Indiana University-Purdue University Indianapolis (IUPUI) / Pompe disease (PD) is a rare metabolic myopathy characterized by loss of acid alpha-glucosidase (GAA), the enzyme responsible for breaking down glycogen to glucose within the lysosomes. PD cells accumulate massive quantities of glycogen within their lysosomes, and as such, PD is classified as a “lysosomal storage disease” (LSD). GAA-deficient cells also exhibit accumulation of autophagic debris. Symptoms of severe infantile PD include extreme muscle weakness, hypotonia, and hypertrophic cardiomyopathy, resulting in death before one year of age. Certain LSDs are currently being successfully treated with enzyme replacement therapy (ERT), which involves intravenous infusion of a recombinant enzyme to counteract the endogenous deficiency. ERT has been less successful in PD, however, due to ineffective delivery of the recombinant enzyme. Alternatively, specific genes deletion may reduce lysosomal glycogen load, and could thus be targeted in PD therapy development. Absence of malin (EPM2B) or laforin (EPM2A) has been proposed to impair autophagy, which could reduce lysosomal glycogen levels. Additionally, deficiency of Stbd1 has been postulated to disable lysosomal glycogen import. Furthermore, Ptg deficiency was previously reported to abrogate Lafora body formation and correct neurological abnormalities in Lafora disease mouse models and could have similar effects on PD pathologies. The goal of this study was to characterize the effects of homozygous disruption of Epm2a, Epm2b, Stbd1, and Ptg loci on total glycogen levels in PD mouse model heart tissue, as in severe infantile PD, it is accumulation of glycogen in the heart that results in fatal hypertrophic cardiomyopathy. Gaa-/- mice were intercrossed with Epm2a-/-, Epm2b-/-, Stbd1-/-, and Ptg-/- mice to generate wildtype (WT), single knockout, and double knockout mice. The results indicated that Gaa-/- hearts accumulated up to 100-fold more glycogen than the WT. These mice also displayed cardiac hypertrophy. However, deficiency of Epm2a, Epm2b, Stbd1, or PTG in the Gaa-/- background did not reveal changes of statistical significance in either heart glycogen or cardiac hypertrophy. Nevertheless, since total glycogen was measured, these deficiencies should not be discarded in future discussions of PD therapy, as increasing sample sizes and/or distinguishing cytosolic from lysosomal glycogen content may yet reveal differences of greater significance.

Objective: Anterior cruciate ligament (ACL) injuries are increasing in adolescents and increase the risk for early-onset knee osteoarthritis (OA). Biomarkers can be a non-invasive measure to assess physiological properties following knee injury or trauma. The objective of this thesis was to i) perform a systematic review to determine the most studied biomarkers of knee healing following ACL reconstruction (ACLR), and age of these patients, and ii) explore the feasibility of measuring these biomarkers in adolescents with ACL injuries. Design: Studies were included if i) participants underwent ACLR, and ii) at least one biomarker of healing was measured. Participant age, sample(s) collected, and biomarker(s) studied were recorded. Interleukin-6 (IL-6), c-terminal crosslinking telopeptide of type II collagen (CTX-II) and procollagen type II collagen propeptide (PIICP) were then measured using ELISA in adolescents prior to ACLR in urine (u) and synovial fluid (sf). Spearman’s Rho (rs) coefficients were calculated to determine the association between uCTX-II/sfCTX-II, and uIL-6/sfIL-6. A ratio of PIICP: CTX-II was calculated to represent the ratio of cartilage synthesis to degradation. Results: The review produced six studies evaluating healing following ACLR. IL-6 and CTX-II were the most studied (3/6 studies), and only one study included adolescents (age 19.6±4.5). Due to multiple undetectable biomarker levels, we could only report rs for uCTX-II/sfCTX-II (rs = -.200, p-value = .800, n=4). We also reported a ratio for sfPIICP: sfCTX-II (23.06 ±19.23). Conclusion: Exploring biomarkers in adolescents was motivated by their unique physiology due to puberty, and this was the first study to do so. The findings from this pilot study indicate that further analysis is required to determine optimal sample preparation. This will allow for reliable results while studying the feasibility of these biomarkers during ACLR recovery. This insight can ensure more informed decision making by clinicians clearing patients for return-to-activity.

