La maladie cardiovasculaire (MCV) représente encore aujourd’hui l’une des principales causes de décès et d’hospitalisation au Canada. Parmi les facteurs de risque de la MCV, la dyslipidémie est l’un des plus importants. En effet, des concentrations plasmatiques élevées de cholestérol transporté par les lipoprotéines de faibles densités (c-LDL), de triglycérides, ainsi que des concentrations faibles de cholestérol transporté par les lipoprotéines de hautes densités (c-HDL) ont été à maintes reprises identifiées comme des facteurs de risque indépendants de la MCV. Plusieurs facteurs héréditaires et environnementaux ont été associés aux concentrations de lipides plasmatiques. Toutefois, les facteurs héréditaires permettraient d’expliquer la plus grande proportion de la variabilité interindividuelle du bilan lipidique, particulièrement pour le c-HDL. Malgré l’étude de plusieurs millions de modifications génétiques, les principales causes moléculaires responsables de la forte héritabilité des concentrations de c-HDL demeurent pour l’instant encore inconnues. Afin d’expliquer l’héritabilité manquante des concentrations de lipides plasmatiques, plusieurs hypothèses ont été avancées. La présente thèse de doctorat se concentre sur celle suggérant que l’étude de la méthylation de l’ADN, une modification épigénétique considérée comme un facteur héréditaire non traditionnel, permettrait d’identifier de nouveaux fondements moléculaires associés aux dyslipidémies. Dans un premier temps, nous avons analysé la méthylation de l’ADN de plusieurs gènes du métabolisme lipoprotéique chez des sujets atteints d’hypercholestérolémie familiale (HF), un modèle humain de la MCV. Grâce à cette approche, nous avons pu démontrer que la méthylation de l’ADN de plusieurs gènes candidats (ABCA1, ABCG1, CETP, LIPC, LPL et PLTP) était associée à la variabilité du bilan lipidique, ainsi qu’avec les antécédents de maladies coronariennes athérosclérotiques. Dans un deuxième temps, une étude de la méthylation à l’échelle du génome d’un sous-groupe de patients HF nous a permis d’identifier de nouveaux loci associés à la concentration de c-HDL. Nous avons notamment observé que la méthylation de l’ADN du promoteur des gènes TNNT1 et ADRB3 était non seulement associée aux concentrations de c-HDL, mais également avec d’autres facteurs de risque de la MCV. L’ensemble des résultats présentés dans cette thèse démontre que la méthylation de l’ADN contribue à la variabilité du bilan lipidique à jeun de patients atteints d’HF et que l’étude des modifications épigénétiques pourrait aider à expliquer l’héritabilité manquante des concentrations de c-LDL, de c-HDL et de triglycérides plasmatiques.

No description available.

Mutations found in genes encoding human Elongator complex subunits have been linked to neurodevelopmental disorders such as familial dysautonomia (FD), rolandic epilepsy and amyotrophic lateral sclerosis. In addition, loss-of-function mutations in genes encoding Elongator complex subunits cause defects in neurodevelopment and reduced neuronal function in both mice and nematodes. The Elongator complex is a conserved protein complex comprising six subunits (Elp1p-Elp6p) found in eukaryotes. The primary function of this complex in yeast is formation of the 5-methoxycarbonylmethyl (mcm5) and 5-carbamoylmethyl (ncm5) side chains found on wobble uridines (U34) in tRNAs. The aim of this thesis is to investigate the physiological consequences of Elongator complex inactivation in humans and in the yeast Saccharomyces cerevisiae. Inactivation of the Elongator complex causes widespread defects in a multitude of different cellular processes in S. cerevisiae. Thus, we investigated metabolic alterations resulting from Elongator complex inactivation. We show that deletion of the S. cerevisiae ELP3 gene leads to widespread metabolic alterations. Moreover, all global metabolic alterations observed in the elp3Δ strain are not restored in the presence of elevated levels of hypomodified tRNAs that normally have the modified nucleoside mcm5s2U. Collectively, we show that modified wobble nucleosides in tRNAs are required for metabolic homeostasis. Elongator mutants display sensitivity to DNA damage agents, but the underlying mechanism explaining this sensitivity remains elusive. We demonstrate that deletion of the S. cerevisiae ELP3 gene results in post-transcriptional reduction of Ixr1p levels. Further, we show that the reduced Ixr1p levels prevent adequate Rnr1p levels upon treatment with DNA damage agents. These findings suggest that reduced Ixr1p levels could in part explain why Elongator mutants are sensitive to DNA damage agents. Depletion of Elongator complex subunits results in loss of wobble uridine modifications in plants, nematodes, mice and yeast. Therefore, we investigated whether patients with the neurodegenerative disease familial dysautonomia (FD), who have lower levels of the ELP1 protein, display reduced amounts of modified wobble uridine nucleosides. We show that tRNA isolated from brain tissue and fibroblast cell lines derived from FD patients have 64–71% of the mcm5s2U nucleoside levels observed in total tRNA from non-FD brain tissue and non-FD fibroblasts. Overall, these results suggest that the cause for the neurodegenerative nature of FD could be translation impairment caused by reduced levels of modified wobble uridine nucleosides in tRNAs. Thus, our results give new insight on the importance of modified wobble uridine nucleosides for neurodevelopment.

