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Análise da deformação de envelopes motores foguete devido à ação do tratamento térmicoPaulo Roberto Sakai 21 December 2005 (has links)
O tratamento térmico, considerado um processo especial, induz deformações em estruturas metálicas tratadas. Este trabalho propõe um método, baseado em técnicas estatísticas aplicadas a dados históricos, que permite visualizar, atestar de maneira significativa e obter uma previsão das variações dimensionais devidas ao tratamento térmico. O método proposto foi aplicado na averiguação das deformações ocorridas na têmpera e no revenimento de envelopes motores S40 e S43, usados correntemente no VLS-1 (veículo lançador de satélites). As variáveis "Diâmetro", "Comprimento" e "Erro de Forma Longitudinal" da região cilíndrica de tais motores foram avaliados antes e após tratamento térmico. Os resultados indicaram uma diminuição de "Diâmetro" e "Comprimento" e um aumento do "Erro de forma longitudinal". Finalmente, o método proposto obteve um intervalo de valores, com um nível de confiança de 95%, que permite o estabelecimento de tolerâncias de projeto para as variáveis trabalhadas, os quais devem ser usados como critérios na aceitação de um envelope motor.
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Análise de fabricação e das proteções térmicas de um envelope-motor S-30 em compósitoRafael Fernando Heitkoetter 07 October 2009 (has links)
O propulsor S-30 é utilizado nos veículos de sondagem VSB-30, VS-30 e Sonda III, do Instituto de Aeronáutica e Espaço (IAE), é alimentado com propelente sólido e possui envelope-motor fabricado em aço SAE 4140. O presente trabalho tem por objetivo analisar a bobinagem filamentar e as proteções térmicas internas e externas de um envelope-motor S-30 em compósito, para poder ser utilizado nos veículos VSB-30 e VS-30 do IAE. O envelope-motor em compósito visa manter as interfaces com partes já qualificadas dos veículos, como porta-empenas, ignitor, tubeira e dispositivos de carregamento de propelente, com o objetivo de substituir o envelope-motor metálico, mantendo as características propulsivas do propulsor S-30. Neste trabalho, foram realizados os dimensionamentos da geometria e das espessuras dos domos e da parte cilíndrica, análises de bobinagem filamentar usando o software CadWind e análises das proteções térmicas internas e externas. Foram realizadas análises para duas configurações: a primeira para um envelope-motor com aberturas polares iguais, por bobinagem helicoidal geodésica isotensoidal, e a segunda para um envelope-motor com aberturas polares diferentes por bobinagem não-geodésica. A conclusão principal baseada nas análises realizadas para as duas configurações estudadas, proporciona um propulsor S-30 bobinado com melhor desempenho que o S-30 com envelope-motor metálico, em razão da sua menor massa, ou seja, proporciona um maior apogeu para uma mesma carga útil ou uma maior carga útil para o mesmo apogeu.
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Characterization of spike glycoprotein fusion core and 3C-like protease substrate specificity of the severe acute respiratory syndrome (SARS) coronavirus: perspective for anti-SARS drug development.January 2006 (has links)
Chu Ling Hon Matthew. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2006. / Includes bibliographical references (leaves 201-223). / Abstracts in English and Chinese. / Declaration --- p.i / Thesis/Assessment Committee --- p.ii / Abstract --- p.iii / 摘要 --- p.vi / Acknowledgements --- p.viii / General abbreviations --- p.xi / Abbreviations of chemicals --- p.xv / Table of Contents --- p.xvi / List of Figures --- p.xxiii / List of tables --- p.xxviii / Chapter 1 --- Introduction --- p.1 / Chapter 1.1 --- Severe Acute Respiratory Syndrome (SARS) - Three Years in Review --- p.1 / Chapter 1.1.1 --- Epidemiology --- p.1 / Chapter 1.1.2 --- Clinical