HIV/AIDS is raging and causing millions of deaths around the world. The major challenge in treating HIV/AIDS is the establishment of HIV reservoirs where the viruse escapes both drug and immune system attempts at eradication. Throughout the course of HIV/AIDS, productive HIV infection occurs primarily in the lymphoid follicles or germinal centers (GC) surrounding follicular dendritic cells (FDC). In the GCs, FDCs trap and maintain infectious HIV for years and provide these infectious viruses to the host cells. FDCs also attract B and T cells into the GCs and increase the ability of CD4+ T cells to be infected. Additionally, FDCs also mediate the increase of HIV replication in HIV-infected CD4+ T cells. Recently, several clinical cases and in vitro studies suggest that alpha-1-antitrypsin (AAT) might inhibit HIV infection and replication. Therefore, I hypothesized that AAT inhibited both the infection and replication of HIV in primary CD4+ T cells. I also postulated that AAT inhibited the FDC-mediated contributions that potentiate HIV infection and replication. To test whether AAT inhibited HIV infection in lymphocytes, CD4+ T cells were pretreated with AAT and then incubated with HIV to detect HIV infection. To exam whether AAT inhibited HIV replication, infected CD4+ T cells were cultured with AAT to detect the replication of HIV. To determine whether AAT blocked the FDC-mediated contributions to HIV pathogenesis, activated or resting FDCs were treated with AAT to detect the trapping and maintenance of HIV. The results suggested that AAT inhibited HIV entry into CD4+ T cells by directly interacting with gp41 and thereby inhibiting the interaction between HIV and CD4+ T cells. AAT also inhibited HIV replication in infected CD4+ T cells. Further study revealed that AAT interacted with low-density lipoprotein-receptor related protein to mediate the internalization of AAT through a clathrin-dependent endocytic process in CD4+ T cells. Subsequently, internalized AAT was transported from the endosome to the lysosome and then released into the cytosol. In the cytosol, AAT directly interacted with IκBα to block its polyubiquitinylation at lysine residue 48, which resulted in the accumulation of phosphorylated/ubiqutinylated IκBα in the cytosol. In turn, the dissociation of IκBα from NF-κB was blocked, which thereby inhibited the nuclear translocation and activation of NF-κB. Additionally, AAT also down-regulated FDC-CD32 and FDC-CD21 expression, which are regulated by NF-kB, thereby inhibiting the trapping and maintenance of HIV on FDCs. Hence, AAT not only suppresses HIV replication, but also blocks HIV replication in CD4+ T cells. Moreover, AAT also inhibits the activation of FDCs thereby affecting the trapping and maintenance of HIV.

<p>The joint censoring scheme is of practical significance while conducting comparative life-tests of products from different units within the same facility. In this thesis, we derive the exact distributions of the maximum likelihood estimators (MLEs) of the unknown parameters when joint censoring of some form is present among the multiple samples, and then discuss the construction of exact confidence intervals for the parameters.</p> <p>We develop inferential methods based on four different joint censoring schemes. The first one is when a jointly Type-II censored sample arising from $k$ independent exponential populations is available. The second one is when a jointly progressively Type-II censored sample is available, while the last two cases correspond to jointly Type-I hybrid censored and jointly Type-II hybrid censored samples. For each one of these cases, we derive the conditional MLEs of the $k$ exponential mean parameters, and derive their conditional moment generating functions and exact densities, using which we then develop exact confidence intervals for the $k$ population parameters. Furthermore, approximate confidence intervals based on the asymptotic normality of the MLEs, parametric bootstrap intervals, and credible confidence regions from a Bayesian viewpoint are all discussed. An empirical evaluation of all these methods of confidence intervals is also made in terms of coverage probabilities and average widths. Finally, we present examples in order to illustrate all the methods of inference developed here for different joint censoring scenarios.</p> / Doctor of Science (PhD)

