O Vírus da Imunodeficiência Humana (HIV) é o agente etiológico da Síndrome da Imunodeficiência Adquirida (AIDS). A AIDS é uma doença de distribuição mundial, e estima-se que existam atualmente pelo menos 36,9 milhões de pessoas infectadas com o vírus. Durante o seu ciclo replicativo, o HIV promove diversas alterações na fisiologia da célula hospedeira a fim de promover sua sobrevivência e potencializar a replicação. A rápida progressão da infecção pelo HIV-1 em humanos e em modelos animais está intimamente ligada à função da proteína acessória Nef. Dentre as diversas ações de Nef está a regulação negativa de proteínas importantes na resposta imunológica, como o receptor CD4. Sabe-se que esta ação resulta da indução da degradação de CD4 em lisossomos, mas os mecanismos moleculares envolvidos ainda são totalmente elucidados. Nef forma um complexo tripartite com a cauda citosólica de CD4 e a proteína adaptadora 2 (AP-2), em vesículas revestidas por clatrina nascentes, induzindo a internalização e degradação lisossomal de CD4. Pesquisas anteriores demonstraram que o direcionamento de CD4 aos lisossomos por Nef envolve a entrada do receptor na via dos corpos multivesiculares (MVBs), por um mecanismo atípico, pois, embora não necessite da ubiquitinação de carga, depende da ação de proteínas que compõem os ESCRTs (Endosomal Sorting Complexes Required for Transport) e da ação de Alix, uma proteína acessória da maquinaria ESCRT. Já foi reportado que Nef interage com subunidades dos complexos AP-1, AP-2, AP-3 e Nef não parece interagir com subunidades de AP-4 e AP-5. Entretanto, o papel da interação de Nef com AP-1 e AP-3 na regulação negativa de CD4 ainda não está totalmente elucidado. Ademais, AP-1, AP-2 e AP-3 são potencialmente heterogêneos devido à existência de isoformas múltiplas das subunidades codificadas por diferentes genes. Todavia, existem poucos estudos para demonstrar se as diferentes combinações de isoformas dos APs são formadas e se possuem propriedades funcionais distintas. O presente trabalho procurou identificar e caracterizar fatores celulares envolvidos na regulação do tráfego intracelular de proteínas no processo de regulação negativa de CD4 induzido por Nef. Mais especificamente, este estudo buscou caracterizar a participação do complexo AP-1 na modulação negativa de CD4 por Nef de HIV-1, através do estudo funcional das duas isoformas de ?-adaptina, subunidades de AP-1. Utilizando a técnica de Pull-down demonstramos que Nef é capaz de interagir com ?2. Além disso, nossos dados de Imunoblot indicaram que a proteína ?2-adaptina, e não ?1-adaptina, é necessária no processo de degradação lisossomal de CD4 por Nef e que esta participação é conservada para degradação de CD4 por Nef de diferentes cepas virais. Ademais, por citometria de fluxo, o silenciamento de ?2, e não de ?1, compromete a diminuição dos níveis de CD4 por Nef da membrana plasmática. A análise por imunofluorêsncia indireta também revelou que a diminuição dos níveis de ?2 impede a redistribuição de CD4 por Nef para regiões perinucleares, acarretando no acúmulo de CD4, retirados por Nef da membrana plasmática, em endossomos primários. A depleção de ?1A, outra subunidade de AP-1, acarretou na diminuição dos níveis celulares de ?2 e ?1, bem como, no comprometimento da eficiente degradação de CD4 por Nef. Além disso, foi possível observar que, ao perturbar a maquinaria ESCRT via super-expressão de HRS (uma subunidade do complexo ESCRT-0), ocorreu um acumulo de ?2 em endossomos dilatados contendo HRS-GFP, nos quais também detectou-se CD4 que foi internalizado por Nef. Em conjunto, os resultados indicam que ?2-adaptina é uma importante molécula para o direcionamento de CD4 por Nef para a via ESCRT/MVB, mostrando ser uma proteína relevante no sistema endo-lisossomal. Ademais, os resultados indicaram que as isoformas ?