presentation --- p.3 / Chapter 1.1.3 --- Diagnostic tests --- p.5 / Chapter 1.2 --- Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) --- p.7 / Chapter 1.2.1 --- SARS - Identification of the etiological agent --- p.7 / Chapter 1.2.2 --- The coronaviruses --- p.9 / Chapter 1.2.3 --- The genome organization of SARS-CoV --- p.11 / Chapter 1.2.4 --- The life cycle of SARS-CoV --- p.13 / Chapter 1.3 --- Spike Glycoprotein (S protein) of SARS-CoV --- p.15 / Chapter 1.3.1 --- SARS-CoV S protein --- p.15 / Chapter 1.3.2 --- S protein-driven infection --- p.17 / Chapter 1.4 --- SARS-CoV S Protein Fusion Core --- p.22 / Chapter 1.4.1 --- Heptad repeat and coiled coil --- p.22 / Chapter 1.4.2 --- The six-helix coiled coil bundle structure --- p.25 / Chapter 1.5 --- 3C-like Protease (3CLpro) of SARS-CoV --- p.28 / Chapter 1.5.1 --- Extensive proteolytic processing of replicase polyproteins --- p.28 / Chapter 1.5.2 --- SARS-CoV 3CLpro --- p.30 / Chapter 1.5.3 --- Substrate Specificity of SARS-CoV 3CLpro --- p.31 / Chapter 1.6 --- SARS Drug Development --- p.32 / Chapter 1.6.1 --- Drug targets of SARS-CoV --- p.32 / Chapter 1.6.2 --- Current anti-SARS drugs --- p.36 / Chapter 1.7 --- Project Objectives --- p.39 / Chapter 1.7.1 --- Characterization of SARS-CoV S protein fusion core --- p.39 / Chapter 1.7.2 --- Characterization of SARS-CoV 3CLpr0 substrate specificity --- p.40 / Chapter 2 --- Materials and Methods --- p.42 / Chapter 2.1 --- Characterization of SARS-CoV S Protein Fusion Core --- p.42 / Chapter 2.1.1 --- Bioinformatics analyses of heptad repeat regions of SARS- CoV S protein --- p.42 / Chapter 2.1.2 --- Recombinant protein approach --- p.43 / Chapter 2.1.2.1 --- Plasmids construction --- p.43 / Chapter 2.1.2.2 --- Protein expression and purification --- p.52 / Chapter 2.1.2.3 --- Amino acid analysis --- p.57 / Chapter 2.1.2.4 --- GST-pulldown experiment --- p.58 / Chapter 2.1.2.5 --- Laser light scattering --- p.61 / Chapter 2.1.2.6 --- Size-exclusion chromatography --- p.62 / Chapter 2.1.2.7 --- Circular dichroism spectroscopy --- p.62 / Chapter 2.1.3 --- Synthetic peptide approach --- p.64 / Chapter 2.1.3.1 --- Peptide synthesis --- p.64 / Chapter 2.1.3.2 --- Native polyacrylamide gel electrophoresis --- p.65 / Chapter 2.1.3.3 --- Size-exclusion high-performance liquid chromato-graphy --- p.66 / Chapter 2.1.3.4 --- Laser light scattering --- p.66 / Chapter 2.1.3.5 --- Circular dichroism spectroscopy --- p.67 / Chapter 2.2 --- Identification of SARS-CoV Entry Inhibitors --- p.70 / Chapter 2.2.1 --- HIV-luc/SARS pseudotyped virus entry inhibition assay --- p.70 / Chapter 2.2.2 --- Recombinant protein- and synthetic peptide-based biophysical assays --- p.74 / Chapter 2.2.3 --- Molecular modeling --- p.75 / Chapter 2.3 --- Characterization of SARS-CoV 3CLpro Substrate Specificity --- p.79 / Chapter 2.3.1 --- Protein expression and purification --- p.79 / Chapter 2.3.2 --- """Cartridge replacement"" solid-phase peptide synthesis" --- p.80 / Chapter 2.3.3 --- Peptide cleavage assay and mass spectrometric analysis --- p.83 / Chapter 3 --- Results --- p.84 / Chapter 3.1 --- Characterization of SARS-CoV S Protein Fusion Core --- p.84 / Chapter 3.1.1 --- Bioinformatics analyses of heptad repeat regions of SARS- CoV S protein --- p.84 / Chapter 3.1.2 --- Recombinant protein approach --- p.87 / Chapter 3.1.2.1 --- "Plasmids construction of pET-28a-His6-HRl, pGEX-6P-l-HR2 and pGEX-6P-l-2-Helix" --- p.87 / Chapter 3.1.2.2 --- Protein expression and purification --- p.92 / Chapter 3.1.2.3 --- GST-pulldown experiment --- p.101 / Chapter 3.1.2.4 --- Laser light scattering --- p.103 / Chapter 3.1.2.5 --- Size-exclusion chromatography --- p.105 / Chapter 3.1.2.6 --- Circular dichroism spectroscopy --- p.107 / Chapter 3.1.3 --- Synthetic peptide approach --- p.112 / Chapter 3.1.3.1 --- Peptide synthesis --- p.112 / Chapter 3.1.3.2 --- Native polyacrylamide gel