Frontal encephalographic (EEG) alpha asymmetry has been proposed as a measure of the relative difference in average cortical activity between the right and left anterior cortex, where this difference is taken as a physiological marker of trait and state level variables associated with affect. The validity of asymmetry as an indicator of both physiological and psychological variables is in part determined by the psychometric properties of asymmetry scores. The present studies focus on the psychometric assessment of frontal alpha asymmetry measured during rest. The first study involves a novel approach in the assessment of the internal consistency reliability of asymmetry scores. Previous studies estimated internal consistency reliability via Cronbach's alpha, using a relatively small set of asymmetry score that summarized activity over segments of the EEG data (e.g. one minute). Such an approach, however, will create estimates dependent on the number of segments utilized rather than the total amount of data recorded. Thus in the first study, individual FFT epochs were treated as items, thereby maximizing the total number of items used to estimate internal consistency reliability. Results of this study suggest internal consistency reliability is greater than previously reported, and as such, the duration of resting EEG data necessary to achieve a reasonable reliability criterion may be shorter than the current standard. In the second study, asymmetry scores were assessed as a specific case of difference scores, which are susceptible to a statistical artifact associated with differences in true-score variance for the component measures. Predicted asymmetry scores associated with the statistical artifact were obtained by estimating the true-score variance of right and left alpha power. The use of hierarchical linear regression showed some influence of the statistical artifact on the relationship between asymmetry scores and a measure of depressive severity, suggesting that some caution may be warranted in interpreting asymmetry results with relatively small effect sizes.

No description available.

Glucagon-like peptide-1 (GLP-1) has received much attention as a novel diabetes therapeutic due to its pleotropic blood glucose-lowering effects, including enhancement of glucose-stimulated insulin secretion, inhibition of gastric emptying and glucagon secretion, and promotion of beta-cell survival and proliferation. GLP-1 is produced in the intestinal L-cell via processing of the proglucagon precursor by prohormone convertase (PC) 1/3. Proglucagon is also expressed in the pancreatic alpha-cell; however, in this tissue PC2 is typically expressed instead of PC1/3, resulting in differential cleavage of proglucagon to yield glucagon as the major product. We hypothesized that expression of PC1/3 in the alpha-cell would induce GLP-1 production in this tissue, and that this intervention would improve islet function and survival. Initial studies in alpha-cell lines demonstrate that adenoviral delivery of PC1/3 to alpha-cells increases GLP-1 production. By encapsulating and transplanting either PC1/3- or PC2-expressing alpha-cells, the following studies show that while PC2-expressing alpha-cells increase fasting blood glucose and impair glucose tolerance, PC1/3-expressing alpha-cells decrease fasting blood glucose and dramatically improve glucose tolerance in normal mice and in mouse models of diabetes. We further show that transplantation of PC1/3-expressing alpha-cells prevents streptozotocin (STZ)- induced hyperglycemia. We also found that PC1/3-expressing alpha-cells also improve cold-induced thermogenesis in db/db mice, demonstrating a previously unappreciated effect of one or more of the PC1/3-derived proglucagon products. Studies in isolated mouse islets demonstrate that adenoviral delivery of PC1/3 to isolated islets increases islet GLP-1 secretion and improves glucose-stimulated insulin secretion and islet survival. Experiments with diabetic mice show that these GLP-1-producing islets are better able to restore normoglycemia in recipient mice following islet transplantation. Taken together, these studies demonstrate that the alpha-cell can be induced to process proglucagon into PC1/3-derived products, and that this shift redirects the alpha-cell from a hyperglycemia-promoting fate to a blood glucose-lowering one. This research opens up avenues for further investigating the therapeutic potential of inducing islet GLP-1 production in isolated human islets and in vivo in diabetes patients, and may represent a novel way to intervene in the progressive loss of beta-cells that characterizes diabetes.

