The RAS-mitogen-activated protein kinase (MAPK) pathway is an essential signaling mechanism that regulates cellular processes and culminates in the activation of specific gene expression programs. Alterations in the RAS-MAPK signaling cascade can modify epigenetic programs and confer advantages in cell growth and transformation. In fact, deregulation of the cascade is a key event in tumour development with 30% of human cancers harbouring RAS mutations. In breast and pancreatic epithelial cancers, characterization of an aberrant RAS-MAPK pathway has focused on upstream mediators such as receptors and oncogenic RAS molecules but the impact of downstream targets remain poorly defined. Stimulation of the RAS-RAF-MEK-MAPK pathway leads to activation of mitogen- and stress-activated protein kinases 1 and 2 (MSK1/2) which are responsible for the phosphorylation of histone H3 on S10 and S28. We postulate that deregulation of the RAS-MAPK pathway produced by constitutive activation and/ or over-expression of upstream components or mitogen stimulation consequently leads to enhanced MSK1 activity and elevated histone H3 phosphorylation levels. We further hypothesize that MSK1-mediated H3 phosphorylation is critical for immediate early gene (IEG) expression, Ras-driven transformation and is associated with regulatory regions upon gene transcription. In mouse fibroblasts, we present evidence for the critical involvement of MSK1 and H3 phosphorylation as mediators that bridge the aberrant signals driven by the RAS-MAPK pathway with nucleosomal modifications, chromatin remodeling, IEG expression and malignant transformation. We then examined if activation of RAS-MAPK signaling in breast cancer cells elicits similar molecular events. We demonstrate that the RAS-MAPK pathway is induced and enhances the association of MSK1 and H3 phosphorylation on the IEG Trefoil Factor 1 resulting in transcriptional activation. We further observed that mutated K-RAS expression did not correlate with genomic instability or altered signaling in pancreatic cancer cell lines while overexpressed HER2 and EGFR breast cancer cell lines generally exhibit upregulated ERK1/2 and H3 phosphorylation levels. Taken together, our studies contribute to the further understanding of MSK-mediated transcriptional activation in response to RAS-MAPK signaling in oncogene-transformed and cancer cell lines. Inhibition of MSK activity may be an unexplored avenue for combination cancer therapy with abnormal RAS-MAPK signaling pathways.

This study explores radical pacifists’ intellectual engagement with the black freedom movement by examining the New York-based magazine Liberation between 1956 and 1965. It argues that two priorities shaped Liberation’s responses to the movement: the concern to promote the philosophy and practice of nonviolent direct action, and the concern to advocate radical social change in the United States. Until 1965 Liberation promoted the civil rights movement as a potential catalyst for the nonviolent reconstruction of U.S. democracy. Liberation became a forum for exploring the common ground as well as the tensions between radical pacifist priorities and those of various black freedom activists. The tensions are particularly apparent in Liberation’s reflections on the challenges of linking peace activism with the freedom struggle in the early 1960s, and in its 1964-65 debate over civil rights leaders’ strategy of coalition with the Democratic Party in the context of the escalating war in Vietnam.

Predictive models are used to identify potentially problematic components that decrease product quality. Design and source code metrics are used as input features for predictive models; however, there exist a large number of structural measures that capture different aspects of coupling, cohesion, inheritance, complexity and size. An important question to answer is: Which metrics should be used with a model for a particular predictive objective? Identifying a metric subset that improves the performance for the classifier may also provide insights into the structural properties that lead to problematic modules. In this work, a genetic algorithm (GA) is used as a search-based metric selection strategy. A comparative study has been carried out between GA, the Chidamber and Kemerer (CK) metrics suite, and principal component analysis (PCA) as metric selection strategies with different datasets. Program comprehension is important for programmers and the first dataset evaluated uses source code inspections as a subjective measure of cognitively complexity. Predicting the likely location of system failures is important in order to improve a system’s reliability. The second dataset uses an objective measure of faults found in system modules in order to predict fault-prone components. The aim of this research has been to advance the current state of the art in predictive models of software quality by exploring the efficacy of a search-based approach in selecting appropriate metrics subsets. Results show that GA performs well as a metric selection strategy when used with a linear discriminant analysis classifier. When predicting cognitive complex classes, GA achieved an F-value of 0.845 compared to an F-value of 0.740 using PCA, and 0.750 for the CK metrics. By examining the GA chosen metrics with a white box predictive model (decision tree classifier) additional insights into the structural properties of a system that degrade product quality were observed. Source code metrics have been designed for human understanding and program comprehension and predictive models for cognitive complexity perform well with just source code metrics. Models for fault prone modules do not perform as well when using only source metrics and need additional non-source code information, such module modification history or testing history.

The purpose of this study was to answer the question: how do children influence attraction choice while on vacation? A cross-sectional, self-administered, web-based survey of 99 adult facilitators visiting one of three tourist attractions in Winnipeg, Canada with at least one child between the ages of six and 17 was used to: 1) gain insight on how groups with a child/children prefer to travel; 2) understand the reasons why groups with a child/children choose to visit a select type of attraction; 3) examine the views of adult facilitators who travel with a child/children on the child/children’s participation with regards to the selection of tourist attractions; and 4) investigate which attraction characteristics adult facilitators believe provide their entire group with the most satisfying experience. Results indicate that children have relatively little direct influence within the family or group unit on attraction choice.