-adaptinas não só possuem funções distintas, mas também parecem compor complexos AP-1 com diferentes funções celulares, já que apenas a variante AP-1 contendo ?2, mas não ?1, participa da regulação negativa de CD4 por Nef. Estes estudos contribuem para o melhor entendimento dos mecanismos moleculares envolvidos na atividade de Nef, que poderão também ajudar na melhor compreensão da patogênese do HIV e da síndrome relacionada. Em adição, este trabalho contribui para o entendimento de processos fundamentais da regulação do tráfego de proteínas transmembrana no sistema endo-lisossomal. / The Human Immunodeficiency Virus (HIV) is the etiologic agent of Acquired Immunodeficiency Syndrome (AIDS). AIDS is a disease which has a global distribution, and it is estimated that there are currently at least 36.9 million people infected with the virus. During the replication cycle, HIV promotes several changes in the physiology of the host cell to promote their survival and enhance replication. The fast progression of HIV-1 in humans and animal models is closely linked to the function of an accessory protein Nef. Among several actions of Nef, one is the most important is the down-regulation of proteins from the immune response, such as the CD4 receptor. It is known that this action causes CD4 degradation in lysosome, but the molecular mechanisms are still incompletely understood. Nef forms a tripartite complex with the cytosolic tail of the CD4 and adapter protein 2 (AP-2) in clathrin-coated vesicles, inducing CD4 internalization and lysosome degradation. Previous research has demonstrated that CD4 target to lysosomes by Nef involves targeting of this receptor to multivesicular bodies (MVBs) pathway by an atypical mechanism because, although not need charging ubiquitination, depends on the proteins from ESCRTs (Endosomal Sorting Complexes Required for Transport) machinery and the action of Alix, an accessory protein ESCRT machinery. It has been reported that Nef interacts with subunits of AP- 1, AP-2, AP-3 complexes and Nef does not appear to interact with AP-4 and AP-5 subunits. However, the role of Nef interaction with AP-1 or AP-3 in CD4 down-regulation is poorly understood. Furthermore, AP-1, AP-2 and AP-3 are potentially heterogeneous due to the existence of multiple subunits isoforms encoded by different genes. However, there are few studies to demonstrate if the different combinations of APs isoforms are form and if they have distinct functional properties. This study aim to identify and characterize cellular factors involved on CD4 down-modulation induced by Nef from HIV-1. More specifically, this study aimed to characterize the involvement of AP-1 complex in the down-regulation of CD4 by Nef HIV-1 through the functional study of the two isoforms of ?-adaptins, AP-1 subunits. By pull-down technique, we showed that Nef is able to interact with ?2. In addition, our data from immunoblots indicated that ?2- adaptin, not ?1-adaptin, is required in Nef-mediated targeting of CD4 to lysosomes and the ?2 participation in this process is conserved by Nef from different viral strains. Furthermore, by flow cytometry assay, ?2 depletion, but not ?1 depletion, compromises the reduction of surface CD4 levels induced by Nef. Immunofluorescence microscopy analysis also revealed that ?2 depletion impairs the redistribution of CD4 by Nef to juxtanuclear region, resulting in CD4 accumulation in primary endosomes. Knockdown of ?1A, another subunit of AP-1, resulted in decreased cellular levels of ?1 and ?2 and, compromising the efficient CD4 degradation by Nef. Moreover, upon artificially stabilizing ESCRT-I in early endosomes, via overexpression of HRS, internalized CD4 accumulates in enlarged HRS-GFP positive endosomes, where co-localize with ?2. Together, the results indicate that ?2-adaptin is a molecule that is essential for CD4 targeting by Nef to ESCRT/MVB pathway, being an important protein in the endo-lysosomal system. Furthermore, the results indicate that ?-adaptins isoforms not only have different functions, but also seem to compose AP-1 complex with distinct cell functions, and only the AP-1 variant comprising ?2, but not ?1, acts in the CD4 down-regulation induced by Nef. These studies contribute to a better understanding on the molecular mechanisms involved in Nef activities, which may also help to improve the understanding of the HIV pathogenesis and the related syndrome. In addition, this work contributes with the understanding of primordial process regulation on intracellular trafficking of transmembrane proteins.

