hadronically decaying τ-leptons. The data considered are collected by the ATLAS experiment at the Large Hadron Collider. The reconstruction and identification of hadronically decaying τ-leptons in the ATLAS experiment during Run 2 of the Large Hadron Collider are described, and the performance of the τ trigger is measured in events with top–antitop-quark pairs using data from 13 TeV proton–proton collisions, corresponding to an integrated luminosity of 3.2 fb-1, collected in 2015, and 11.5 fb-1, collected in 2016. Hadronically decaying τ-leptons are of importance to many physical processes involving Higgs bosons. The coupling of the Standard Model Higgs boson to fermions is measured in decays to two τ-leptons using 7 TeV data corresponding to an integrated luminosity of 4.5 fb-1, collected in 2011, and 8 TeV data corresponding to an integrated luminosity of 20.3 fb-1, collected in 2012. The signal strength is measured to be μ = 1.4, corresponding to an excess over the background-only model of 4.5σ. Charged Higgs bosons are searched for in decays to a τ-lepton and a neutrino, where the τ-lepton decays hadronically. 13 TeV data corresponding to an integrated luminosity of 14.7 fb-1, collected in 2015 and 2016, are used. No excess over the Standard Model background is observed, and the 95 % confidence-level exclusion limits on σ(pp → [b]tH+) × (H+ → τν) are set to 2.0 pb–8 fb in the range 200–2000 GeV.

Modern computational software is increasingly large in terms of lines of code, number of developers, intended longevity, and complexity of intended architectures. While tools exist to mitigate the problems this type of software causes for the development of functional software, no solutions exist to deal with the problems it causes for performance. This thesis introduces a design called the Software Development Performance Analysis System, or SDPAS. SDPAS observes the performance of software tests as software is developed, tracking builds, tests, and developers in order to provide data with which to analyze a software development process. SDPAS integrates with the CMake build and test suite to obtain data about builds and provide consistent tests, with git to obtain data about how software is changing. SDPAS also integrates with TAU to obtain performance data and store it along with the data obtained from other tools. The utility of SDPAS is observed on two pieces of production software.