electrophoresis --- p.116 / Chapter 3.1.3.3 --- Size-exclusion high-performance liquid chromatography --- p.117 / Chapter 3.1.3.4 --- Laser light scattering --- p.122 / Chapter 3.1.3.5 --- Circular dichroism spectroscopy --- p.124 / Chapter 3.2 --- Identification of SARS-CoV Entry Inhibitors --- p.129 / Chapter 3.2.1 --- HIV-luc/SARS pseudotyped virus entry inhibition assay --- p.129 / Chapter 3.2.2 --- Recombinant protein- and synthetic peptide-based biophysical assays --- p.131 / Chapter 3.2.3 --- Molecular modeling --- p.135 / Chapter 3.3 --- Characterization of SARS-CoV 3CLpro Substrate Specificity --- p.141 / Chapter 3.3.1 --- Protein expression and purification --- p.141 / Chapter 3.3.2 --- Substrate specificity preference of SARS-CoV 3CLpr0 --- p.142 / Chapter 3.3.3 --- "Primary and secondary screening using the ""cartridge replacement strategy""" --- p.142 / Chapter 4 --- Discussion --- p.149 / Chapter 4.1 --- Characterization of SARS-CoV S Protein Fusion Core --- p.149 / Chapter 4.1.1 --- Design of recombinant proteins and synthetic peptides of HR regions --- p.149 / Chapter 4.1.2 --- Recombinant protein approach --- p.151 / Chapter 4.1.3 --- Synthetic peptide approach --- p.153 / Chapter 4.1.4 --- Summary of the present and previous studies in the SARS-CoV S protein fusion core --- p.157 / Chapter 4.2 --- Identification of SARS-CoV Entry Inhibitors --- p.167 / Chapter 4.2.1 --- HIV-luc/SARS pseudotyped virus entry inhibition assay --- p.167 / Chapter 4.2.2 --- Identification of peptide inhibitors --- p.168 / Chapter 4.2.3 --- Identification of small molecule inhibitors --- p.172 / Chapter 4.3 --- Characterization of SARS-CoV 3CLpro Substrate Specificity --- p.183 / Chapter 4.3.1 --- A comprehensive overview of the substrate specificity of SARS-CoV 3CLpro --- p.184 / Chapter 4.3.2 --- The development of the rapid and high-throughput screening strategy for protease substrate specificity --- p.188 / Appendix --- p.191 / Chapter I. --- Nucleotide Sequence of S protein of SARS-CoV --- p.191 / Chapter II. --- Protein Sequence of S protein of SARS-CoV --- p.194 / Chapter III. --- Protein Sequence of 3CLpro of SARS-CoV --- p.195 / Chapter IV. --- Vector maps --- p.196 / Chapter 1. --- Vector map and MCS of pET-28a --- p.196 / Chapter 2. --- Vector map and MCS of pGEX-6P-l --- p.197 / Chapter V. --- Electrophoresis markers --- p.198 / Chapter 1. --- GeneRuler´ёØ 1 kb DNA Ladder --- p.198 / Chapter 2. --- GeneRuler´ёØ 100bp DNA Ladder --- p.198 / Chapter 3. --- High-range Rainbow Molecular Weight Markers --- p.199 / Chapter 4. --- Low-range Rainbow Molecular Weight Markers --- p.199 / Chapter VI. --- SDS-PAGE gel preparation protocol --- p.200 / References --- p.201
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NETS coordinate genome organisation and gene expression changes in T-cells and during myogenesisRobson, Michael Ian January 2015 (has links)
Gene positioning changes with respect to the nuclear periphery correlate with their activation in a number of tissues during development. However, the determination of the function this serves or the mechanism through which this was achieved has been remarkably difficult to resolve. It may now be possible to address these questions due to the recent identification of a number of tissue-specific nuclear envelope transmembrane proteins (NETs) which are capable of promoting the repositioning of specific subsets of chromosomes and concomitantly inducing changes to gene expression (Zuleger et al,. 