No description available.

Coxsackievirus B3 (CVB3) is the primary cause of viral myocarditis. The role of cystein-x-cystein (CXC) chemokine ligand 10 (CXCL10, formerly interferon-y-inducible protein 10) in CVB3-induced myocarditis is unknown. To explore the contribution of CXCL10 to CVB3-induced myocarditis, we performed functional analyses using newly generated transgenic mice with cardiac-specific CXCL10 overexpression (Tg) and CXCL10 knock out (KO) mice. The mRNA levels of CXCL10 peaked in the myocardium at day 3 post-infection prior to immune infiltration, suggesting that mainly resident cells of the heart are the sources of CXCL10. Indeed, we showed that CXCL10 can be induced by IFN-y but not by CVB3 infection in cultured cardiomyocytes. Further, a transgenic mouse model with cardiac-specific overexpression of CXCL10 was generated. CXCL10 Tg mice had spontaneous infiltrations of mononuclear cells with limited mRNA upregulation of IFN-y and IL-10, which were not sufficient to cause the impairment of cardiomyocyte or cardiac function. Following CVB3 infection, the viral titre in the mouse hearts inversely correlated with the levels of CXCL10 at day 3 post-infection. Further, the decreased virus titers in the CXCL10 Tg mouse hearts led to reduced cardiac damage indicated by low serum cTnI levels and improved cardiac functional performance and vice versa in the KO mice. This antiviral ability of CXCL10 may be through increased recruitment of natural killer (NK) cells to the heart and increased IFN-y expression early post-infection. At days 7 and day 10 post-infection with massive influx of mononuclear cells, the expression of CXCL10 enhanced the infiltration of CXCR3+ cells, CD4+, and CD8+ T cells as well as their associated inflammatory cytokines. However, the augmented accumulation of these immune cells and associated cytokines did not alter the viral clearance and mouse survival. Our data demonstrate for the first time that CXCL1 0 confers the protection to the heart during the early course of CVB3 infection, which may be primarily attributed to NK cell recruitment to the site of infection. This data suggest that CXCL10 is an important player in the orchestrated action of a group of cytokines and chemokines in combating against the CVB3-induced myocarditis in the early phase of infection. / Medicine, Faculty of / Pathology and Laboratory Medicine, Department of / Graduate

Indiana University-Purdue University Indianapolis (IUPUI) / Enteric viruses are among the most common infectious human viruses worldwide, causing an estimated 10-15 million infections per year in the United States. Among enteric viruses, Coxsackievirus is commonly isolated and can lead to the development of meningitis, encephalitis, pancreatitis, and hepatitis. Furthermore, Coxsackievirus B3 is the primary cause of viral myocarditis and can lead to pleurodynia, with nearly 40,000 symptomatic cases reported in the United States each year. The enteroviral ssRNA genome contains a 5’ untranslated region (5’UTR) which consists of two structural components, the cloverleaf and the internal ribosome entry site (IRES), both shown to be integral to viral success. Additionally, the viral genome encodes four structural VP proteins as well as 11 non-structural proteins. Polymorphisms found within the CVB3 population have been linked to viral virulence. Here, we compare two CVB3 Nancy variants to elucidate the downstream effects observed in response to mutations found in the CVB3 genome. Implementing our novel oral inoculation model, we aimed to determine the impact mutations found in the 5’UTR and VP regions exert on viral pathogenesis. We also aimed to delineate the in vitro effects of the observed mutations. We investigated the role mutations found in the structural regions played in virus host cell attachment, in vitro cell viability, and replication. Our work has further confirmed the relevance and impact of mutations found in the VP region of the CVB3 genome.

This research was directed toward the development of a non-interacting, competitive decision-making game involving a maintenance facility in a textile fibers plant. The first part of this paper is a discussion and analysis of decision-making games in general. The second part contains the description of the objectives and the model of the game. An important feature of the game is that the participants must decide what data they need instead of being automatically provided with all of the available information. The validation of the game is presented in the last part of the paper. A test was conducted in a senior industrial engineering course. The appendix contains the administrator and player instructions. In addition, the program listing and sample output are included. / M.S.

