La traduction d'une séquence nucléotidique d'ARNm dans plus d'un cadre de lecture est un phénomène découvert chez les virus vers la fin des années 1970. Depuis, quelques exemples de ce phénomène de traduction alternative ont été découverts chez l'humain dans les gènes INK4a, GNAS1, XBP1, et PRNP. La protéine alternative du gène GNAS , nommée ALEX, interagit et régule la protéine de référence et une mutation dans la protéine alternative peut engendrer certains phénotypes pathologiques. Plusieurs groupes de recherche ont effectué des analyses bio-informatiques sur le génome humain et ont suggéré que la traduction alternative de gènes pourrait être beaucoup plus importante que les quelques exemples connus à ce jour. Nous avons créé une base de données dans le but de prédire ces protéines alternatives à partir du transcriptome humain. Le gène ATXN1 semblait un candidat très intéressant à valider puisque la protéine de référence du gène, l'ATXN1, est impliquée dans une maladie neurodégénérative importante: l'ataxie spinocérébelleuse de type 1 (SCA1). Cette pathologie est causée par l'expansion d'une région CAG dans l'ADN qui est traduite en région polyglutamique. La protéine pathologique tend à agréger dans des inclusions nucléaires, ce qui induit l'altération de nombreux interacteurs de l'ATXN1 et pourrait interférer avec la fonction normale de ATXN1. Nous avons observé la présence de deux sites d'initiation alternatifs dans la séquence codante du gène ATXN1, situés dans le cadre de lecture +3. Expérimentalement, nous avons montré l'existence de deux isoformes de la protéine alternative nommée Alt-ATXN1, l'isoforme long étant fortement majoritaire. Alt-ATXN1, qui se localise dans le noyau, interagit de façon directe avec l'ATXN1 et coagrège avec celle-ci dans les inclusions nucléaires caractéristiques de la SCA1. Cette caractéristique intéressante suggère que la fonction biologique d'Alt-ATXN1 pourrait être altérée dans les cas de pathologie due à l'agrégation de l'ATXN1. Nous démontrons qu'Alt-ATXN1 lie les ARNm et possède une localisation nucléaire dépendante de la transcription, ce qui est caractéristique des protéines impliquées dans le processing de l'ARNm. L'existence d'Alt-ATXN1 a été confirmée in vivo dans une lignée neuronale humaine et dans des extraits de cervelets humains. Suite à ces découvertes, la fonction approfondie ainsi que la détermination du rôle d'Alt-ATXN1 dans la SCA1 demeurent sous investigation.

Emerging evidence has shown that an abnormal postprandial accumulation of dietary tat IS atherogenic. The aim of this study is to measure triacylglycerol (TAG) kinetics in endogenous and exogenous lipoproteins in both fed and fasted states using stable isotopes.

Transplantation of the islets of Langerhans is a promising technique for restoring the impairedinsulin production in brittle type 1 diabetics. The downside is that the patient will have to takeimmunosuppressant drugs in order to protect the islet cells from the immune system. Donorsare also sparse, making the quest of finding sufficient amounts of islets for transplantationhard. Encapsulation of the islets of Langerhans has been proposed as a means of protectingthe cells from the immune system taking away the need for immunosuppresives. The mostcommon encapsulation technique is extravascular capsules, which are categorized into micro-and macrocapsules. The microcapsules hold only one or a small set of islet whereas themacrocapsules hold a large quantity of islets.This thesis investigates the encapsulation impact on the beta-cells rapid insulin response torising plasma glucose levels. This was done by simulating the glucose-insulin system inMATLAB with included encapsulation of the islets. Two current macro-encapsulation set upswere used in the model, Beta-Air and ViaCyte devices, and they were compared against anormal case. The results showed that the Beta-Air device would not be able to restorenormoglycemia in a T1DM patient but rather showed a delay in insulin response, while theViaCyte device could mimic the normal case well.