Text in English and Arabic / In pre-colonial Africa, the Southwestern Sahara which includes Mauritania, Mali and Senegal belonged to what was then referred to as the Sudan and extended from the Atlantic seaboard to the Red Sea. The advent of Islam and the Arabic language to West Africa in the 11th century heralded an intellectual marathon whose literary output still fascinates us today. At a time when Europe was emerging from the dark ages and Africa was for most Europeans a terra incognita, indigenous African scholars were composing treatises as diverse as mathematics, agriculture and the Islamic sciences. A twentieth century Mauritanian, Arabic monograph, Irshād al- Muqallidīn ʿinda ikhtilāf al-Mujtahidīn1, written circa 1910/1332, by a yet unknown Mauritanian jurist of the Mālikī School, Bāba bin al-Shaykh Sīdī al- Shinqīṭī al-Ntishā-ī (d.1920/1342), a member of the muchacclaimed Shinqīṭī fraternity of scholars, is a fine example of African literary accomplishment. This manuscript hereinafter referred to as the Irshād, is written within the legal framework of Islamic jurisprudence (usūl al-fiqh). A science that relies for the most part on the intellectual and interpretive competence of the independent jurist, or mujtahid, in the application of the methodologies employed in the extraction of legal norms from the primary sources of the sharīʿah. The subject matter of the Irshād deals with the question of juristic differences. Juristic differences invariably arise when a mujtahid exercises his academic freedom to clarify or resolve conundrums in the law and to postulate legal norms. Other independent jurists (mujtahidūn) may posit different legal norms because of the exercise of their individual interpretive skills. These differences, when they are deemed juristically irreconcilable, are called ikhtilāfāt (pl. of ikhtilāf). The author of the Irshād explores a corollary of the ikhtilāf narrative and posits the hypothesis that there ought not to be ikhtilāf in the sharīʿah. The proposed research will comprise an annotated translation of the monograph followed by a synopsis and commentary on its dominant themes. / Religious Studies and Arabic / D. Litt. et Phil. (Islamic Studies)

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SLOVENE NATIONAL THEATRE IN LJUBLJANA Author Report Of The Diploma Work Author: Bc. Petr Hýl Supervisor: doc. ing. arch. Zdeněk Makovský

The thesis of this study is that both Pentecostal and non-Pentecostal churches can grow at a time when only the Pentecostal churches have grown. The stagnation that has occurred in many ''mainline" churches.need not be allowed to increase or continue. In Venda (Northern Province) both the Lutherans and the Pentecostals have enjoyed visible growth. Chapter 1 introduces the thesis, the choice of the study area, the objectives of the study, and the typology, methodology and relevance of the study. Chapter 2 looks at the history and socio-economic backgrowtd of the Vhavenda. Chapter 3 describes traditional Vhavenda beliefs and rituals. The Vhavenda world-view is different from that of the West but closer to that of the East and the Bible. Chapter 4 concentrates on missionary Christianity in Venda and briefly discusses the missionary methods adopted by the Berlin Missionary Society. Chapter 5 discusses the coming of Pentecostalism to South Africa and Venda. Chapter 6 examines how the Lutherans and the Apostolic Faith Mission church conducted their mission during the "maturation of Apartheid'' in Venda. Major events in the collision between apartheid and the Vhavenda are highlighted. Chapter 7 discusses the unfinished work of the church in Venda. Chapter 8 examines the challenge for Christian mission in the twenty-first century. / Christian Spirituality, Church History and Missiology / D.Th (Missiology)

The thesis of this study is that both Pentecostal and non-Pentecostal churches can grow at a time when only the Pentecostal churches have grown. The stagnation that has occurred in many ''mainline" churches.need not be allowed to increase or continue. In Venda (Northern Province) both the Lutherans and the Pentecostals have enjoyed visible growth. Chapter 1 introduces the thesis, the choice of the study area, the objectives of the study, and the typology, methodology and relevance of the study. Chapter 2 looks at the history and socio-economic backgrowtd of the Vhavenda. Chapter 3 describes traditional Vhavenda beliefs and rituals. The Vhavenda world-view is different from that of the West but closer to that of the East and the Bible. Chapter 4 concentrates on missionary Christianity in Venda and briefly discusses the missionary methods adopted by the Berlin Missionary Society. Chapter 5 discusses the coming of Pentecostalism to South Africa and Venda. Chapter 6 examines how the Lutherans and the Apostolic Faith Mission church conducted their mission during the "maturation of Apartheid'' in Venda. Major events in the collision between apartheid and the Vhavenda are highlighted. Chapter 7 discusses the unfinished work of the church in Venda. Chapter 8 examines the challenge for Christian mission in the twenty-first century. / Christian Spirituality, Church History and Missiology / D.Th (Missiology)