Bakgrund: Diabetes mellitus är ett växande folkhälsoproblem då allt fler insjuknar i sjukdomen. Det är en kronisk sjukdom och förekommer i två olika typer, typ I och typ II varav typ II är den mest utbredda. Övervikt är en bidragande orsak till att personer utvecklar diabetes mellitus typ II, därför är det viktigt att göra livsstilsförändringar när diagnosen erhållits. Det är betydelsefullt att som sjuksköterska hjälpa och stödja personer utifrån deras behov. Syfte: Att beskriva kvinnors upplevelser av att leva med diabetes mellitus typ II. Metod: En litteraturöversikt med kvalitativ design där 16 artiklar har analyserats och sammanställts till ett resultat. Resultat: Flertalet kvinnor upplevde en ökad oro och stress över hur de skulle hantera sin sjukdom. Det fanns flera olika faktorer som påverkade hur kvinnorna skötte sin sjukdom. För att de skulle förändra sin vardag och genomföra livsstilsförändringar var det nödvändigt med kunskap och information. Slutsats: För att hantera sin sjukdom krävs adekvat information ifrån hälso- och sjukvården. Brist på adekvat information kan visa på att det inte finns så stor kompetens kring sjukdomen. För att kunna optimera vården är det viktigt att som sjuksköterska ha kunskap om hur sjukdomen upplevs. / Background: Diabetes mellitus is a growing public health problem as more fall ill with the disease. It is a chronic disease and occurs in two types, type I and type II, which type II is the most widespread. Obesity is a contributing factor to people developing diabetes mellitus type II, so it is important to make lifestyle changes when diagnosed been acquired. It is significant as a nurse to help and support people based on their needs. Aim: To describe women's experience of living with diabetes mellitus type II. Method: A literature review where a qualitative design has been implemented, 16 articles have been analyzed to the result. Results: Most women experienced increased anxiety and stress over how to manage their disease. There were several factors that influenced how women managed their disease. To change their daily lives and to implement lifestyle changes, it was necessary to have knowledge and information. Conclusion: To manage their condition it requires adequate information from healthcare. Lack of adequate information can demonstrate that there is not so much expertise about the disease. In order to optimize the care it is important that as a nurse to have knowledge of how the disease is experienced.

No description available.

La bactérie Gram négative Pseudomonas aeruginosa produit un grand nombre d’exoprotéines remplissant de multiples fonctions. Pour rejoindre la surface ou le milieu extracellulaire, ces exoprotéines doivent franchir successivement la membrane interne, le périplasme et la membrane externe. De multiples systèmes de sécrétion ont été mis en place par P.aeruginosa pour réaliser ces différentes étapes. Ainsi, les exoprotéines peuvent traverser l’enveloppe par le système le plus approprié à leur transport. Un de ces systèmes, le système de sécrétion de type II (T2SS) est présent en deux exemplaires. Ces deux T2SS, complets et fonctionnels ont été appelés Xcp (« extracellular deficient protein ») et Hxc (« Homologue toXcp »). Si les éléments constitutifs des T2SSs sont bien identifiés, leur assemblage au sein de l’enveloppe ainsi que leur mode de sécrétion sont très peu documentés. Le modèle communément admis suggère cependant l’existence d’une plateforme de membrane interne, d’un composant demembrane externe et d’un pseudopilus, qui va tel un piston, pousser les substrats au travers du pore formé par l’unique composant de membrane externe, la sécrétine. Les sécrétines formentdans la membrane externe de larges pores homo-multimériques de 12 à 14 monomères.L’adressage et l’assemblage de telles structures nécessitent en général l’implication d’une petite lipoprotéine, connue sous le nom de pilotine. A ce jour, aucune protéine de ce type n’est connue pour assister les multiples sécrétines répertoriées chez P. aeruginosa dans leur adressage à lamembrane externe. Ce travail de thèse à principalement porté sur le second T2SS de P.aeruginosa, le système Hxc. Nous avons en particulier démontré que la sécrétine du système Hxc,HxcQ ne dépendait d’aucune pilotine pour son adressage à la membrane externe et que cette sécrétine était une lipoprotéine dont l’ancre lipidique N-terminale jouait le rôle de pilotine. / The Gram negative bacteria Pseudomonas aeruginosa produces a large number of exoproteins that have multiple functions. To reach the cell surface or the extracellular medium, an exoprotein must successively cross the inner membrane, the periplasm and the outer membrane.P. aeruginosa has developed a number of secretion systems that carry out these different steps.Thus, a specific exoprotein will cross the envelope using the most suitable secretion system. Oneof these systems, the type II secretion system (T2SS), is present in two copies on the P.aeruginosa genome. Both T2SS are complete and functional, and have been named Xcp(« extracellular deficient protein ») and Hxc (« Homologue to Xcp »). While the different components that make up each T2SS have been clearly identified, their assembly in the envelopeand their mode of secretion are poorly documented. Nevertheless, the commonly acceptedworking model suggests the existence of an inner membrane platform, a component in the outer membrane, and a pseudopilus which, acting as a piston, pushes the substrate through a pore formed by the sole component of the outer membrane, the secretin. Secretins form large homomultimeric pores (12 to 14 monomers) in the outer membrane. Targeting and assembly ofsuch structures requires the involvement of a small lipoprotein known as pilotin. To date, no suchprotein is known to assist the targeting of P. aeruginosa secretins to the outer membrane. This thesis work has mainly focused on the second T2SS of P. aeruginosa, the Hxc system. One of ourmajor findings is that the outer membrane targeting of the Hxc secretin, HxcQ, does not dependon any pilotin, but that instead HxcQ is a lipoprotein with a lipid anchor that acts as a pilotin.