Diabetes type 2 is a fast growing illness and a global health problem, often a result from less appropriate standard of living. Lifestyle changes related to diet and physical activity are important lifestyle changes regarding to get control of the self-management and to avoid vascular complications. Aim The aim of this study was to describe patient's experiences of lifestyle changes in diabetes type 2. Method A literature study was carried through based on 12 qualitative scientific articles. Results The analysis result into two main themes and eight subthemes. Main themes where barriers and motivators for lifestyle changes and the subthemes where struggle, denial, lack of knowledge, alienation, support, motivation, acceptance and knowledge. Conclusion This study shows that lifestyle changes are experienced different by patient with diabetes and nurses should therefore be aware of the unique and specific demands these patients require. This is important for providing a good diabetic healthcare and to help patients with their self-management

Abstract Background: Patients diagnosed with Type 1 diabetes mellitus (T1DM) require insulin therapy. Although necessary, insulin therapy is associated with an immediate increase in Body Mass Index (BMI). Excessive increase in BMI may lead to obesity, which is associated with both short and long-term negative health outcomes. The objective of this study was to determine whether weight change in the six months after diagnosis in children and adolescents with T1DM is related to obesity status at age 18. Methods: Data from the Diabetes Education Resource for Children and Adolescents database was used for this study. This unique database combines extensive clinical information on each patient with virtually universal coverage. The study population comprised all children 2-18 years old diagnosed with T1DM by DER-CA endocrinologists in Manitoba between 1997 and 2012 (N=377). BMI z- scores calculated from measured height and weight were used to classify BMI group membership using the 2000 Centers for Disease Control growth charts. Regression models were used to assess the association between change in BMI z-score six months after diagnosis, and BMI z-score at last visit prior to transfer to adult care. The models controlled for BMI z-score at diagnosis, sex, pubertal status and length of follow up. Additional stratified analyses examined sub-groups within the sample, to determine whether the effects were different for children with different characteristics (e.g. sex and pubertal status at diagnosis). Results: At diagnosis, 9% of the study cohort was underweight, 68% normal weight, 15% overweight and 8% obese. Most, (91%) but not all patients gained weight in the six months after T1DM diagnosis and initiation of insulin therapy. The pattern of weight change differed by BMI group at diagnosis, sex, and pubertal status. At last visit, average BMI z-scores for all groups of patients were above zero, and varied less than BMI z-scores at diagnosis. Results of the multivariate analytic model (adjusted R2= 0.56) show that BMI z-score at diagnosis was most important, followed by female sex, change in BMI z-score in the six months after diagnosis, the interaction between BMI z-score at diagnosis and change in BMI z-score in the six months after diagnosis, and duration of follow up. Conclusion: Results of this study demonstrate that patients’ BMI group, sex, and pubertal status at diagnosis influenced the pattern of their BMI z-score change in the six months after diagnosis, and thereafter. Diabetic care teams may need to monitor not only the amount of weight change in the period after T1DM diagnosis, but also consider BMI at diagnosis.

During the Paleoproterozoic Era (ca. 2.5 Ga to 1.6 Ga), Earth underwent dramatic changes to its tectonic and atmospheric parameters. These changes included: the formation and breakup of the supercontinent Nuna (Columbia) and the gradual rise in atmospheric oxygen levels. The gradual rise in atmospheric oxygen, referred to as the Great Oxidation Event (GOE), altered the behaviour of silicate mineral weathering, and permitted the formation of new types of economic uranium deposits. Beaverlodge Lake, Northwest Territories (NT), allows for the study of a weathering profile and uranium mineralization post GOE. At Beaverlodge Lake, NT, a regolith is preserved in a rhyodacitic porphyry of the ca. 1.93 Ga Hottah plutonic complex, which is unconformably overlain by the ca. 1.9 Ga quartz arenite of the Conjuror Bay Formation. Coincident with the unconformity is a past-producing uranium deposit (called the Tatie U deposit), which was mined out in the 1930s. Other uranium showings have been discovered at Beaverlodge Lake including the Bee showing. The initial purpose of this project was to examine the regolith through field, petrography, electron microprobe analysis (EMPA), whole-rock geochemistry, and mass balance calculations. The weathering profile shows an increase in Al2O3, Fe2O3T, K2O, P2O5, Ba, and Rb, a loss in SiO2, Na2O, MgO, and Sr, and constant and low abundance of CaO. Titanium remains constant in the weathering profile. Rare earth element (REE) analysis reveals remobilization of light REE (LREE) on a micrometer scale, but no cerium anomaly is preserved in the weathering profile. The weathering profile displays characteristics similar to other post GOE paleoweathering profiles developed on felsic parental material. The timing of uranium mineralization at Tatie and Bee was constrained by in-situ U-Pb uraninite dating by Secondary Ion Mass Spectrometer (SIMS), which yielded two variably discordant ages of 1370.2 ± 7.9 Ma and 407 ± 21 Ma. In addition, REE contents of uraninite were determined by in-situ Laser Ablation Inductively Coupled Plasma Mass Spectrometry (LA-ICP-MS). Results revealed two types of uraninite mineralization are preserved at Beaverlodge Lake and they consist of synmetamorphic at Bee and basement-hosted unconformity-type at Tatie similar to those in the Athabasca Basin. The ca. 1370 Ma uraninite (Tatie) is characterized by an asymmetric bell-shaped REE pattern centered on Tb to Er where LREEs are depleted compared to heavy REEs (HREE). The ca. 407 Ma uraninite at Bee has low La concentrations and a flat to slightly negative REE pattern. The Mesoproterozoic age is similar to a Pb loss age of ca. 1400 Ma found in the Athabasca Basin. The younger Devonian age may be related to meteoric fluids cycling and uranium remobilization during the Phanerozoic.