Emaranhados neurofibrilares intraneuronais, juntamente com as placas beta-amilóide e astrogliose são importantes marcadores neuropatológicos da doença de Alzheimer (DA). Apesar dos mecanismos envolvidos na DA do tipo esporádica ainda não estarem bem esclarecidos, a hiperfosforilação da proteína tau é sugerida como grande fator para o desenvolvimento dos emaranhados neurofibrilares, que podem gerar disfunção neuronal e morte. A toxina ácido ocadáico (AO) é considerada um efetivo inibidor das fosfatases 1 e 2A, as quais podem gerar a hiperfosforilação da tau. Dessa forma, este trabalho tem como objetivo, avaliar alterações neurogliais em hipocampo e líquido cerebroespinhal (LCE) de ratos expostos ao AO intracerebroventricular após 3 e 12 semanas da infusão. E ainda, verificar alterações neurogliais de fatias hipocampais expostas de forma aguda ao AO (in vitro). Como resultados encontramos no modelo in vivo, declínio cognitivo, hiperfosforilação da tau (Ser 396) e alteração astroglial hipocampal principalmente devido a redução da captação de glicose e aumento da expressão da GFAP e ainda, redução da S100B no LCE, a qual pode atuar na sinalização neurônio-astrócito, em condições fisiológicas ou patológicas, como na DA. Ao observar as alterações neurogliais 12 semanas após a infusão, verificamos que o modelo é parcialmente reversível, uma vez que a fosforilação da proteína tau não mostrou alteração, mas foi observado declínio cognitivo em um dos comportamentos realizados e hipometabolismo da glicose. E ainda, in vitro, o AO foi capaz de hiperfosforilar a proteína tau (Ser 396), mas não alterou parâmetros astrogliais. Portanto, o modelo animal se mostra adequado para avaliação de alterações neuroquímicas. Mas nossos resultados também apontam para uma reversibilidade parcial do modelo a longo prazo, indicando a necessidade de cautela na avaliação de estratégias terapêuticas com este modelo. E ainda, nossos dados reforçam a importância de investigar alterações do metabolismo cerebral da glicose em indivíduos com déficit cognitivo. / Intraneuronal aggregates of neurofibrillary tangles (NFTs), together with beta-amyloid plaques and astrogliosis, are important markers of Alzheimer’s disease (AD). The underlying mechanism of sporadic AD remains poorly understood, but abnormal hyperphosphorylation of tau protein is suggested to have a role in NFTs genesis, which leads to neuronal dysfunction and death. The okadaic acid (OKA) toxin is a protein phosphatase 1 e 2A inhibitor and can lead to tau protein hyperphosphorylation. We have investigated the effects of intracerebroventricular (ICV) OKA on neuroglial alterations 3 and 12 weeks after OKA infusion. We have also researched the effects on neuroglial parameters on hippocampal slices treated with OKA in vivo. Our results have shown cognitive impairment, hippocampal astrogliosis, based on GFAP increment, decreased glucose uptake and increase on tau phosphorylation (at Ser396) in hipocamppus and decrease in S100B protein on cerebrospinal fluid 3 weeks after ICV OKA-infusion. Moreover, 12 weeks after ICV OKA infusion we also observed a cognitive impairment and decreased on glucose uptake. In vitro, exposure of hippocampal slices to OKA altered tau phosphorylation at Ser396 without any associated change in astroglial function. In conclusion, the OKA-animal model proved to be a suitable model for neurochemical parameters assessment. Our results also indicate a partial reversibility of long-term animal model, suggesting that therapeutics strategies evaluations must be caution on this model; and reinforce how important is to investigate on brain glucose metabolism alterations on cognitive impairment.

Alzheimer's disease (AD) is characterised by memory loss, insidious cognitive decline, profound neurodegeneration, and the extracellular accumulation of amyloid-beta (Aβ) peptide in senile plaques and intracellular accumulation of tau in neurofibrillary tangles. Synaptic dysfunction and loss is the strongest pathological correlate of cognitive decline in AD with increasing evidence implicating neuropathological forms of both amyloid-beta and tau protein in this process. A large amount of evidence suggests that oligomeric forms of Aβ, associated with senile plaques, are toxic to synapses but the precise localisation of Aβ and which forms are synaptotoxic remain unknown. Using the high-resolution technique, array tomography, this thesis characterised the synaptic localisation of different forms of Aβ oligomers in a mouse model of amyloidopathy. These results show that different oligomeric Aβ species are present in both presynapses and postsynapses. This study highlights the potential of array tomography for rapid testing of aggregation state specific Aβ antibodies in brain tissue. Following these results, the presence of tau at synapses was examined. Despite the knowledge that tau spreads through defined synaptic circuits, it is currently unknown whether synapse loss occurs before the accumulation of tau or as a consequence. To address this, array tomography was used to examine a mouse model in which mutant P301L human tau is expressed primarily in the entorhinal cortex (rTgTauEC). It has previously been shown that rTgTauEC mice exhibit neuronal loss in the entorhinal cortex and synapse density loss in the middle molecular layer (MML) of the dentate gyrus at 24 months of age. The density of tau-expressing and total presynapses, and the spread of tau into the postsynapse in the MML of 3-6, 9, and 18 month old mice were examined. No loss of synapse density was observed in the MML up to 18 months of age, even in axons expressing tau. Despite the maintenance of synapse density, we see spread of human tau from presynaptic terminals to postsynaptic compartments in the MML at very early ages. This indicates that the spread of tau through neural circuits is not due to the degeneration of axon terminals and is an early feature of the disease process. Following examination of both synaptic amyloid-beta and tau in separate models, this thesis then examined how these two proteins may be synergistically working together to drive synaptic pathology. To investigate this a novel mouse model was used in which amyloid-beta deposits are present in combination with non-mutated human tau expression (APP/PS1 + hTau). These results suggested that the addition of human tau expression does not increase plaque associated synapse loss, neither does it increase the proportion of synapses colocalising with amyloid-beta. Similarly the presence of human tau at individual postsynapses was not enhanced in the presence of oligomeric Aβ. Surprisingly, intact long-term recognition memory was observed in APP/PS1 + hTau mice. However a hyperactive phenotype was detected in these mice that could be prevented upon tau suppression. This suggests a synergistic relationship may exist in the presentation of this phenotype. Finally in the last part of this thesis, synapses from post-mortem human Alzheimer's disease and age-matched controls were investigated. It has previously been suggested that both amyloid-beta and tau can interfere with mitochondrial transport to the synapse and mitochondrial function. For this reason the presence of synaptic mitochondria at both the presynapse and postsynapse was determined in order to investigate any alteration in the diseased state. A reduction in the proportion of presynapses with multiple mitochondria present was detected in anterior/posterior transverse temporal cortex (BA41/42). This was not observed in dorsolateral prefrontal cortex (BA46), suggesting either a selective vulnerability of the former brain region or a selective resistance of the latter brain region, to mitochondrial depletion at the synapse. The findings presented in this thesis demonstrate that when investigated in isolation, pathological forms of amyloid-beta are present at a subset of synapses where they may contribute to toxicity, whilst the spread of tau protein is an early feature of the disease process and occurs prior to overt synapse loss. This thesis also explores the proposed synergistic relationship between amyloid-beta and tau using a novel mouse model and human post-mortem brain tissue. Since these two proteins both have been implicated in synaptic dysfunction, investigating Aβ and tau in new mouse models and human brain tissue will be instrumental in furthering our understanding of mechanisms and features of synaptotoxicity that could be important therapeutic targets.