Synchronous cultures of Chlorella pyrenoidosa (strain 7- 11-05) have been utilized to measure the potential expression of the structural gene for isocitrate lyase (three D_S-Isocitrate glyoxylate-lyase, EC 4.1.3.1) during the cell cycle. Synthesis of the enzyme could be induced by placing cultures in the dark on acetate, with the induction process occurring in a quadratic fashion. By addition of cycloheximide during the course of induction, the increase in isocitrate lyase activity was shown to result from de novo protein synthesis. In the absence of protein synthesis the enzyme was stable for at least five hours. The pattern of uninduced isocitrate lyase synthesis during the cell cycle in continuous light, paralleled the stepwise increase of total cellular DNA. The enzyme appeared to be fully repressed for most of the cell cycle, and was derepressed during the time of DNA replication. Isocitrate lyase could be induced at all times in the cell cycle, indicating that the potential for gene expression is continuous in this eukaryote. A time lag was observed between the beginning of DNA replication and the initial rise in potential for isocitrate lyase gene expression. The control of gene expression in Chlorella appeared to be similar to that found in a fission yeast. / Ph. D.

Indiana University-Purdue University Indianapolis (IUPUI) / Enteric viruses are infectious human pathogens that initiate infection in the gastrointestinal tract. They follow a fecal-oral route of transmission and are spread by contamination of food, water, or contact between individuals. Furthermore, enteric viruses also cause significant morbidity, mortality, and economic burdens yearly. Coxsackievirus (CV) is commonly isolated among enteric viruses and is an etiological agent of hand, foot, and mouth disease, hemorrhagic conjunctivitis, and myocarditis. The virus predominantly infects infants and young children and accounts for 11% of the fatality rate in neonates. Despite CV’s impact on human health, there are no treatments or vaccines for CV infections. Using a mouse model to study a key CV, Coxsackievirus B3 (CVB3), our laboratory has found two critical factors that impact CVB3 replication and pathogenesis. First, we have demonstrated that intestinal bacteria enhance intestinal CVB3 replication. We found that certain specific bacteria (Salmonella enterica) and its cell wall components, like lipopolysaccharides (LPS), enhanced CVB3 stability and infectivity in vitro. Additionally, we found that particular constituents of LPS are required for stability to occur. These data suggest that specific bacteria may be integral in maintaining CVB3 infectivity in the intestine. Besides virus-microbiome interaction, CVB3 is also impacted by sex hormones. Using castrated mice models, we observed a sex bias to CVB3 infection, with male mice succumbing to CVB3-induced disease at an increased rate compared to female mice. Our data suggest that testosterone, a predominant male sex hormone, enhanced CVB3 intestinal replication and viral dissemination to organs in male and female mice, but lethality only in male mice. Moreover, testosterone also affected the immune response by reducing the activation of the CD8+ T cells. CD8+ T cells are required to clear the viral infection and are integral in vaccine development. In contrast, we found an enhanced CD8+ T cell response in female mice to CVB3 infection, suggesting a sex-dependent T cell response that may underlie the sex bias in disease. Overall, these data represent an essential advancement in the CV field and will help develop future therapeutics and aid in vaccine design to limit CV infections.

No description available.

M.S.

M.S.