2013). In this thesis I describe the role of NETs in the positioning of genes to the nuclear envelope (NE) during muscle differentiation and the role this activity plays in the optimisation of myogenic gene expression in as myoblasts (MTs) differentiate to myotubes (MTs). To do this I identified four NETs with the capacity to reposition a chromosome to the periphery that are present specifically in the NEs of skeletal muscle. Using a combination of genome-wide gene expression analysis and DamID I determined that depletion of these NETs disrupted myogenic gene expression and, more significantly, prevented the targeting to and silencing of normally repressed genes at the NE. I also investigated an analogous role for the blood-specific NET TAPBPL in the regulation of the critical T-cell regulator interleukin 2 (IL-2) at the NE in T-cells. Depletion of this NET caused release of the IL2 locus from the periphery and promoted its inappropriate and long-term activation. Interestingly, depletion of TAPBPL also prevented IL2 silencing following the end of T-cell activation, suggesting this genome organisation activity is critical for the maintenance of normal T-cell function. Collectively, the results discussed herein describe a new role for NETs in the regulation of gene expression through the manipulation of spatial genome organisation and may serve as an additional layer of higher order tissue-specific gene regulation in higher organisms.
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Simulação energética para análise da arquitetura de edifícios de escritório além da comprovação de conformidade com códigos de desempenho / Building performance simulation for analysis of the architecture of office buildings beyond code compliance checkingCavalcante, Rodrigo de Castro Dantas 07 April 2010 (has links)
No Brasil e em São Paulo, a ASHRAE Standard 90.1 Energy Standard for Buildings Except Low-Rise Residential Buildings ganhou rápida aceitação nos últimos anos. A norma é referenciada pelo sistema de certificação Leadership in Energy and Environmental Design - LEED para estabelecer padrões mínimos de desempenho energético. Apesar do desenvolvimento de atividade de consultoria para comprovação de conformidade com esse código, a consultoria tem se limitado a intervir no projeto de arquitetura após sua concepção. A fim de investigar a influência da arquitetura no desempenho de edifícios de escritório e justificar a consultoria desde as primeiras etapas do projeto, o desempenho de uma série de modelos é estimado com auxílio da ferramenta de simulação computacional EnergyPlus. As alternativas avaliadas incluem diferentes percentagens de área de fachada envidraçada, propriedades ópticas e térmicas dos fechamentos transparentes, persianas automatizadas, orientação do edifício e proporções do pavimento tipo. Os resultados comprovaram a influência da arquitetura no desempenho energético de edifícios de escritório. Portanto, as decisões tomadas durante a fase de concepção do projeto têm impacto considerável no desempenho final do edifício e, apesar do tempo e dos esforços necessários, devem ser estudadas. / In Brazil and Sao Paulo, ASHRAE Standard 90.1 Energy Standard for Buildings Except Low-Rise Residential Buildings has rapidly gained acceptance in recent years. The standard is referred by the Leadership in Energy and Environmental Design - LEED rating system to set minimum energy performance levels. Although consulting activity was developed to demonstrate compliance to the code, it has been limited to intervene in the architectural design after its conception. With the aim of investigating the influence of architecture on the performance of office buildings and justify the consultancy since early design stages, the performance of a set of models is estimated using EnergyPlus computer simulation tool. The assessed alternatives include different Window-to-Wall Ratios - WWR, optical and thermal properties of glazing systems, automated roller shades, building orientation and proportions of typical floors. The results confirmed the influence of architecture on the energy performance of office buildings. Therefore, decisions taken during early design stages have considerable impact on the final performance of buildings and, despite the time and effort involved, should be studied.
