Neural tube defects (NTDs) are a world health issue, affecting approximately 1 in every 1000 live births. These congenital defects arise from the improper closure of the neural tube during development, resulting in significant, life-threatening malformations of the central nervous system. Although it has been observed that supplementing women of child-bearing age with folates greatly decreases the chances of having an NTD affected baby, unfortunately these defects still occur. It is accepted that these complex disorders arise from a combination of genetic, environmental, and dietary influences. One such dietary influence is the one-carbon metabolism metabolite, homocysteine. Homocysteine is a byproduct of methylation reactions in the cell that exists in an inverse homeostasis with folate. Homocysteine can also undergo a transformation that allows it to then react with exposed lysine or cysteine residues on proteins, in a process known as N-homocysteinylation or S-homocysteinylation respectively. High levels of homocysteine have been long correlated with many disease states, including NTDs. One potential mechanism by which homocysteine confers its negative effects is through protein N-homocysteinylation. Here, a novel and high-throughput assay for N-homocysteinylation determination is described. This assay is shown to be accurate with mass spectrometry then shown to be biologically relevant using known hyperhomocysteinemia mouse models. This assay was then applied to a cohort of neural tube closure staged mouse embryos with two different genetic mutations that have previously been shown to predispose mice to NTDs. The genotypes explored here are mutations to the LRP6 gene and the Folr1 gene, both of which have been described as folate-responsive NTD mouse models. It was seen that maternal diet and embryonic genotype had the largest influence on the developmental outcome of these embryos; however, the inverse relationship between folate and homocysteine seemed to be established at this early time point, emphasizing the importance of the balance in one-carbon metabolism. One of these genes, LRP6, was then explored in a human cohort of spina bifida cases. Four novel mutations to the LRP6 gene were found and compared to the mouse model used in the previous study. One of the mutations found in the human population was seen to mimic that of the LRP6 mouse model, therefore expanding the potential of this NTD model. / text

Notre objectif dans cette étude aura été de se rapprocher progressivement du comportement et des caractéristiques des polyéthylènes afin de décrire les mécanismes de formation des contraintes résiduelles lors du calibrage des tubes.<br/>Le modèle le plus simple, basé sur une loi de comportement liquide - solide élastique, a mis en évidence deux mécanismes de formation des contraintes résiduelles. Le premier est relié aux différences de température lors du refroidissement qui provoquent des différences de retrait dans l'épaisseur. Ceci met les couches extérieures du tube en compression et les couches intérieures en traction. Ce profil de contrainte fait se refermer le tube lorsqu'on le découpe suivant la génératrice<br/>Le second mécanisme est relié aux efforts extérieurs qui s'appliquent sur le tube. La dépression dans le calibreur maintient le tube contre la chambre de calibrage et l'empêche de se rétracter lors du refroidissement ce qui induit des contraintes de traction dans les couches solidifiées. En fait la dépression bloque le retrait thermique qui était à l'origine du premier mécanisme. Si la dépression est suffisante pour maintenir le tube jusqu'à la fin de la solidification le profil de contraintes résiduelles est nul. Les profils de contraintes intermédiaires sont obtenus par une évolution des conditions aux limites lors de la solidification, la dépression n'étant en faite pas suffisante pour maintenir le contact pendant toute la solidification.<br/>Le modèle élastique a également mis en avant l'influence des forces axiales et en particulier les forces de frottement entre le tube et la chambre de calibrage. En étirant le tube, elles tendent à diminuer son diamètre. La dépression bloque cette rétraction en plus du retrait thermique. Ceci accentue les contraintes de traction dans les couches extérieures jusqu'à inverser le profil des contraintes résiduelles. Le tube peut alors s'ouvrir lorsqu'on le découpe suivant la génératrice.<br/>Le modèle élastique est suffisant pour expliquer l'influence de la dépression sur le profil des contraintes résiduelles. Cependant les propriétés des matériaux que ce modèle peut prendre en compte restent assez éloignées de celui des polyéthylènes pendant le refroidissement.<br/>Le modèle viscoélastique que nous avons développé est original par rapport à la bibliographie dans le sens où la variation du volume spécifique et les propriétés mécanique lors de la transition fluide -- solide sont directement basés sur l'évolution du taux de cristallinité, paramètre du premier ordre sur le comportement physique du matériau.<br/>Le taux de cristallinité peut être obtenu dans le modèle soit par le modèle de cristallisation d'Ozawa soit en reprenant directement les résultats obtenus par DSC. Celui-ci est alors utilisé pour déterminer l'évolution du volume spécifique et permet de tenir de l'importante rétraction du matériau qui se produit lors de la cristallisation. L'influence du retrait du à la cristallisation doit cependant être nuancé car il se produit à des températures pour lesquelles la relaxation des contraintes n'est pas négligeable. Pour des matériaux semi-cristallins tel que les polyéthylènes, il est donc nécessaire d'utiliser un modèle viscoélastique pour pouvoir prendre en compte le retrait lors de la cristallisation.<br/>Afin de pouvoir appliquer les forces d'étirage et de frottement dès le début de la solidification, nous avons montré qu'il était nécessaire de tenir compte des contraintes dans les couches non solidifiées afin de charger progressivement les couches solidifiées. Le comportement viscoélastique des matériaux est pris en compte dans les états fluides et solide par des lois de Maxwell multimode. La répartition des contraintes prédit dans les couches fluides et solides par le modèle viscoélastique permet d'avoir une première information sur l'importance des propriétés mécaniques du matériau à l'état fluide. Les calculs permettent d'expliquer en partie l'orientation mesurée dans les couches extérieures lors de l'étude des polyéthylènes basse densité linéaire.<br/>Le modèle viscoélastique apporte peu de renseignements supplémentaires sur les mécanismes de formation des contraintes résiduelles finales mais il permet de les quantifier en utilisant des caractéristiques matériaux proches de celles des polyéthylènes lors du refroidissement.<br/>Une étude numérique confirme que le procédé de calibrage est relativement sensible à tous les paramètres du procédé et caractéristiques du matériau même si la dépression reste le paramètre de premier ordre.<br/>Finalement, les comparaisons entre les calculs et l'expérience montrent que nous sommes parvenus à borner la réalité en expliquant l'origine des contraintes résiduelles qui se forment lors du calibrage des tubes.<br/>