The purpose of this study was to evaluate the amount of change in transverse tibial rotation at the knee achieved through the use of shoe modification. In addition, an attempt to evaluate the Q-angle dynamically through the stance phase to reflect changes in transverse tibial rotation was made. Ten male subjects were filmed as they ran on a treadmill at a 2.82 m/sec pace and transverse tibial rotation data was collected simultaneously from an affixed electrogoniometer at the knee joint. The subjects were tested under three conditions: 1) barefoot, 2) running shoe, and 3) shoe plus standard orthotic. The results of the study showed that an unprescribed, standard orthotic was ineffective in changing foot pronation and transverse tibial rotation at the knee. It also showed that there was no relationship between leg-heel alignment measurements of pronation and electrogoniometric measurements of transverse tibial rotation. Q-angle measurements could not be obtained from the film date due to difficulty in visualizing body landmarks.

With the emergence of the Internet of Things (IoT), wireless body area networks (WBANs) are becoming increasingly pervasive in everyday life. Most WBANs are currently working at the IEEE 802.15.4 Zigbee standard. However there are growing interests to investigate the performance of BANs operating at higher frequencies (e.g. millimetre-wave band), due to the advantages offered compared to those operating at lower microwave frequencies. This thesis aims to realise printed conductive traces on flexible substrates, targeted for high frequency wearable electronics applications. Specifically, investigations were performed in the areas pertaining to the surface modification of substrates and the electrical performance of printed interconnects. Firstly, a novel methodology was proposed to characterise the dielectric properties of a non-woven fabric (Tyvek) up to 20 GHz. This approach utilised electromagnetic (EM) simulation to improve the analytical equations based on transmission line structures, in order to improve the accuracy of the conductor loss values in the gigahertz range. To reduce the substrate roughness, an UV-curable insulator was used to form a planarisation layer on a non-porous substrate via inkjet printing. The results obtained demonstrated the importance of matching the surface energy of the substrate to the ink to minimise the ink de-wetting phenomenon, which was possible within the parameters of heating the platen. Furthermore, the substrate surface roughness was observed to affect the printed line width significantly, and a surface roughness factor was introduced in the equation of Smith et al. to predict the printed line width on a substrate with non-negligible surface roughness (Ra ≤ 1 μm). Silver ink de-wetting was observed when overprinting silver onto the UV-cured insulator, and studies were performed to investigate the conditions for achieving electrically conductive traces using commercial ink formulations, where the curing equipment may be non-optimal. In particular, different techniques were used to characterise the samples at different stages in order to evaluate the surface properties and printability, and to ascertain if measurable resistances could be predicted. Following the results obtained, it was demonstrated that measurable resistance could be obtained for samples cured under an ambient atmosphere, which was verified on Tyvek samples. Lastly, a methodology was proposed to model for the non-ideal characteristics of printed transmission lines to predict the high frequency electrical performance of those structures. The methodology was validated on transmission line structures of different lengths up to 30 GHz, where a good correlation was obtained between simulation and measurement results. Furthermore, the results obtained demonstrate the significance of the paste levelling effect on the extracted DC conductivity values, and the need for accurate DC conductivity values in the modelling of printed interconnects.