Made available in DSpace on 2011-05-04T12:36:18Z (GMT). No. of bitstreams: 0 Previous issue date: 2009 / O objetivo desta dissertação consiste em investigar o processo de construção da identidade profissional de médicos que se dedicam à assistência a pacientes que apresentam doenças progressivas e ameaçadoras da continuidade existencial e que têm contribuído para o desenvolvimento dos Cuidados Paliativos no Brasil. Buscamos conhecer a trajetória profissional destes médicos desde a escolha da medicina como profissão até o encontro com a filosofia e a prática dos Cuidados Paliativos. Com este intuito, realizamos entrevistas semiestruturadas,colhidas segundo a metodologia de História Oral de Vida. Foram entrevistados seis médicos de diferentes especialidades que ocupam cargos diretivos em uma das associações profissionais voltadas para a disseminação e legitimação política e social dos Cuidados Paliativos no Brasil. Os depoentes se destacam no cenário nacional no que diz respeito às discussões sobre esta temática e mantêm contato com importantes instituições internacionais. Por esta razão, chamamos o conjunto de entrevistados de elite médica paliativista. Percebemos uma pobre interlocução entre os médicos paliativistas, o que se reflete na ausência de uma identidade integrada desse grupo profissional. Os entrevistados acentuaram as competências humanitárias necessárias ao bom exercício da Medicina Paliativa, mas, no entanto, não foram explicitadas as competências específicas a este campo profissional, que justificariam seu reconhecimento pelas entidades médicas competentes comouma nova área de atuação ou especialidade.

For many years, community colleges that chose to offer community college baccalaureate (CCB) programs were looked upon in a negative light (Rice, 2015). However, as the need for specialized baccalaureates within specific fields and job markets have continued to grow (McKee, 2005), CCB programs are becoming more widely accepted throughout the United States. In spite of this paradigm shift, Mississippi is one of the remaining states that have not embraced the idea of CCB programs, in spite of its statistical deficiency in regards to baccalaureate degree holding citizens (Williams, 2010). The focus of this study was to explore the perceptions of community college administrators in Mississippi with regards to the influence of CCB programs to the community college mission of institutions in their state. This study indicates that administrators in Mississippi recognize the benefits of offering CCB programs, but do not want CCB programs to take away from the well-established statewide higher education system through mission creep. Many of the strong position statements received overwhelmingly neutral responses. In contrast, Administrators who chose to give their opinion indicated that they are not familiar with how CCB programs are implemented, and do not believe that Mississippi is ready for CCB programs across the state. However, respondents felt that the community college mission is always evolving, should meet students’ needs, and varies from location to location. The findings also show that administrators are favorable to the piloting of CCB programs at a few (1-2) institutions, even though they believe the programs will take funding away from current programs and do not want community colleges evolving into 4-year institutions. The study also concludes that there is a significant difference between institution size and survey questions #18 and #20. There is also a significant difference between length of time in the community college sector and survey questions #15, #17, and #18.

The design of cultural centre is situated in part Kozia Hôrka( well-known city swimming pool), in its advantage takes natural scenery and calm atmosphere of place. Into action of performance brings a message in form of body of reservoir, function of centre is divided into small parts placed in area Kozia Hôrka. Orientation of objects comes mainly from local natural ispirations. Complex is multifunctional in concept, counts with several sorts of culture - sports events. Whereby the main function of swimming pool is preserved and added for higher comfort of inhabitants. Architecture of objects comes from idea of floating leaf on water level and body of reservoir. Objects stylizely illustrate this idea. The design takes the game of solids of organic and strictly ortogonal shapes. Two mutual opposites, in interaction. Objects smoothy and with respect encroach the environment, which is enough marked by human. Simplicity in used materials ( glass, steel, wood ) give transparency and purity to whole solution.