A single-stage pulse tube cryocooler was designed and fabricated to provide cooling at 50 K for a high temperature superconducting (HTS) magnet, with a nominal electrical input frequency of 50 Hz and a maximum mean helium working gas pressure of 2.5 MPa. Sage software was used for the thermodynamic design of the pulse tube, with an initially predicted 30 W of cooling power at 50 K, and an input indicated power of 1800 W. Sage was found to be a useful tool for the design, and although not perfect, some correlation was established. The fabricated pulse tube was closely coupled to a metallic diaphragm pressure wave generator (PWG) with a 60 ml swept volume. The pulse tube achieved a lowest no-load temperature of 55 K and provided 46 W of cooling power at 77 K with a p-V input power of 675 W, which corresponded to 19.5% of Carnot COP. Recommendations included achieving the specified displacement from the PWG under the higher gas pressures, design and development of a more practical co-axial pulse tube and a multi-stage configuration to achieve the power at lower temperatures required by HTS.

Kinetic data is presented for a variety of ion-neutral reactions which are relevant to the atmosphere of Titan and to the chemistry occurring in interstellar clouds. The data were recorded with a Selected Ion Flow Tube (SIFT) operating at room temperature (294 ± 4 K) and at a pressure of 0.46 Torr. Results of the recent Cassini-Huygens mission to Saturn and Titan have identified several species in the atmosphere of Titan not predicted by pre-Cassini models of the atmosphere. In order to determine the fate of three of these species (methylenimine, propionitrile and cyanodiacetylene) in Titan's ionosphere, their reactivity with the principal ions in Titan's upper ionosphere has been examined. As expected, collision rate proton transfer reactions dominate the chemistry with association channels also observed with many of the hydrocarbon ions. The results of the Cassini mission also identified several individual reactions as being of potential importance to models of Titan's atmosphere and this chemistry has also been examined. The above studies are also relevant to the interstellar medium where each of the neutral reactants have also been detected. The results of some proton transfer equilibrium studies are also presented. The gas phase basicities of propyne and acetylene have been determined to be 681 kJ mol⁻¹ and 617.4 kJ mol⁻¹ respectively. Their relative proton affinities can be estimated from these values. A combined experimental/theoretical study of the proton affinity of cyanodiacetylene (HC₅N) has enabled this value to be estimated at 770 ± 20 kJ mol⁻¹. Details of an attempt to complete the first laboratory measurement of the crucial reaction between H₃⁺ and atomic carbon are presented. The generation of atomic carbon in sufficient quantities for reaction in the SIFT was not possible with the microwave discharge source used. Other generation methods have also been explored with the laser photolysis of carbon suboxide expected to provide a possible solution to the problems encountered. The results of an investigation into the applicability of lithium ions (Li⁺) to SIFT-MS are presented. The lithium ions associated with each of the twenty-one neutral analytes examined to form pseudo-molecular ions. The association reactions were rapid (k ~ 10⁻⁹ cm³ s⁻¹) for large hydrocarbons but were much slower for smaller analytes (k < 10⁻¹¹ cm³ s⁻¹). In order to clarify some unusual experimental observations, the effect of water molecules on the observed chemistry has been examined in detail. The measured chemistry has important consequences for the applicability of Li⁺ to SIFT-MS where the presence and detection of an identifiable ion of the analyte is essential. Details of new SIFT operating software which can be run on a modern computer are given. Mass spectra and kinetic data recorded with the new software are also presented.