The purpose of this correlational study was to determine if women alcoholics (n = 31) percieve their surroundings differently, and thereby make decisions differently, than men alcoholics (n = 29), women nonalcohoics (n = 30) and men nonalcoholics (n = 29).The Myers-Briggs Type Indicator (Form 6) was utilized to determine reported preferences on extraversion-introversion (EI), sensing-intuition (SN), thinking-feeling (TF) and judgment-perception (JP). A 2 x 2 factorial analysis was conducted to tests the research questionsthe .05 level of significance. Other statistical analyses included a multiple regression analysis and Cronbacks Alpha coefficient of reliability.Findings1. Female alcoholics do not demonstrate an extraversion-introversion attitudinal preference that is significantly different than male alcoholics, female nonalcoholics and male nonalcoholics.2. Female alcoholics do not perceive their surroundings significantly different as reported on the sensing-intuition index than male alcoholics, female nonalcoholics and male nonalcoholics.3. Female alcoholics report no significant difference on preference for the thinking-feeling modes of judging than male alcoholics, female nonalcoholics and male nonalcoholics.4. Female alcoholics report no significant difference on preference for judgment-perception modes than male alcoholics, female nonalcoholics and male nonalcoholics.5. The main effect of Alcoholic Status accounted for differences between groups on EI. Alcoholics reported a preference for extraversion.6. A two-way interaction of Gender and Alcoholic Status on SI indicated that male alcoholics preferred the sensing mode while the male nonalcoholics preferred the intuition mode.7. The main effect of Gender showed that the women preferred the feeling mode and the men reported a preference for thinking.8. Demographic information indicated that the women alcoholics identified specific precipitating events to their drinking more often than men alcoholics and that the time between the onset of drinking and treatment was less for the women than for the men. The women reported a more frequent occurence of alcoholism among family members than the men.ConclusionsWomen alcoholics did not report a preference on any of the Myers-Briggs Type Indicator indices of EI, SN, TF, and JP that was significantly different from men alcoholics, women nonalcoholics and men nonalcoholics. In addition, the MBTI was not validated as a reliable clinical instrument. Recommendations for further research are made.