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Simulação energética para análise da arquitetura de edifícios de escritório além da comprovação de conformidade com códigos de desempenho / Building performance simulation for analysis of the architecture of office buildings beyond code compliance checkingRodrigo de Castro Dantas Cavalcante 07 April 2010 (has links)
No Brasil e em São Paulo, a ASHRAE Standard 90.1 Energy Standard for Buildings Except Low-Rise Residential Buildings ganhou rápida aceitação nos últimos anos. A norma é referenciada pelo sistema de certificação Leadership in Energy and Environmental Design - LEED para estabelecer padrões mínimos de desempenho energético. Apesar do desenvolvimento de atividade de consultoria para comprovação de conformidade com esse código, a consultoria tem se limitado a intervir no projeto de arquitetura após sua concepção. A fim de investigar a influência da arquitetura no desempenho de edifícios de escritório e justificar a consultoria desde as primeiras etapas do projeto, o desempenho de uma série de modelos é estimado com auxílio da ferramenta de simulação computacional EnergyPlus. As alternativas avaliadas incluem diferentes percentagens de área de fachada envidraçada, propriedades ópticas e térmicas dos fechamentos transparentes, persianas automatizadas, orientação do edifício e proporções do pavimento tipo. Os resultados comprovaram a influência da arquitetura no desempenho energético de edifícios de escritório. Portanto, as decisões tomadas durante a fase de concepção do projeto têm impacto considerável no desempenho final do edifício e, apesar do tempo e dos esforços necessários, devem ser estudadas. / In Brazil and Sao Paulo, ASHRAE Standard 90.1 Energy Standard for Buildings Except Low-Rise Residential Buildings has rapidly gained acceptance in recent years. The standard is referred by the Leadership in Energy and Environmental Design - LEED rating system to set minimum energy performance levels. Although consulting activity was developed to demonstrate compliance to the code, it has been limited to intervene in the architectural design after its conception. With the aim of investigating the influence of architecture on the performance of office buildings and justify the consultancy since early design stages, the performance of a set of models is estimated using EnergyPlus computer simulation tool. The assessed alternatives include different Window-to-Wall Ratios - WWR, optical and thermal properties of glazing systems, automated roller shades, building orientation and proportions of typical floors. The results confirmed the influence of architecture on the energy performance of office buildings. Therefore, decisions taken during early design stages have considerable impact on the final performance of buildings and, despite the time and effort involved, should be studied.
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Use of Drone and Infrared Camera for a Campus Building Envelope StudyAriwoola, Raheem Taiwo 01 May 2016 (has links)
Presently, there are concerns that buildings in the USA under-performs in terms of energy efficiency when compared with the original design specifications. A significant percentage of the energy loss in these buildings is associated with the building’s envelope. This study provides a qualitative and analytical understanding of the R-value, which indicates the thermal performance of the elements that make up a building envelope. Infrared thermography is used as a methodology to assess the thermal performance of envelopes of ten buildings on East Tennessee State University Campus. A Fluke Ti25 infrared hand-held camera and a DJI phantom-2 drone mounted with FLIR Vue Pro infrared camera were used for data collection. Data analyses were carried out using ‘Smartview’ and ‘FLIR Reporter Pro’ software. The data analyses revealed energy loss, insulation deficiencies, the associated energy costs of the inefficiencies and the potential savings that could result from correcting these deficiencies in the evaluated building’s envelopes.
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Properties of HIV-1 env and human seminal fluid that determine virus inhibition by antibodies and microbicidesJohnson, Jacklyn 01 August 2019 (has links)
Human immunodeficiency virus type 1 (HIV-1) establishes a persistent infection that leads to acquired immunodeficiency syndrome (AIDS). Approximately 36 million people worldwide are living with HIV-1, which is commonly acquired through sexual contact. Antiviral therapies control disease progression, but do not eliminate this virus from the host. Thus, global efforts are focused on developing vaccines that prevent HIV-1 transmission. Such vaccines are based on eliciting the production of protective antibodies that target the envelope glycoproteins (Envs) of this virus. Unfortunately, HIV-1 immunization trials have shown limited efficacy. A better understanding of the antibody-mediated inactivation process is needed to improve vaccine strategies. In this work we describe two novel factors that contribute to HIV-1 inactivation. First, we show that structural stability of the Env protein determines its sensitivity to vaccine-elicited antibodies. Different interactions within Env contribute to its stability. Perturbation of the Env-stabilizing interactions by physical and chemical treatments enhances sensitivity of HIV-1 to antibodies. Second, we found that the chemical composition of the transmission medium affects Env inhibition by antibodies and other inhibitory agents. Semen is the most common vehicle for HIV-1 transmission. This medium contains high concentrations of the sugar fructose. We found that semen fructose competitively blocks binding of antiviral agents that target sugar residues on Env. Together, this work advances our understanding of the mechanism that underlies HIV-1 inactivation by vaccine-elicited antibodies and provides novel strategies to enhance their potency.