Dans un avion, un hélicoptère ou un lanceur actuel, des milliers de capteurs, pour la plupart non critiques sont utilisés pour la mesure de divers paramètres (températures, pressions, positions...) Les résultats sont ensuite acheminés par des fils vers les calculateurs de bord qui les traitent. Ceci implique la mise en place de centaines de kilomètres de câbles (500 km pour un avion de ligne) dont le volume est considérable. Il en résulte une grande complexité de conception et de fabrication, des problèmes de fiabilité, notamment au niveau des connexions, et une masse importante. Par ailleurs l'instrumentation de certaines zones est impossible car leur câblage est difficilement envisageable par manque d'espace. En outre, s'il est souvent intéressant d'installer de nouveaux capteurs pour faire évoluer un aéronef ancien, l'installation des câbles nécessaires implique un démantèlement partiel, problématique et coûteux, de l'appareil. Pour résoudre ces problèmes, une idée innovante a émergé chez les industriels de l'aéronautique : commencer à remplacer les réseaux filaires reliant les capteurs d'un aéronef et leur centre de décision par des réseaux sans fil. Les technologies de communication sans fil sont aujourd'hui largement utilisées dans les marchés de l'électronique de grande consommation. Elles commencent également à être déployées pour des applications industrielles comme l'automobile ou le relevé à distance de compteurs domestiques. Cependant, remplacer des câbles par des ondes représente un défi technologique considérable comme la propagation en milieu confiné, la sécurité, la sureté de fonctionnement, la fiabilité ou la compatibilité électromagnétique. Cette thèse est motivée d'une part par l'avancée non négligeable dans le milieu aérospatial que pourrait être l'établissement d'un réseau sans fil à bord d'aéronefs dans la résolution de problématique classiques comme l'allégement et l'instrumentation. Il en résulterait donc : * Une meilleure connaissance de l'environnement et de la santé de l'aéronef * Un gain sur le poids. * Un gain en flexibilité. * Un gain en malléabilité et en évolutivité. * Un gain sur la complexité. * Un gain sur la fiabilité D'autre part, étant donnée la complexité de la conception de ce réseau de capteur sans fil, il a été nécessaire d'appliquer une méthodologie évolutive et adaptée mais inspirée de l'ingénierie système. Il est envisageable, vu le nombre de sous-systèmes à considérer, que cette méthodologie soit réutilisable pour d'autre cas pratiques. Une étude aussi complète que possible a été réalisée autour de l'existant déjà établi sur le sujet. En effet, on peut en lisant ce mémoire de thèse avoir une idée assez précise de ce qui a été fait. Une liste a été dressée de toutes les technologies sans fil en indiquant leur état de maturité, leurs avantages et leurs inconvénients afin de préciser les choix possibles et les raisons de ces choix. Des projets de capteurs sans fil ont été réalisés, des technologies sans fil performantes et personnalisables ont été développées et arrivent à maturité dans des secteurs variés tels que la domotique, la santé, l'automobile ou même l'aéronautique. Cependant aucun capteur sans fil n'a été véritablement installé en milieu aérospatial car de nombreux verrous technologiques n'ont pas été levés. Fort des expériences passées, et de la maturité qu'ont prise certaines technologies, des conclusions ont été tirées des projets antérieurs afin de tendre vers des solutions plus viables. Une fois identifiés, les verrous technologiques ont été isolés. Une personnalisation de notre solution a été à envisager afin de remédier tant que faire se peut à ces points bloquants avec les moyens mis à disposition. La méthodologie appliquée nous a permis d'identifier un maximum de contraintes, besoins et exigences pour mieux focaliser les efforts d'innovation sur les plus importantes et choisir ainsi les technologies les plus indiquées.