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

The emergence of semiconducting nanowires as the new building blocks for photovoltaic (PV) devices has drawn considerable attention because of the great potential of achieving high efficiency and low cost. In special, nanowires with a coaxial structure, namely, core-shell structures have demonstrated significant advantages over other device configurations in terms of radial charge collection and cost reduction. In this dissertation, several core-shell nanowire structures, including ZnO/ZnSe, ZnO/ZnS, and CdSe/ZnTe, have been synthesized and the photovoltaic devices processed from a ZnO/ZnS core-shell nanowire array and a single CdSe/ZnTe core-shell nanowire have been demonstrated. By combining the chemical vapor deposition and pulsed laser deposition (PLD) techniques, type-II heterojunction ZnO/ZnSe and ZnO/ZnS core-shell nanowire array were synthesized on indium-tin-oxide substrates. Their structures and optical properties have been investigated in detail, which revealed that, despite highly mismatched interfaces between the core and shell, both systems exhibited an epitaxial growth relationship. The quenching in photoluminescence but enhancement in photocurrent with faster response upon coating the core with the shell provides the evidence that the charge separation and collection in the type II core-shell nanowire is greatly improved. This demonstration brings much greater flexibility in designing next generation PV devices in terms of material selection and device operation mechanisms for achieving their maximum energy conversion efficiencies at a low cost and in an environmentally friendly manner. In order to achieve a high quality interface in the core-shell nanowire, CdSe and ZnTe, which have close lattice parameters and thermal expansion coefficients, were chosen to fabricate nanowire solar cells. ZnTe and CdSe nanowires were first synthesized by thermal evaporation and the shells were subsequently deposited by PLD. ZnTe/CdSe nanowires represented an inhomogeneous coating while the CdSe/ZnTe core-shell exhibited a conformal coating with obvious ZnTe eptilayer. The final PV device based on an individual CdSe/ZnTe nanowire demonstrated an efficiency of ~1.7%. In addition, a controllable synthesis of CdSe nanowire array on muscovite mica substrate was presented, providing the possibility to harvest hybrid energies in an all-inorganic nanowire array.

Diabetes typ II är en kronisk sjukdom som ökar bland ungdomar. Fetma och övervikt ses som en bidragande faktor till att diabetes typ II ökar. Mer stillasittande och sämre kostvanor påverkar kroppen med insulinresistens och trötta insulinproducerande celler som till slut kan leda till diabetes typ II. Att som ungdom drabbas av en kronisk sjukdom kan upplevas som en turbulent tid i ungdomars liv. Familjens och samhällets stöd påverkar ungdomarnas levnadsvanor och deras val av livsstil. För att sjuksköterskan skall kunna arbeta preventivt med stöd och motivation samt sätta in rätt resurser måste sjuksköterskan veta vilka faktorer som främjar och hindrar följsamhet till de livsstilsförändringar som ungdomarna behöver göra. Bra kostvanor och regelbunden fysisk aktivitet kan bidra till att förebygga diabetes typ II. Syftet med denna studie är att beskriva faktorer som främjar och hindrar livsstilsförändringar hos ungdomar med diabetes typ II. Litteraturstudien innehåller tio artiklar, både kvalitativa och kvantitativa. Det framkommer av resultatet att familj och vänner spelar en avgörande roll i följsamheten till livsstilsförändringar. Att som ungdom ha tillgång till bra mat och att utöva fysisk aktivitet med vänner, ökade följsamheten hos ungdomen. Resultatet visar också betydelsen av att ungdomar vill vara som alla andra och inte känna sig annorlunda.