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Operator algebras, matrix bundles, and Riemann surfacesMcCormick, Kathryn 01 August 2018 (has links)
Let $\overline{R}$ be a finitely bordered Riemann surface, and let $\mathfrak{E}_\rho(\overline{R})$ be a flat matrix $PU_n(\mathbb{C})$-bundle over $\overline{R}$. Let $\Gamma_c(\overline{R}, \mathfrak{E}(\overline{R}))$ denote the $C^*$-algebra of continuous cross-sections of $\mathfrak{E}(\overline{R})$, and let $\Gamma_h(\overline{R},\mathfrak{E}(\overline{R}))$ denote the subalgebra consisting of the continuous holomorphic sections, i.e.~the continuous cross-sections that are holomorphic on the interior of $\overline{R}$. The algebra $\Gamma_c(\overline{R}, \mathfrak{E}(\overline{R}))$ is an example of an $n$-homogeneous $C^*$-algebra, and the subalgebra $\Gamma_h(\overline{R},\mathfrak{E}(\overline{R}))$ is the principal object of study of this thesis. The algebras $\Gamma_h(\overline{R},\mathfrak{E}(\overline{R}))$ appeared in the earlier works \cite{Abrahamse1976} and \cite{Blecher2000}. Operators that can be viewed as elements in $\Gamma_h(\overline{R},\mathfrak{E}(\overline{R}))$ are the subject of \cite{Abrahamse1976}. The Morita theory of $\Gamma_h(\overline{R},\mathfrak{E}(\overline{R}))$, under the guise of a fixed-point algebra and in the special case of an annulus $R$, is studied in \cite[Ex.~8.3]{Blecher2000}. This thesis studies these algebras and their topological data $\mathfrak{E}_\rho(\overline{R})$ motivated by several problems in the theory of nonselfadjoint operator algebras.
Boundary representations are an invariant of operator algebras that were introduced by Arveson in 1969. However, it took nearly 50 years to show that boundary representations existed in sufficient abundance in all cases. I show that every boundary representation of $\Gamma_c(\overline{R}, \mathfrak{E}(\overline{R}))$ for $\Gamma_h(\overline{R}, \mathfrak{E}(\overline{R}))$ is given by evaluation at some point $r \in \partial R$. As a corollary, the $C^*$-envelope of $\Gamma_h(\overline{R},\mathfrak{E}(\overline{R}))$ is $\Gamma_c(\partial R, \mathfrak{E}(\partial R))$. Using the $C^*$-envelope, I show that for certain choices of fibre and base space, $\Gamma_h(\overline{R}, \mathfrak{E}_\rho(\overline{R}))$ is not completely isometrically isomorphic to $A(\overline{R})\otimes M_n(\mathbb{C})$ unless the representation $\rho$ is the trivial representation.
I also show that $\Gamma_h(\overline{R},\mathfrak{E}(\overline{R}))$ is an Azumaya over its center. Azumaya algebras are the ``pure-algebra'' analogues to $n$-homogeneous $C^*$-algebras \cite{Artin1969}. Thus the structure of the nonselfadjoint subalgebra $\Gamma_h(\overline{R},\mathfrak{E}(\overline{R}))$ reflects some of the structure of its $C^*$-envelope (which is $n$-homogeneous). Finally, I answer a question raised in \cite[Ex.~8.3]{Blecher2000} on the $cb$ and strong Morita theory of $\Gamma_h(\overline{R},\mathfrak{E}_\rho(\overline{R}))$, showing in particular that $\Gamma_h(\overline{R},\mathfrak{E}_\rho(\overline{R}))$ is $cb$ Morita equivalent to its center $A(\overline{R})$. As suggested in \cite[Ex.~8.3]{Blecher2000}, I provide additional evidence that $\Gamma_h(\overline{R},\mathfrak{E}_\rho(\overline{R}))$ may not be strongly Morita equivalent to its center. This evidence, in turn, suggests that there may be a Brauer group -like analysis for these algebras.