Preparatory steps for the experimental investigation of the highly forbidden 5s - 6s transition in rubidium using an atom trap and laser cooling are reported. A magneto-optical trap (MOT) has been assembled including saturation spectroscopy and a dichroic vapor laser lock. A frequency-doubled diode laser system has been installed to perform the spectroscopy of the forbidden transition with cold Rb atoms in the trap. The properties of the ns - n's transition in the presence of an external electric fi#12;eld have been investigated theoretically. A fi#12;rst measurement will be exploring the Stark-induced transition amplitude and the very faint magnetic dipole amplitude. The rubidium experiment is a precursor study for a long-term project at TRIUMF, Canada's National Laboratory for nuclear and particle physics, to measure atomic parity violation in the equivalent 7s - 8s transition in francium, the heaviest alkali atom which has no stable isotopes.

Recently, Hudson Bay experienced unidirectional trends in temperature, sea-ice extent, time of break-up, and length of the open-water season. Predicted impacts on population dynamics of ice-associated species include habitat loss and shift in prey availability. The ringed seal (Phoca hispida) depends on a stable ice platform with sufficient snow depth and a productive open-water season for reproduction and survival. Evidence of ringed seal sensitivity to environmental variations has been reported, but mechanisms involved were poorly understood. In western Hudson Bay, density, life-history traits, and diet of ringed seals were monitored over two decades, providing an opportunity to understand the effects of climatic variations on the population dynamics of this long-lived carnivore. Ringed seal density was estimated through strip-transect analyses after aerial surveys were flown in western Hudson Bay in late spring during the annual moult in the 1990s and 2000s. During these periods, ringed seals were also sampled from Inuit subsistence fall harvests In Arviat, NU, and ages, reproductive status, percentage of pups in the harvest, body condition, and diet were assessed. Strong inter-annual variations in these parameters were observed, and a decadal cycle was suggested and related to variations in the sea-ice regime. The cold and heavy ice conditions that prevailed in western Hudson Bay in 1991-92 likely induced a decrease in pelagic productivity, reducing the availability to ringed seals of sand lances (Ammodytes sp.), their major prey. The nutritional stress endured, combined with a strong predation pressure, led to a decrease in ringed seal reproductive performances, pup survival, and density during the 1990s. The recovery of ringed seal demographic parameters and number in the 2000s was associated with the immigration of pups, juveniles, and young adults into western Hudson Bay. Impact of current climatic trends on ringed seal population dynamics was not apparent, but considering the limited range of environmental variations tolerated by ringed seals, the response of this species to climate warming might be of a catastrophic type. Ringed seals were found to be good indicators of ecosystem changes, and long-term monitoring of the species in Hudson Bay should be a priority.

The sewing operation is an integral component of both Geometric Function Theory and Conformal Field Theory and in this thesis we explore the interplay between the two fields. We will first generalize Huang's Geometric Sewing Equation to the quasi-symmetric case. That is, given specific maps g(z) and f^{-1}(z), we show the existence of the sewing maps F_{1}(z) and F_{2}(z). Second, we display an algebraic procedure using convergent matrix operations showing that the coefficients of the Conformal Welding Theorem maps F(z) and G(z) are dependent on the coefficients of the map phi(z). We do this for both the analytic and quasi-symmetric cases, and it is done using a special block/vector decomposition of a matrix representation called the power matrix. Lastly, we provide a partial result: given specific maps g(z) and f^{-1}(z) with analytic extensions, as well as a particular analytic map phi(z), it is possible to provide a method of determining the coefficients of the complementary maps.

Type 2 diabetes is now recognized as a worldwide epidemic. Pancreatic beta-cell decompensation in the presence of insulin resistance is a major mechanism for the development of type 2 diabetes and may be triggered by mitochondrial dysfunction. Alcoholism is a known risk factor for type 2 diabetes. Excessive or chronic alcohol consumption leads to increased oxidative stress and mitochondrial dysfunction in beta-cells. Prohibitin is a multifunctional protein that also regulates mitochondrial biogenesis and function. Although it has anti-oxidant effects in some cell types, its role in pancreatic beta-cells is not known. This study has investigated the effects of prohibitin in ethanol treated pancreatic beta-cells using RINm5F and INS-1E cell lines. Prohibitin was found to be expressed in pancreatic beta-cells with localization to the nucleus and the perinuclear area. Ethanol increased the expression of prohibitin and induced its translocation from the nucleus to the mitochondria. Ethanol, through its metabolism by alcohol dehydrogenase (ADH), increased oxidative stress and altered mitochondrial membrane potential, decreased the activity of mitochondrial respiratory complexes I and IV, and uncoupled energy production with resulting reduction in ATP production. This was associated with activation of the proinflammatory enzyme c-Jun N-terminal kinase and proapoptotic proteins Bax and caspase-3, leading to beta-cell apoptosis. Ethanol also reduced glucose induced insulin secretion without alteration of the beta-cell transcription factors PDX-1 and MafA. Treatment with exogenous prohibitin or cellular overexpression of endogenous prohibitin attenuated ADH activity, prevented the deleterious effects of ethanol on mitochondrial function and reduced apoptosis, whereas prohibitin knockdown enhanced ethanol-induced apoptosis. In addition, prohibitin per se increased PDX-1 and MafA levels. Through the above mechanisms, prohibitin restored glucose induced insulin secretion in ethanol exposed beta-cells. In brief, ethanol causes mitochondrial dysfunction and induces apoptosis in beta-cells, which result in a reduction of insulin secretion; whereas prohibitin prevents mitochondrial dysfunction, apoptosis, and -cell failure by stabilizing mitochondrial complexes I and IV and inhibiting ADH activity during ethanol metabolism. In addition, prohibitin in itself increases the levels of beta-cell transcription factors. As a consequence, prohibitin maintains normal pancreatic beta-cell function and could be useful in diabetes prevention and treatment.