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

Alternative splicing (AS) is involved in expansion of transcriptome and proteome during cell growth, cell death, pluripotency, cell differentiation and development. There is increasing evidence to suggest that splicing decisions are made when the nascent RNA is still associated with chromatin. Here, I studied regulation of AS via chromatin modification with main focus on histone acetylation. First, we demonstrate that activity of histone deacetylases (HDACs) influences splice site selection in 700 genes. We provided evidence that HDAC inhibition induces histone H4 acetylation and increases RNA Polymerase II (RNA Pol II) processivity along an alternatively spliced element. In addition, HDAC inhibition reduces co-transcriptional association of the splicing regulator SRp40 with the target fibronectin exon. Further we showed that histone acetylation reader, Brd2 protein, affect transcription of 1450 genes. Besides, almost 290 genes change their AS pattern upon Brd2 depletion. We study distribution of Brd2 along the target and control genes and find that Brd2 is specifically localized at promoters of target genes only. Surprisingly, Brd2 interaction with chromatin cannot be explained solely by histone acetylation, which suggests that other protein-domains (in addition to bromodomains) are important for...

The purpose of this study was to examine the attitudes of teachers towards providing accommodations and modifications required for students with special needs in general education classes. The study also examined the differences between these educators’ willingness, preparedness, and selected demographic and descriptive characteristics, which included teacher education, educational setting, and support provided for inclusion. As such, it contributed to both the theory and the practice of teaching students with disabilities in inclusive settings. The sample included willing general and special education teachers in one suburban school district in the southeastern United States. The instrument was a modified version of the Teacher Acceptability and Use Scale (TAUS) (Boulton, 2003). Statistical analysis revealed little significant difference in willingness between special education and general education teachers, although special education teachers perceived themselves as slightly more prepared than general education teachers to make accommodations and modifications to the general curriculum for the student with special needs included in the general education classroom. In conclusion, the results of this study indicate that teachers’ perceptions of their preparedness for accommodating students with special needs has improved in recent years.

M.Sc. (Eng.), Faculty of Engineering and the Built Environment, University of the Witwatersrand, 2012 / The aim of this research project was to test the response of ultra fine coal sourced at Klipspruit Colliery to froth flotation and the response of the froth flotation products to dewatering using two different types of filter presses, namely the Tecnicas Hidraulicas (TH) and the Ishigakhi presses. During test work, some difficulty was experienced with coarse material feeding the froth flotation pilot plant. This led to pilot plant modifications. Further process complexities necessitated laboratory scale flotation test work on the Klipspruit coal to be carried out. The results for both the laboratory scale and pilot plant test work for froth flotation indicated that froth flotation as applied to the Klipspruit fines was not economically feasible because neither the required quality of the product (calorific value of 27.80 MJ/kg) nor the product yield of 50% could be achieved when subjected to a primary and secondary stage of froth flotation. The coarse material, which fed the pilot plant and the Ishigakhi filter press, gave low moisture values (12.3%) not typical of ultra fine coal moisture values. However when fed with very fine particle size distributions, prior test work with the Ishigakhi showed that moisture values below 20% could be achieved. The moisture values obtained for very fine particles using the TH filter press on product thickener underflow material sourced at Goedehoop colliery reached values below 20%. Thus both of the two dewatering options, i.e. the Ishigakhi filter press equipment or TH filter press equipment for the ultra fine coal dewatering, can be utilized. Since the filter rate is the determining factor specifying filter press size, it was determined that a larger TH filter area is required in 1 comparison with the Ishigakhi press. Based upon the pilot and laboratory scale test work undertaken and the assessment of the results, it appears that both dewatering options could be successfully employed on a technical basis for the dewatering of coal flotation products, tailings and the arising raw ultra fine fraction. Froth flotation for Klipspruit ultra fine coal was deemed unfeasible for both pilot plant and laboratory scale tests conducted. For this reason a capital expenditure for the construction of a froth flotation plant at the Western Coal Complex Phola plant was not considered feasible since Klipspruit coal forms part of the feed that will feed the Phola plant. In conclusion, following dewatering using either the TH filter press or the Ishigakhi filter press, it was established that both froth flotation concentrate and unbeneficiated ultra fines gave acceptable total moisture results (below 20%). These dewatered raw ultra fines may therefore be blended into inland product as thermal coal to be utilised by Eskom for power generation. Based upon this premise, it is estimated that profits of 76.5 million Rand could be generated by blending Klipspruit ultra fine coal into thermal coal production at the new Phola plant.

