O projeto de pesquisa analisa os rumos do pensamento escultórico moderno em direção a uma escala ambiental, processo que tem origem no final do séc. XIX, momento em que a obra A Porta do Inferno, de Auguste Rodin, modifica o espaço narrativo clássico, rompendo com a premissa do monumento e passando a pleitear cada vez mais uma imersão da obra no espaço do observador. O período das vanguardas históricas também foi fundamental para se repensar as fronteiras entre as linguagens tradicionais e o reconhecimento de outras esferas que não a das belas-artes, desde a dissolução da base na escultura de Constantin Brancusi, passando pela renovação do estatuto de arte em Marcel Duchamp, até as experiências de colagem com a obra Merzbau, de Kurt Schwitters. A dissertação examina especialmente a produção que desde então problematizou a tradição da escultura, privilegiando as manifestações contemporâneas que derivam da tradição moderna, projetando o campo da arte para além dos gêneros artísticos fixados até então, buscando expandir a noção de escultura em termos espaciais, temporais e experienciais. Entre as décadas de 1940 e 1960, a ruptura com essa tradição culmina na radicalidade das ações corporais de Jackson Pollock, que conferem uma nova escala às pinturas; e, mais à frente, numa produção que emergia como crítica aguda ao mercado e à institucionalização cada vez mais precoce do trabalho de arte. A arte contemporânea, então, teria sua origem num processo de crítica do objeto, precipitado pelo problemas da cultura de massa, onde os trabalhos se reconhecem num mundo da cultura, mesmo ao resistirem a sua cooptação. Sem ter sido objeto de análises abrangentes, a escultura contemporânea, se é que ainda podemos denominar escultura os trabalhos produzidos a partir da década de 1960, parece ter colocado em crise a noção moderna de forma, e passa a operar num contexto ampliado, aberta ao espaço e à dinâmica cultural urbana. É nesse momento que a dissertação se aproxima das obras de Richard Serra, José Resende e Hélio Oiticica e passa a dedicar uma análise mais atenta sobre aqueles trabalhos que lidaram com uma escala ambiental, ou ainda, se aproximaram das contingências do lugar onde atuam, quer físicas, sociais ou culturais, operando próximos à poética do site specificity. / The research project analyses the directions of the modern sculptural thoughts towards an environmental scale, a process that begins in the end of the 19th Century, a moment in which Auguste Rodins The Gates of Hell modifies the classic narrative space breaking up with the premise of the monument and defend every time more an immersion of the work in the observer space. The historical vanguard period was also fundamental to rethink the boundaries between the traditional languages and the recognition of spheres that are not of fine arts ñ from the dissolution of the base in sculpture of Constantin Brancusi, passing through the renovation of the art statute of Marcel Duchamp, to the collage experiences of Kurt Schwitters Merzbau. The dissertation examines specially the production that has questioned the sculpture tradition, the contemporary manifestations that come from modern tradition, projecting the art field beyond the so far fixed artistic genders and searching to expand the notion of sculpture in terms of space and time, as well as your artistic practice significance. Between the decades of 1940 and 1960, the break with this tradition culminates in the radically body actions of Jackson Pollock that gives a new scale to paintings; and afterwards, in a production that emerged as a deep critique of the market and the every time earlier institutionalization of the art work. The contemporary art, therefore, would have its origin in a process of the object critique precipitated by mass culture problems where the works are recognized in a cultural word, even when they resist to their cooptation. Without being object of comprehensive analyses, the contemporary sculpture, if we still can denominate sculpture the works produced from the 1860 decade on, seems to have placed the modern notion of form in crisis, and started to operate in an enlarged context, open to space and to the urban cultural dynamic. It is at his moment that the dissertation approaches Richard Serra, José Resende and Hélio Oiticicas work and dedicates more careful analyses over those works that deal with environmental scale, or yet, approach either physical, social or cultural contingencies of the place in which they act, operating to the poetic of the site specificity.