Fabric as a flexible formwork for concrete is an alternative giving builders, engineers, and architects the ability to form virtually any shape. This technique produces a superb concrete surface quality which requires no further touch up or finishing. Woven polyole-fin fabrics are recommended for this application. A permeable woven fabric allows excess water from the concrete mix to bleed through the mold wall, and therefore reduce the water-cement ratio of the concrete mix. Due to the reduction in water-cement ratio, higher compressive strength in fabric formed concrete may be achieved, as also suggested by earlier research. The current research study was conducted to investigate and document the changes in concrete strength and overall quality due to use of commercially available woven polyolefin fabrics. Use of fabric formwork will contribute to decreased construction cost, construction waste, and greenhouse gas emissions. Two sets of tests were conducted as a part of this research study including comparison of compressive strength of fabric formed versus PVC formed concrete cylinders and comparison of be-haviour of the fabric formed reinforced columns versus cardboard formed reinforced concrete columns. Variables in this research were limited to two types of fabric with dif-ferent permeability (Geotex 104F and Geotex 315ST) and two types of concrete; concrete made with conventional Portland cement and no flyash herein called normal concrete (NC) and concrete with 30 percent flyash in its mix design (FAC). The laboratory results revealed that fabric Geotex 315ST is an ideal geotextile for forming concrete. It was also found that the effects of fabric formwork on concrete quality in a large member are limited mostly to the surface zone and the core of the concrete remains the same as a conventionally formed concrete. Even though fabric formed cylinder tests showed an average of 15% increase in compressive strength of the concrete samples, compressive strength of the reinforced columns did not dramatically change when com-pared to the companion cardboard formed control columns. This research confirmed that fabric formwork is structurally safe alternative for forming reinforced concrete columns.

Les Métis francophones ont été maîtres de leur territoire pendant moins de 100 ans. Leur nombre domine jusqu’à la Confédération, mais par la suite, ils subissent un recul. Mais, après la Confédération, ils ont connu un recul. Leur situation ne s’est améliorée qu’à la fin du XXe siècle. Aujourd’hui, les Métis francophones retrouvent leur place dans la société et à l’intérieur de la nation métisse, malgré leur statut de double minorité. Les défis ont été nombreux pour ces Métis. Dès le commencement, ils ont dû se battre contre des Indiens pour protéger leur territoire de chasse. Puis, ils ont fait face à un grand nombre de Blancs qui viennent coloniser l’Ouest. De plus, la Compagnie de la baie d’Hudson abuse de son pouvoir et cherche à monopoliser la traite des fourrures. Les Métis ont pu garder le libre-échange de la traite avec la Compagnie de la baie d’Hudson et les autres compagnies. Le clergé a souvent appuyé les Métis, mais quand les Blancs sont devenus plus nombreux, les Métis ont un peu été mis à l’écart. Le gouvernement canadien tente de prendre le contrôle du Manitoba en 1869, mais les Métis résistent et gagnent certains droits, pour les francophones, les Métis et les anglophones. Ces droits sont en partie ce qui aidera les Métis à sortir du Temps noir. Malgré cela, après leur défaite à Batoche et la mort de Louis Riel, les Métis sont contraints de cacher leur véritable identité pendant cent ans. En 1982, les Métis sont inclus dans la Loi constitutionnelle de 1982, ce qui provoque une nouvelle visibilité dans les recensements, qui continue encore aujourd’hui. L’étude de l’évolution démographique des Métis francophones n’est pas simple, mais il existe assez d’informations pour en tirer des conclusions. Grâce aux données de recensements et à des témoignages, nous avons suivi leur parcours démographique. De plus, en utilisant les sources historiques et les histoires personnelles des Métis, nous avons déterminé les facteurs qui ont influencé leur croissance ou leur décroissance démographique. Toutes ces données, étalées au fil du temps, nous ont permis de voir que la famille métisse, les Charrettes, ont connu trois origines différentes, ce qui explique aujourd’hui le nombre croissant de personnes qui se déclarent métisses pour la première fois.