The study of acoustic resonance in fluid-filled piping systems with and without mean flow is important for the nuclear industry. For this industry, it is vital to understand the acoustic resonance in their systems; however, no comprehensive experimental benchmark data or accurate modeling tool exists for predicting such a phenomenon. The main goals of the current research are to create a new experimental data bank for the conditions not tested earlier using the configurations of straight lines and branches, and to evaluate the applicability of the linear wave solution using different damping methods and a computational fluid dynamic (CFD) code to simulate the acoustic resonance in fluid-filled piping systems. In this experimental study, data on resonant frequencies and resonant amplitudes are collected and analyzed for a frequency range of 20–500 Hz for straight and branched tubes by varying their wall thicknesses, materials, and branch configurations at different flow rates and outlet boundary conditions. To be closer to the nuclear industry medium, water is employed in our experiments, contrasting to the fact that most of the available experiments reported were with air at a much lower sonic velocity. I consider here, in particular, measurements at the end of closed branches, upstream, downstream, and at different locations of the main line, as well as the interactions of different sonic velocities along the main pipes. A small diameter is chosen for the branched experiments since the decrease in the width of the main line and the branches has a pronounced effect on the resonant amplitudes due to an increased interaction among the unsteady shear layers forming across the side branches. The experimental results show that there is a strong effect of turbulent flow, wall material, and wall thickness on resonant amplitudes at frequencies above ∼250 Hz. Numerical investigations are performed solving the one-dimensional (1D) linear wave equation with constant and frequency-dependent damping terms and a CFD code. Employing frequency-dependent damping methodologies shows improvement in terms of resonant amplitude prediction over constant volumetric drag method. Comparing the 1D and CFD results shows that the CFD solution yields better predictions. / February 2017

The work in this thesis focuses on the development of a Stochastic Model Predictive Control (SMPC) algorithm for linear systems with additive and multiplicative stochastic uncertainty subjected to linear input/state constraints. Constraints can be in the form of hard constraints, which must be satisfied at all times, or soft constraints, which can be violated up to a pre-defined limit on the frequency of violation or the expected number of violations in a given period. When constraints are included in the SMPC algorithm, the difficulty arising from stochastic model parameters manifests itself in the online optimization in two ways. Namely, the difficulty lies in predicting the probability distribution of future states and imposing constraints on closed loop responses through constraints on predictions. This problem is overcome through the introduction of layered tubes around a centre trajectory. These tubes are optimized online in order to produce a systematic and less conservative approach of handling constraints. The layered tubes centered around a nominal trajectory achieve soft constraint satisfaction through the imposition of constraints on the probabilities of one-step-ahead transition of the predicted state between the layered tubes and constraints on the probability of one-step-ahead constraint violations. An application in the field of Sustainable Development policy is used as an example. With some adaptation, the algorithm is extended the case where the uncertainty is not identically and independently distributed. Also, by including linearization errors, it is extended to non-linear systems with additive uncertainty.

Critically ill patients who require MV are at risk for a number of complications, including the development of ventilator-associated events (VAE) and agitation that may require the use of sedation. Patients experience anxiety and discomfort during mechanical ventilation from a variety of sources including unfamiliar breathing assistance and an inability to communicate anxiety and pain verbally, but a primary cause of discomfort identified by these patients is the simply the presence of the endotracheal tube (ETT). Discomfort often leads to agitation and may be exacerbated by ETT movement. Management of agitation typically involves the use of sedative therapy and has been shown to increase the length of stay in the hospital. Additionally, when ETT cuff pressure is not adequately maintained, risk of microaspiration increases and these microaspirations increase the risk of ventilator-associated events. ETT movement may adversely affect the cuff seal against the tracheal mucosa, increasing leakage around the cuff and microaspiration. To date, no studies have described the effect of ETT movement on patient comfort and agitation. Noting the frequency of ETT movement during the provision of nursing care and plausible inadvertent consequences on discomfort and agitation, a research model was created and specific instruments selected in order to study this topic. This dissertation will provide a review of the literature regarding the role of the ETT in microaspiration, as well as detail a study that explores the frequency and amount of ETT movement and its potential effect on agitation.