A acne é uma doença de pele com alta prevalência e seu tratamento é importante para evitar lesões cutâneas permanentes ou o agravamento de transtornos psicológicos provenientes do abalo à autoestima. Dessa forma, o desenvolvimento de formulações dermocosméticas eficazes que possam melhorar as condições desse tipo de pele é de grande valia. Dentre os ativos com potenciais benefícios para o controle de alguns dos principais fatores causadores da acne, estão a vitamina B3, um derivado de vitamina B6 e o PCA zinco. Assim o objetivo deste estudo foi o desenvolvimento de formulações dermocosméticas para a pele acnéica contendo vitamina B3, derivado lipossolúvel de vitamina B6 e PCA zinco bem como a avaliação da estabilidade e eficácia clínica dessas formulações. Para tal, foram desenvolvidas diferentes formulações, as quais, em um primeiro momento, foram avaliadas quanto à estabilidade frente à adição do ingrediente ativo Zinc PCA. Após esta etapa, os demais ingredientes ativos foram adicionados e as formulações foram submetidas a testes preliminares de estabilidade e ao estudo da estabilidade física por determinação do comportamento reológico. A formulação mais estável foi avaliada quanto à compatibilidade cutânea e também em relação à comedogenicidade do veículo. A formulação composta pelos ingredientes ativos foi avaliada, ainda, quanto as suas características sensoriais e eficácia clínica. Os estudos de eficácia foram realizados por meio de métodos objetivos e subjetivos, após seis semanas do uso da formulação. Os métodos objetivos consistiram no uso de metodologias in vivo, não invasivas (métodos biofísicos e de imagem), sendo avaliados parâmetros relacionados à hidratação, função barreira, conteúdo lipídico, pH cutâneo, contagem de porfirinas, de microcomedões e de lesões inflamatórias. Em relação aos métodos subjetivos, foi realizada a percepção da eficácia por meio de um questionário para a comparação da pele antes e após o tratamento. Os resultados mostraram que, de todas as formulações desenvolvidas, apenas uma mostrou-se estável frente aos testes de estabilidade realizados. A formulação (veículo e adicionada de ingredientes ativos) apresentou compatibilidade cutânea considerada como \"muito boa\", de acordo com o teste realizado, e o veículo sem potencial comedogênico. Na avaliação sensorial as frequências obtidas para os parâmetros considerados como ruins foram baixas, indicando que o sensorial da formulação mostrou-se adequado para as finalidades propostas. No estudo de eficácia clínica, a formulação não alterou a hidratação e a função barreira da pele e mostrou-se eficaz na redução da contagem de porfirinas e das lesões inflamatórias (p<0,05). A avaliação clínica por métodos subjetivos mostrou a eficácia da formulação quanto à melhora da acne inflamatória, oleosidade da pele, hidratação e maciez. Por fim, os resultados obtidos mostraram que a formulação desenvolvida é eficaz e compatível com a pele, bem como a importância da pesquisa e desenvolvimento para a obtenção de formulações estáveis, seguras, eficazes e com sensorial adequado. / Acne is a skin disease with high prevalence and its treatment is important to prevent permanent skin lesions or the aggravation of psychological disorders due to self-esteem shaken. This way, the development of effective dermocosmetic formulations, that can improve the conditions of this skin type, is very important. Vitamin B3, a vitamin B6 derivative and zinc PCA are among the active ingredients which present potential benefits in the controlling of some pathogenic factors of acne. Thus, the aim of this research was to develop cosmetic formulations for acneic skin containing vitamin B3, vitamin B6 lipophilic derivative and zinc PCA, as well as the evaluation of stability and clinical efficacy. For this purpose, were developed different formulations which, at first, were evaluated in terms of stability face to zinc PCA addition. After this, the others active ingredients were added and the formulations were submitted to preliminary tests of stability and physical stability studies by rheological behavior determination. The most stable formulation was subject to skin compatibility evaluation and vehicle comedogenicity. The formulation with the active ingredients was also evaluated regarding their sensorial characteristics and clinical efficacy. Efficacy studies were performed by means of objective and subjective methods, after a sixweek- period of use of the formulation. The objective methods consisted in non-invasive in vivo methodologies (biophysical techniques and image analysis) where were evaluated hydration, barrier function, lipid content, skin pH and the counting of porphyrins, microcomedones and inflammatories lesions. In relation to subjective methods, was performed the efficacy perception using a questionnaire in order to compare the skin before and after the treatment. The results showed that among the formulations developed, only one kept stable after the stability tests. The formulations were considered as \"very good\" on skin compatibility test and showed no comedogenic potential. In sensorial evaluation, frequencies obtained for the parameters considered bad were low, which indicate the sensorial of the formulation was adequate for the purposes. In clinical efficacy study, the formulation under study did not alter the parameters related to hydration and skin barrier function and was effective in reducing the counting of porphyrins and inflammatories lesions (p<0,05). Clinical evaluation by subjective methods showed the formulation effectiveness regarding the improvement of inflammatory acne, skin oiliness, hydration and softness. Finally, the results obtained showed the formulation developed is effective and compatible with the skin and, besides the importance of research and development for obtaining stable, safe and effective formulations with suitable sensorial.