Reversible adenosine methylation (N6-methylation; m6A) at the RNA level was described in connection to the regulation of RNA fate. The N6-methyladenosine pathway is important for cognitive function and mechanisms related to memory, including the regulation of adult neurogenesis and synaptic plasticity. The objective of this study was to test the hypothesis that a decreased activity of the RNA-demethylase FTO is associated with improved cognitive function in rats. The RNA-demethylase FTO is a key regulator of the m6A pathway. In this study, we administered MO-I-500, a pharmacological inhibitor of FTO in TgF344-AD transgenic rats, which resulted in an improvement of spatial cognition. We further investigated the cognitive enhancement induced by a caloric restriction as a possible compensatory mechanism of cognitive disorders and its effect on the proteins regulating the N6-methyladenosine pathway. Long-term caloric restriction ameliorated cognitive functions and led to changes in the expression of the major proteins controlling the m6A pathway (FTO, METTL3) which are consistent with the aforementioned hypothesis. Although we do not know the exact mechanism of action, these findings support the hypothesis that m6A pathway regulators, such as the FTO demethylase, may be a promising molecular target for...

<p>This report presents work done in the field of linear and nonlinear system identification on robots. The subject of study has been a new parallel manipulator called Gantry-Tau. The work shall be seen as one of the first steps in the dynamical analysis of the robot. All practical work presented in the report was conducted on a prototype situated at University of Queensland.</p><p> </p><p>The actuators have been analysed and modelled with the aim to gain knowledge of weaknesses and dynamical behaviour. The analysis resulted in a study of nonlinear grey-box identification of hysteresis in the drive train of the actuators. A very compact nonlinear hysteresis model was used together with a three-step identification procedure. The results show that a model of the nonlinear system can be successfully identified from measurement data.</p><p>Finally a method for estimation of parameters in the model for the inverse dynamics of the leg structure has been investigated. It turns out that the investigated method is not able to give accurate estimates. This is thought to be a result of unmodelled behaviour in the system and noisy data.</p>