The major purpose of this study was to test the ability of the MyersBriggs Type Indicator (MBTI) to predict job satisfaction. Sixteen hypotheses were advanced and tested. They were grouped into four categories: (a) the ability of Judges to predict a subject's job satisfaction based upon their assessment that the subject's MBTI Type was compatible with their occupation; (b) the ability of the Minnesota Importance Questionnaire (MIQ) to predict job satisfaction; (c) acomparison of the predictive ability of the MBTI with the MIQ; (d) and, an exploration of the relationship of MBTI Type with the Needs measured by the MIQ.A review of related literature showed that the ability of the MBTI to predict job satisfaction had not been demonstrated satisfactorily in previous research while the MIQ had a demonstrated ability to predict satisfaction. Therefore, the MBTI was compared with the MIQ to see which could better predict satisfaction.The subjects used in this research were 369' Masters in Business Administration students from a medium sized private college in the Midwest. Sixty-five percent of the subjects were male and 35% were female. They had an average age of 30.5 years and 93% of the subjects were employed full-time.Three test instruments were used in this study. The MBTI was used to assess Psychological Type. The MIQ was used to measure Vocational Needs. A biographical information form was used to gather demographics on each subject. A question from the Hoppock Job Satisfaction Blank was included on the information form to measure job satisfaction.This study found that MBTI Type and various components of Type could be used by judges to predict job satisfaction based on judges' assessment of congruence between Type and occupation. It was found that the MIQ could predict job satisfaction based on congruence between MIQ profile and occupation. Comparison of the MBTI and MIQ showed that the MIQ was the better predictor of satisfaction but neither instrument was able to account for more than a small part of the satisfaction variance. Last, it was found that several of the MIQ Needs were related to components of the MBTI.This study provided support for the predictive ability of both the MBTI and the MIQ. It supported the use of the MBTI in career counseling and theory and pointed to several areas where additional research is needed. It provided an initial exploration into the relationship of the MBTI to the domain of vocational Needs as measured by the MIQ. / Department of Counseling Psychology and Guidance Services

Evidence is presented that Lymnaea contains homologues for mammalian Cav3 and NALCN 4-domain ion channels, which retain key amino acid sequence motifs that differentiate these channels from other 4-domain types. Molecular cloning and heterologous expression of the first invertebrate Cav3 channel cDNA from Lymnaea confirms that it indeed is a true homologue to mammalian Cav3 channels, retaining some hallmark biophysical and pharmacological features1. Interestingly, the Lymnaea Cav3 channel gene also exhibits alternative splicing that is conserved with mammalian Cav3.1 and Cav3.2 channels, with homologous exons 8b in the I-II linker (Cav3.1) and 25c in the III-IV linker (Cav3.1 and Cav3.2), that can selectively be included or omitted from the full length channel. We show that the developmental and spatial expression patterns of these splice variants are remarkably conserved, and that these splice variants produce analogous changes in membrane localization and biophysical properties when channels are expressed in HEK-293T cells. The Lymnaea Cav3 channel gene also undergoes alternative splicing in the domain II P-loop, with mutually exclusive exons 12A and 12B that code for a large portion of the P-loop just upstream of the selectivity filter. Such splicing is a novel discovery that is not conserved with vertebrates or any other deuterostome animal, all of which only contain 12A homologues of exon 12. However, protostome animals including Lymnaea stagnalis, Drosophila melanogaster, and C. elegans all have mutually exclusive 12A and 12B exons in their Cav3 channel genes. Evidence is presented that exon 12A is likely the ancestral exon for the domain II P-loop, and that alternate exon 12B evolved later. Furthermore, although the two Lymnaea variants possess the same selectivity filter motifs characteristic for Cav3 channels (i.e. EEDD), they exhibit dramatic differences in calcium vs. sodium selectivity, without significant differences in biophysical properties. This is the first account of alternative splicing used to modulate ion selectivity in a Cav3 channel homologue, and given that calcium is such an important electrogenic signaling molecule, these alterations are expected to have profound physiological implications. Amazingly, Lymnaea NALCN was also found to undergo alternative splicing in the domain II P-loop, but in this case, the entire P-loop is replaced by mutually exclusive exons 15a and 15b such that the selectivity filter is converted from the proposed non-selective sodium-permeable configuration (15b/EKEE; EEKE in mammals, nematodes and insects), to a calcium channel-like pore (15a/EEEE). Thorough phylogenetic analysis reveals that NALCN is extremely unconventional, in that alternative splicing has frequently and independently evolved to alter the selectivity filter in domains II or III, in multiple animal clades. Furthermore, the ancestral NALCN channel most likely contained an EEEE pore. This work brings into question NALCN???s proposed role as a major leak sodium conductance that depolarizes neurons to help set the resting membrane potential, since some species possess only an EEEE variant, and based on homology to other 4-domain ion channels, this should render the channel calcium-selective. Unfortunately, heterologous expression and electrophysiological characterization of the two Lymnaea NALCN isoforms was unsuccessful, corroborating with others the inability to record NALCN ionic currents in heterologous systems.