O núcleo desta tese é o conjunto da minha produção artística entre os anos de 2004 e 2008, período em que se deu este doutorado. O texto que acompanha as imagens dos trabalhos descreve cronologicamente cada experiência, desde sua elaboração até a execução, como um evento concatenado a experiências anteriores e posteriores, desdobradas no tempo. Esses trabalhos não apenas partem de indagações a respeito do lugar em que estão inseridos, o que poderia identificá-los com a prática do site-specific, mas têm uma vontade de confundir-se com o próprio lugar, têm a intenção de sê-lo. Nesse sentido, talvez o ânimo da obra aqui relatada não venha de um intrincamento com um lugar específico, mas de intrincamento específico com qualquer lugar. A questão oscila entre dois lados no conjunto do trabalho, e mantém-se em suspenso um julgamento conclusivo sobre a dualidade que nomeia esta tese, que a rigor parece não existir: visto de dentro, visto de fora. / The core of this thesis is the ensemble of my artistic production between the years 2004 and 2008, which was the period when I was undertaking my PhD course. The text accompanying the images chronologically describes each experience, from its inception to its execution, as an event connected to previous and subsequent experiences, unfolded in time. These point of departure of these works go beyond issues apropos of the place in which they are inserted and that might have identified them with the practice of site-specific. The works aim at integrating themselves with each place, they aim at being that very place. In this sense, the moving force behind the works here presented may stem not so much from a relationship of entanglement with a specific place, but with a specific relation of entanglement with any place. Within the ensemble of the work, this issue oscillates between two sides and keeps a conclusive judgement about the duality that names this thesis in suspension. Rigorously speaking, this duality may even seem not to exist: viewed from the inside, viewed from the outside.

A redefinição da escultura e as pautas atuais de criação, fazendo uso da prática de projeto, provocam mudanças na formação do artista. Da aula expandida à aula Site-Specificity. A hipótese estudada: o projeto didático pautado em explorar as possibilidades das formas de experimentação e procedimentos artísticos em projeto Site-Specificity, que traz a vida para a \'sala de aula\', envolve mais o aluno, enquanto articulador de diferentes e complexas atividades no espaço público, supondo que essas características da prática de projeto Site-Specificity possam contribuir na formação do jovem artista e fornecer soluções às crescentes exigências de profissionalização que vem sofrendo a arte contemporânea em relação à sociedade. O principal objetivo: explorar as possibilidades de renovação das formas de experimentação e procedimentos em projeto Site-Specificity para descrever e explorar suas contribuições na formação do artista. Os objetivos específicos correspondem ao percurso da dissertação e ao processo das aulas \'site\', para os quais os três capítulos são como um campo das relações dialéticas, onde o Site-Specificity designa igualmente tanto o que é proposto para ser realizado quanto o que é feito para atingi-lo. Essa relação dialética leva a muitas possibilidades de operacionalizar projetos, tendo em vista as diferentes preocupações dos alunos. Concluindo, cada capítulo, respectivamente, concorre para um objetivo. O primeiro capítulo é uma reflexão sobre a expansão da escultura e as transformações do Site-Specificity; o segundo capítulo é sobre as aulas Site- Specificity e por último, no terceiro capítulo denominado \"Dupla exposição\", apresento exposições realizadas por alunos como resultados do processo de aprendizagem a partir das aulas Site-Specificity. / The redefinition of sculpture and the current guidelines for creation, through the practice of projects, provoke change in the artist\'s formation. The class expanded to learning Site-Specificity. The studied hypothesis, along with the educational project outlined to explore the possibilities of forms of experimentation as well as the artistic procedures in Site-Specificity project, bring life into the \'classroom\' and better involve the students as they perform different and complex activities in public spaces, supposing that these characteristics from the practice of Site-Specificity project can contribute to the formation of the young artist and provide some solutions to the growing demands of professionalization that has been suffering contemporary art in relation to society. The main goal was to explore the possibilities of the renewal of both, the forms of experimentation and the procedures in Site-Specificity project to depict and explain its influences and contributions to an artist\'s formation. The specific goals correspond to the course taken by the dissertation and the \'site\' classes\' process, of which the three chapters stand as fields of dialectical relationships, where Site-Specificity designates equally what is to be accomplished as well as what is done in order to achieve it. This dialectical relationship leads to many possibilities of operating projects, having in mind the different student\'s concerns. In conclusion, each chapter, respectively, collaborates to a goal. The first chapter is a reflection of the expansion of sculpture and the Site-Specificity\'s transformations; the second chapter is about the Site-Specificity classes, and lastly, the third chapter denominated \"Double exposure\", presents student\'s exhibitions as a result of the learning process from the Site-Specificity classes.