Specialized in form and function, the sperm cell is a unique microsystem unto itself where in the cytoskeletal processes and structures of the somatic cell often find new purpose and characteristics within the sperm. Unlike other cells in the human body, this unique cell polarizes and transforms itself from a line of germ cells to evolve into a functional, hydrodynamic haploid spermatozoon. The success of fertilization is dependent on this haploid cell and its specially designed vesicular structure, the acrosome, which provides the leading edge of oocyte penetration. To date, there is little insight into the mechanics of how acrosomic vesicles are successfully targeted and transported to the nuclear envelope and tether to its surface. Our laboratory has identified a novel 15 kDa sperm specific histone variant, SubH2Bv, which possesses a distinct and functional nuclear localization signal (NLS) that associates with the acrosomic vesicle. This study provides evidence that SubH2Bv’s bipartite NLS (an NLS with two basic domains linked together by 10-12 amino acid residues) is responsible for directing acrosomic vesicles to the nuclear envelope using the somatic import receptor, karyopherin alpha (Kap α). Based on bipartite NLS-receptor conventions, where karyopherin alpha is known to specifically associate with this NLS-type, SubH2Bv would be the karyophilic cargo and karyopherin alpha would act as part of the underlying transport mechanism. Western blot analysis and immunohistochemistry characterized Kap α as a membrane-associated sperm protein that is co-localized with SubH2Bv around the proacrosomic granules and the acrosomic vesicle during spermiogenesis. Their co-expression and co-localization, as demonstrated by immunolabelling, suggested a potential binding relationship that was confirmed by a His-tag-recombinant SubH2Bv-pull-down assay. The co-developmental acrosomic expression of Kap α and SubH2Bv in haploid cells, combined with the pull-down evidence of their binding affinity, provides a compelling argument that these two proteins work in concert to traffic the acrosomic vesicles to the nucleus. The exclusion of these two otherwise nuclear proteins from the nucleus, and their co-localization to the subacrosomal region in elongating spermatids, also implies a contingent role for SubH2Bv and Kap α in acrosomal docking, that may involve the classical bipartite/Kap α nuclear import pathway. / Thesis (Master, Anatomy & Cell Biology) -- Queen's University, 2008-09-02 16:11:17.429

No description available.

No description available.

Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal

No description available.

No description available.

La polyarthrite rhumatoïde est une maladie auto-immune caractérisée par une inflammation chronique qui entraîne la destruction progressive des articulations et des os. Les dommages articulaires observés dans cette pathologie sont causés principalement par les ostéoclastes, des cellules spécialisées dans la résorption de la matrice osseuse. Ce processus de résorption dépend de la capacité à générer des ostéoclastes, de leur activité individuelle et de leur survie. De plus, certaines cytokines inflammatoires peuvent avoir un effet sur la différenciation et l'activité des ostéoclastes. Parmi celles-ci, on retrouve notamment le TNF-?, un médiateur pathologique majeur dans la polyarthrite rhumatoïde. En effet, celui-ci peut agir de façon directe sur la résorption osseuse en stimulant l'ostéoclastogénèse, ou de façon indirecte en augmentant l'expression du RANKL par les ostéoblastes. Subséquemment à ces découvertes, plusieurs agents anti-TNF-? ont été développés pour traiter la polyarthrite rhumatoïde. Ces agents s'avèrent être très efficaces pour réduire les dommages articulaires chez les patients atteints de la maladie. Cependant, leurs mécanismes exacts ainsi que leurs effets sur la biologie des ostéoclastes humains sont encore mal définis. Ainsi, l'objectif principal de cette étude est d'étudier l'effet d'une thérapie anti-TNF-? sur le nombre de précurseurs ostéoclastiques dans le sang périphérique de patients atteints de la polyarthrite rhumatoïde, sur le nombre d'ostéoclastes générés in vitro ainsi que leur activité avant et pendant le traitement avec l'adalimumab, un agent anti-TNF-?. Pour ce faire, 25 patients atteints de cette maladie et ayant reçu une prescription d'adalimumab ont été recrutés pour participer à trois visites consécutives, soit les visites d'inclusion (avant traitement) ainsi que les visites 3 mois et 6 mois après le début du traitement. Pour chaque visite, le nombre de précurseurs ostéoclastiques, le nombre d'ostéoclastes et la résorption osseuse générés in vitro ont été évalués. Les mêmes paramètres ont également été vérifiés pour les cellules incubées en présence d'adalimumab exogène. L'activité de la maladie et le statut fonctionnel du patient, mesurés respectivement avec le Disease Activity Score 28 et le Health Assessment Questionnaire ont été évalués à chaque visite de la présente étude. La collecte de ces données a permis de conclure que le traitement avec l'adalimumab pendant 6 mois n'a pas d'impact statistiquement significatif sur le nombre de précurseurs ostéoclastiques, l'ostéoclastogénèse et la résorption osseuse in vitro , même si nous pouvons observer une tendance vers une diminution pour les deux derniers paramètres. En ce qui concerne les résultats cliniques, l'adalimumab a un effet statistiquement significatif sur le score DAS28 et le questionnaire HAQ, tous deux ayant diminué 6 mois après l'initiation du traitement.