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

The central nervous system is formed from epiblast precursor cells through Neurulation. Neural induction can be studied in its main aspects in vitro. However, the process is poorly understood, especially in regard to when and how a cell becomes specified, and then committed, to be a neural cell. It is, on the other hand, well established that neural formation requires absence or, inhibition of the BMP signalling both in vivo and in vitro. ID1 is a direct target of BMP signalling with major influence on in vitro neural differentiation. A cDNA library screen, looking for transcription factors negatively regulated by ID1, reported TWIST1, along with only two other proteins. Twist1 expression is upregulated during in vitro neural differentiation. Furthermore, targeted deletion of Twist1 has dramatic consequences on anterior neural development. Twist1 knock-out mice fail to form the closed neural tube in the prospective brain, followed by exencephaly and, early embryonic death. In this thesis I investigate the influence on in vitro neural differentiation of a TWIST1 constitutively active form, insensitive to ID1 inhibition. I report that this transcriptionally active TWIST1 accelerates neural differentiation, in vitro and, biases it, towards dorsal phenotypes. I provide, for the first time, evidence for Twist1 expression in the neural tissue, observed weakly in a restricted domain, temporally and spatially, in the dorsal part of the neural tube. I propose a new model for TWIST1 influence at this level. I also investigate how TWIST1 actions depend on levels of expression and dimer choice. I found that, TWIST1 can exert its neural modulating actions only at low levels, as high levels divert a cell fate towards non-neural lineages.

L'utilisation de la bactérie C. maltaromaticum dans l'industrie alimentaire n'est pas autorisée en raison de faible connaissance et des pathologies qu'il peut provoquer chez le poisson. Un des objectifs de ce travail est de renforcer la connaissance par la séquence génomique d'une souche fromagère et d'évaluer le devenir de la bactérie après ingestion par le consommateur. L'autre objectif est de mieux connaitre la taxonomie de la bactérie par MLST. La séquence complète de C. maltaromaticum LMA 28 a révélé une taille génomique de 3,8 Mpb qui est atypique dans le genre Carnobacterium. L'analyse génomique indique qu'il contiendrait des gènes d'adaptation à l'environnement intestinal. Il a été montré que la bactérie est capable de survivre le transit gastro-intestinal chez la souris et d'adhérer à des cellules intestinales humaines qui présenteraient des propriétés neutres voire anti-inflammatoires. Le résultat suggère qu'elle est capable de survivre le transit GIT et d'interagir avec l'hôte. Il a été montré que la MLST chez C. maltaromaticum permet d'atteindre un haut niveau de résolution. MLST suggèrent que le lait et les fromages à pâte molle sont peu sélectifs pour C. maltaromaticum. De plus, deux CC majoritaires, principalement représentés par des souches laitières, ont été identifiés. Leur existence suggère qu'une lignée de l'espèce est particulièrement bien adaptée à l'environnement laitier ou qu'un phénomène de domestication est en cours. Un grand nombre de singletons ont été identifiés suggérant que la diversité chez cette espèce est sous-estimée et qu'elle reste à explorer / The bacterium Carnobacterium maltaromaticum is not used in industry due to limited knowledge about this organism and its virulence in fish. One objective of this thesis was to strengthen the body of knowledge by determining the complete genome sequence of the cheese strain and to evaluate the fate of this bacterium after ingestion by the consumer. Another objective was to improve the taxonomic knowledge within the species C. maltaromaticum through the development of a MLST scheme. The complete sequence of the strain C. maltaromaticum LMA 28 revealed a genome size of approximately 3.8 Mbp, which is unusually high in the genus Carnobacterium. The genome analysis of this strain indicates the presence of genes conferring the adaptation to the intestinal environment. The bacterium is able to survive during the gastro-intestinal transit in mice. Moreover, this strain is able to adhere to human intestinal epithelial cell lines and would have neutral or anti-inflammatory properties. These data suggest that C. maltaromaticum LMA 28 is adapted to the digestive tract of mammals. At the taxonomical level, it was shown that MLST is highly discriminatory for the species C. maltaromaticum. In addition, the MLST results suggest that milk and soft cheeses are poorly selective for strains of this species. In addition, two major clonal complexes suggest that a sub-population within this species is well adapted to the dairy environment or that a sub-population is submitted to a domestication process. A high proportion of singletons was obtained suggesting that the diversity was under-estimated and remains to be explored