O governo eletrônico (e-gov) diz respeito a todas as formas de comunicação realizadas por meio de tecnologia de informação (TI) que podem trazer uma série de benefícios para os órgãos públicos de modo geral. Por se tratar de uma tecnologia recente, existem muitos recursos que podem explorados em benefício tanto do governo quanto dos cidadãos e das empresas que interagem por meio dessa ferramenta. Apesar de apresentar um conjunto considerável de oportunidades, o governo eletrônico e as novas formas de interação pública advinda da utilização da TI podem propiciar algumas ameaças como é o caso de, em vez de melhorar um processo burocrático, apenas utilizar a forma eletrônica para seu acesso e processamento de forma informatizada. Para que, neste contexto, as oportunidades sejam aproveitadas e as ameaças evitadas, este estudo propôs um modelo de análise dos serviços de sites de governo eletrônico. Inicialmente, o modelo foi avaliado por meio da análise de conteúdo de sites de e-gov dos cinco estados com o maior número de sites que, somados, representam 50% dos sites de e-gov nacional que são os estados de São Paulo, Paraná, Minas Gerais, Rio Grande do Sul e Santa Catarina. Esta primeira análise possibilitou o desenvolvimento de uma matriz SWOT dos sitess analisados e, então, partiu-se para a avaliação do modelo por meio de pesquisas do tipo grupo focado e pesquisa quantitativa por meio de aplicação de questionários focados no site do Poupa Tempo. Os resultados obtidos por meio destas análises foram semelhantes, o que permitiu concluir que o modelo proposto é um instrumento válido para analisar os serviços de sites de e-gov. Outros resultados importantes também foram encontrados, como identificar os atributos que influenciam na satisfação dos usuários de serviços de e-gov. Dentre estes atributos destacaram-se o site fornecer informações de qualidade, oferecer o que era esperado e disponibilizar opções de comunicação que funcionam. / Electronic government (e-gov) refers to all forms of communication conducted through information technology (IT) that can bring several benefits to public bodies in a general form. Being a recent technology, there are many resources that can be exploited for the benefit of government, citizens and businesses that interact via this tool. Despite presenting a considerable range of opportunities, electronic government and new forms of public interaction arising from the use of IT can provide some threats such as instead of improving a bureaucratic process; just use the electronic form for access and processing in a computerized form. In order to have the opportunities to be exploited, in this context, and threats to be avoided, this study proposed a model for analysis of e-government service sites. Initially, the model was evaluated by analyzing the content of e-gov sites for the five states with the largest number of sites which together represent 50% of all national e-government sites, which are the states of São Paulo, Paraná , Minas Gerais, Rio Grande do Sul and Santa Catarina. This first analysis has made it possible the development of a SWOT of the analyzed sites and then the evaluation of the model through focus group and quantitative surveys using questionnaires focused on the site of \"Poupa Tempo\". The results obtained from these analyzes were similar, which made us conclude that the proposed model is a valid tool to analyze the services of e-gov sites. Other important results were also found, such as identifying the attributes that influence user satisfaction of e-government services. Among these attributes stood out the site to provide quality information, to offer what was expected, and to provide communication options that work out.