L'exposition à une situation de stress entraine des réactions cognitives, affectives, physiologiques et comportementales. Ce travail de thèse s'est attaché à examiner des réponses affectives et physiologiques induites par une situation de stress modéré, plus particulièrement l'état d'anxiété et la tension musculaire, et a également considéré les caractéristiques de la situation et le trait d'anxiété des individus. Une première étude a montré chez des individus de traits d'anxiété différents une réactivité physiologique similaire au cours de la situation stressante, bien que les individus de trait d'anxiété "haut" aient rapporté un état d'anxiété plus élevé que les individus de trait d'anxiété "bas". En revanche, après la situation stressante, les individus de trait d'anxiété "haut" ont montré un délai dans la récupération de certains paramètres végétatifs et musculaires. Ces résultats ont suggéré que des différences dans les réponses physiologiques entre des individus de traits d'anxiété différents pourraient émerger au cours de la période de récupération. Ainsi, les réponses, qu'elles soient affectives ou physiologiques, pourraient dépendre du niveau de trait d'anxiété des individus. Les deux autres études ont montré chez des individus de trait d'anxiété homogène soumis à la situation stressante des patrons d'activation musculaire différents selon les muscles. Ces résultats ont suggéré un lien entre les différentes réponses musculaires et le rôle fonctionnel des muscles. Par ailleurs, les résultats ont montré une diminution de l'état d'anxiété et de ces réponses musculaires au cours d'une deuxième exposition à la situation stressante, excepté pour le muscle trapèze qui semble avoir une réactivité particulière liée à sa fonction. Toutefois, l'adaptation des réponses des différents muscles et de l'état d'anxiété suggère que les réponses affectives et musculaires pourraient être influencées par les caractéristiques de la situation (nouveauté et répétition). Finalement, l'ensemble de ces résultats suggère qu'il est important de considérer les caractéristiques de l'environnement et la personnalité des individus dans l'étude des réponses affectives et physiologiques en situation de stress / Exposure to stressful situations is typically associated with cognitive, affective, physiological and behavioral responses. The aim of this work was to examine the affective and physiological responses to moderate stress, particularly state anxiety and muscle tension and also to consider the characteristics of the situation and the trait anxiety of the subjects.Our results showed that high anxious subjects have a higher level of state-anxiety than low anxious subjects during the stressful task, but no difference in physiological reactivity has been found between both groups. However, after exposure to the stressful situation, high anxious subjects have delayed physiological recovery. This suggests that physiological differences might emerge during the recovery period according to trait anxiety level. Thus, affective and physiological responses could depend on trait anxiety level. Furthermore, our results showed in individuals with homogeneous trait anxiety level that muscle tension induced by the stressful situation could differ depending on the muscles. This result suggests a relationship between the different muscular responses and the functional role of the muscles. Moreover, the results showed that state anxiety and these muscular responses decrease during a second exposure to the same stressful situation, except for the trapezius muscle which seems to have a particular reactivity to the stressor. However, adaptation of these muscular modifications and of state anxiety suggests that affective and muscular responses could be influenced by the characteristics of the situation (novelty and repetition).In conclusion, these findings highlight the importance of considering the environmental characteristics and the personality trait of individuals in research on stress responses