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GB virus C: cellular interactions, HIV inhibition and natural historyMohr, Emma Louise 01 May 2012 (has links)
GB virus C (GBV-C) is a nonpathogenic lymphotropic virus that replicates in B and T lymphocytes. Infection with GBV-C is documented worldwide and is common: between 1% and 5% of healthy blood donors are viremic at the time of donation. Antibodies to GBV-C proteins are not usually detected during viremia, and antibodies to the GBV-C envelope glycoprotein E2 develop following the clearance of viremia. Although GBV-C viremia may persist for decades, viremia usually clears within 2 years following infection in the majority of individuals infected by blood transfusion. A chimpanzee variant of GBV-C, designated GBV-Ccpz, is found in captive and noncaptive chimpanzees and its prevalence and natural history are uncharacterized. GBV-C research was initially performed by viral hepatitis research groups because it was predicted to cause hepatitis. The realization that GBV-C did not cause hepatitis resulted in a marked reduction in research activity. Because Hepatitis C virus co-infection worsens the clinical course of HIV-infected patients, researchers hypothesized that the related virus, GBV-C, may impact HIV disease. In 1998, researchers found that HIV-infected individuals who were co-infected with GBV-C survived longer than those without GBV-C. These findings provide the rationale for examining the relationship of GBV-C and HIV and the development of GBV-C as a novel therapeutic for HIV. GBV-C infection of PBMCs inhibits the replication of HIV isolates and one of the mechanisms for this is the induction of the release of soluble ligands for HIV entry receptors (RANTES, macrophage inflammatory proteins (MIP)-1α and MIP-1β and SDF-1) by GBV-C. The GBV-C envelope glycoprotein E2 contributes directly to the inhibition of HIV infection. Incubation of recombinant E2 with PBMCs at 4°C prior to HIV infection results in a decrease in HIV replication, and only HIV gp160 enveloped pseudoparticle transduction, not VSV-G enveloped pseudoparticle transduction, is inhibited by GBV-C E2. This suggests that GBV-C E2 inhibits HIV infection at an entry step when the HIV gp160 envelope protein interacts with cellular receptors and membranes. How GBV-C E2 interacts with cellular surfaces and which cellular proteins are utilized for GBV-C binding and entry are unknown. Here, we characterize GBV-C E2 binding to human PBMCs, murine cells, and multiple transformed cell lines to identify the PBMC subset which E2 binds and to identify candidate cellular receptors involved in GBV-C binding and entry. Understanding how GBV-C E2 interacts with cellular surfaces is critical to determining how it inhibits HIV entry. Anti-GBV-C E2 antibodies are also associated with improved survival in HIV-infected individuals. Recent studies demonstrated that anti-E2 antibodies neutralize HIV infection in vitro and immunoprecipitate HIV virions. In these studies, we describe how anti-E2 antibodies immunoprecipitate retroviral particles regardless of the specific viral envelope protein on the surface, but only neutralize particles bearing the HIV gp160 envelope protein. We also found that the cellular antigen recognized by anti-E2 antibodies is accessible only in permeabilized cells and not on the cell surface. These studies provide insight into the HIV-inhibitory mechanisms of anti-E2 antibodies, which should aid in the development of GBV-C E2 as an immunogen in an HIV vaccine. Finally, no animal models exist for studying GBV-C infection or GBV-C vaccines as HIV therapeutics in vivo. We examined the natural history GBV-Ccpz in a captive chimpanzee population, and found that the prevalence of GBV-Ccpz viremia and anti-E2 antibodies, as well as the length of persistent infection, were similar to those found in healthy human blood donors. The GBV-Ccpz 5#8217;ntr and RdRp sequences from chimpanzee subspecies troglodytes and verus shared a high level of sequence identity and indicate that the chimpanzee variant should be designated GBV-Ccpz rather than the currently used GBV-Ctrog. These findings demonstrate that GBV-Ccpz viremia and E2 antibody status should be tested in animals involved in clinical research trials because affected animals may have altered responses to GBV-C infection or HIV vaccines, and that the chimpanzee would be a good animal model in which to study GBV-C infection.
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