Esta pesquisa investiga como os sites de duas instituições museológicas ocupam o Ciberespaço. Objetiva identificar aproximações e distanciamentos entre elas, no que diz respeito à qualidade da informação comunicada e ao entendimento do espaço virtual, enquanto local em potencial para a construção do discurso simbólico sobre Artes. Preocupase igualmente em observar a efetivação do papel do Museu como agente de aproximação e integração entre a sociedade e as demandas geradas pelas novas tecnologias. O Ciberespaço institui um novo tipo de espectador/internauta que se relaciona com os bens culturais de maneira contrária à já sacralizada pelas instituições museológicas surgidas nos séculos passados. A análise dos espaços do MAC Virtual, no Brasil, e da TATE Online, na Inglaterra, mostrou que o projeto virtual terá mais sucesso à medida que evita recriar, no ambiente virtual, o espaço consagrado para a exibição da obra de arte. / This research investigates how the websites of two museological institutions occupy the Cyberspace. Its main goal is of identifying approaches and differences between them regarding the quality of published information and the understanding of the virtual space while place in potential for the development of the symbolic speech about Arts. At the same time it focuses on the consolidation of the Museums role as integration agent between society and the demands generated by new technologies. The Cyberspace creates a new kind of spectator/user that relates itself with the cultural assets in an opposite way to the traditional manner of the museological institutions that were created in the last centuries. Analyzing the website MAC Virtual in Brazil and TATE Online in England, showed that the virtual project will be more successful if it avoids recreating, in the virtual space, the traditional space for displaying the Artworks.

Aborda-se aqui a trajetória do compositor Hans-Joachim Koellreutter (1915-2005) e as relações com o debate teórico e prático da arte e estética do século XX, a partir de seus textos e obras. Uma estética que se desenvolve em íntima colaboração com a formulação de uma filosofia da história da arte que o compositor, paralelamente à sua prática composicional, expressa em artigos, palestras e cursos. A filosofia da história que vai construindo apresenta-se como a articulação entre duas temporalidades: grandes e pequenos períodos (Introdução), cujos marcos são transições, caracterizadas por crises entre sistemas que se esgotam ou que emergem para sua superação. Entre uma modernidade e uma contemporaneidade anacrônicas, a trajetória do compositor acaba nos proporcionando um modelo paradigmático dessa caracterização de crise estética apresentando alguns sintomas dessa dupla temporalidade: (i) a ressonância anacrônica dos vanguardismos do século XX aproximação arte vida comum; dessacralização dos valores da arte; quebra de protocolos ou preconceitos; subversão do meio; denúncia ou reflexão sobre os modos de produção; arte contra o consumo (Caps. I e II) , ocorrendo junto com (ii) tópicos que se tornariam marcas na contemporaneidade: arte funcional; autoria em rede colaborativa; arte voltada para a circulação; campo expandido e site específico (Cap. III). Por serem momentos de crise, transformações e hibridismo entre o velho e o novo carregam forças opostas: o primeiro resistindo e constituindo oposição através das formalizações e regulações; o segundo subjetivando-se através de novos paradigmas de forma e performance, momentos onde pode constituir-se uma vanguarda (Caps. II e III): um grupo que, em sintonia com sua época, consegue ligar as aspirações estéticas e formais com os conteúdos relevantes para interferir diretamente nessas transformações. Koellreutter compôs três peças na década de 1980 aqui escolhidas como material básico para exemplos e modelos: Ácronon, Nova-mente e Rôdô, músicas que novamente anunciavam o novo, cinquenta anos depois que aportou no Brasil, já como fenômeno de novidade (Cap. III). Tenta-se mostrar (Considerações Finais) como o compositor, ao lidar com essas duas forças a tradição e a modernidade tenta constituir uma relação que ele denomina de alfa privativaseu conceito de contrário sem contradição onde ele pode integrar tradição e a ruptura assim como o ruído e informação, estabelecendo íntima relação entre a ética e a estética. / We analyze here the trajectory of the German composer emigrated to Brazil in 1937, Hans- Joachim Koellreutter (1915-2005), and his relations with the theoretical and practical debate about art and the aesthetics of the 20th century, based on his original texts and works. An aesthetic that was developed in close collaboration with the formulation of philosophical ideas and art history which the composer, in parallel with his compositional practice, expresses in many articles, lectures and courses. The philosophy of history that he proposes presents itself