Loss of glucose-stimulated insulin secretion (GSIS) from the pancreatic beta-cells is one of the earliest detectable defects in the pathogenesis of type 2 diabetes. However, despite its relevance, the mechanisms that govern GSIS are still not completely understood. ARNT/HIF-1β is a member of the bHLH-PAS family of transcription factors, with a prominent role in the transcriptional regulation of enzymes required for the metabolism of xenobiotics as well as regulation of genes that are critical for cellular responses to hypoxia. Recent research has uncovered a previously unknown function for ARNT/HIF-1β in the pancreatic beta-cells, where the gene was found to be 90% down-regulated in human type 2 diabetic islets and loss of ARNT/HIF-1β protein leads to defective GSIS in pancreatic beta-cells of mice. The main focus of this thesis was to understand the mechanisms by which ARNT/HIF-1β maintains normal GSIS from pancreatic beta-cells and understand how loss of ARNT/HIF-1β leads to beta-cell dysfunction and type 2 diabetes in mice. ARNT/HIF-1β was found to positively regulate GSIS in both INS-1 derived 832/13 cell line and mice islets. In the 832/13 cells, loss of ARNT/HIF-1β leads to a reduction in glycolysis without affecting the glucose oxidation and the ATP/ADP ratio suggesting that the regulation of GSIS takes place in a manner that is independent of the KATP channels. In order to further assess the mechanism of lowered GSIS in the absence of ARNT/HIF-1β in the 832/13 cells, a metabolite profiling was performed which revealed a significant reduction in the metabolite levels of glycolysis and the TCA cycle intermediates and glucose-induced fatty acid production, suggesting the involvement of ARNT/HIF-1β in regulating glucose-stimulated anaplerosis, which is believed to play a key role in the regulation of GSIS from the pancreatic beta-cells. The changes in metabolite levels in the absence of ARNT/HIF-1β were associated with corresponding changes in the gene expression pattern of key enzymes regulating glycolysis, the TCA cycle and fatty acid synthesis in beta-cells. In an attempt to understand how loss of ARNT/HIF-1β leads to beta-cell dysfunction and type 2 diabetes in mice, a pancreatic beta-cell specific ARNT/HIF-1β knock out mouse (β-ARNT KO) was generated using the Cre-loxP technology. Functional characterization of islets from both male and female β-ARNT KO mice revealed a significant impairment in GSIS, which was attributed due to a small, but significant reduction in rise in intracellular calcium upon glucose stimulation. Further analysis revealed reduced secretory response to glucose in the presence of KCl and diazoxide indicating a defect in the amplifying pathway of GSIS in β-ARNT KO islets. Expression of pyruvate carboxylase (PC) was significantly reduced in β-ARNT KO islets suggesting possible impairments in anaplerosis and consistent with this, defect in GSIS in β-ARNT KO islets could be almost completely rescued by treatment with membrane permeable TCA intermediates. Surprisingly, both male and female β-ARNT KO mice have normal glucose homeostasis. In an attempt to assess how β-ARNT KO mice maintained normal blood glucose levels, indirect calorimetry was used to understand changes in whole-body energy expenditure. This investigation revealed that β-ARNT KO mice exhibited a small but significant increase in respiratory exchange ratio (RER), suggesting a preference in utilizing carbohydrates as a fuel source, possibly leading to improved glucose uptake from the blood stream. Response to exogenous insulin was completely normal in β-ARNT KO mice suggesting intact functioning of the skeletal muscles. To conclude, based on our in vitro data, we believe that ARNT/HIF-1β plays an indispensable role in maintaining normal beta-cell secretory function, however, results from β-ARNT KO mice indicates that these mice are protected from the adverse effects of hyperglycemia. Although loss of ARNT/HIF-1β alone is not sufficient for the genesis of type 2 diabetes, it creates a perfect storm in the pancreatic beta-cells that may eventually lead to an imbalance in the whole body glucose homeostasis. Our study provides significant information to the scientific community that engages in assessing the pharmacological potential of gene targets for the treatment of type 2 diabetes.