as an articulation between two temporalities: large and small time intervals, whose marks are transitions, characterized by crises among systems that are exhausted or that emerge one day only to be overcome the nexto day. Inside an modernity and contemporaneity, both considered anacronic, the trajectory of the composer ends up providing us with a paradigmatic model of the characterization of an aesthetic crisis presenting some symptoms of a double temporality: (i) the anachronistic echos of the avantgardes of the twentieth century - common life as art approach; desacralization of art values; breach of protocols and prejudices; subversion of the means of productions ; denunciation or reflection on modes of production; (Caps I and II) -, occurring along with (ii) topics that would become brands in the contemporary world: functional art; collaborative authoring network; art oriented to difusion; expanded field and site specific (Chapter III). Thanks to these moments of crisis, transformations and hybridity between the old and the new carry opposing forces: the first resisting and constituting opposition through formalizations and regulations; the second subjectivizing itself through new paradigms of form and performance, moments in which a vanguard can be constituted (Caps II and III): a group that, in tune with its time, manages to connect the aesthetic and formal aspirations with the contents to interfere directly in these transformations. Koellreutter composed three especial pieces in the 1980s here chosen as the basic material for examples and models: Ácronon, Nova-mente and Rôdo, works that once again announced the new, which fifty years after he introduced in Brazil again as a phenomenon of novelty (Chapter III). Attempts to show (Final Remarks) how the composer, in dealing with these two forces - tradition and modernity. Finally we build a relationship that he calls a retritive alpha. His concept of the opposite without contradiction where he can integrate tradition and rupture as well as noise and information, establishing an intimate relationships between ethics and aesthetics.

La compréhension de la façon dont les consommateurs interagissent avec le site Web d’une entreprise s’avère primordiale pour sa survie à l’heure actuelle. En effet, elle aide les gestionnaires de sites Web à améliorer la performance du site de manière à développer la satisfaction des consommateurs et ainsi leurs comportements d’achat et de fidélité. Le but de ce travail de recherche est double. Il vise dans un premier temps à développer un modèle conceptuel expliquant la fidélité intentionnelle des consommateurs, pour dans un deuxième temps, le tester empiriquement dans le cas des sites Web de voyage. Plus précisément, cette étude examine le rôle des perceptions des consommateurs sur leur satisfaction et leur fidélité. Cette dernière est appréhendée au travers des intentions d’achat, de recommandation et de visite du site. En outre, le rôle médiateur de la satisfaction des consommateurs entre la perception des consommateurs des attributs de site et la fidélité intentionnelle est examiné. Un cadre théorique est établi qui est soutenu par des preuves empiriques dans le contexte de voyage en ligne. Ce cadre théorique se penche essentiellement sur la théorie du choix raisonné de Fishbein et Ajzen (1975), Oliver (1999) et autres travaux majeurs dans le domaine du comportement du consommateur en ligne. Notre étude s’appuie sur une approche quantitative fondée sur les données recueillies auprès des consommateurs par le biais d’un questionnaire ciblant les voyageurs en ligne. Notre analyse est fondée sur des réponses d'un échantillon de 200 voyageurs.En ce qui concerne les résultats empiriques, la recherche apporte plus d’éclairage sur le lien entre les perceptions des consommateurs et leur intention de fidélité. Par conséquent, les résultats montrent l'impact direct de la perception sur les intentions de fidélité. Plus précisément, les résultats suggèrent que la perception du consommateur liée aux attributs fonctionnels et hédoniques du site Web de voyage est susceptible d'affecter son intention de fidélité.Les résultats empiriques montrent également que les deux dimensions de la perception des consommateurs à savoir les attributs hédoniques et fonctionnels peuvent potentiellement améliorer la satisfaction du consommateur. Cependant, la satisfaction est plus déterminée par les perceptions liées aux attributs fonctionnels que celles liées aux aspects hédoniques. En outre, bien que la satisfaction du consommateur est reconnue d’influencer les intentions de fidélité des consommateurs, mais seul ne suffit pas pour conduire les intentions de fidélité des consommateurs. L'étude se termine par une conclusion générale qui résume les principaux résultats mis en évidence dans cette recherche. Il aborde les contributions théoriques, méthodologiques, les implications managériales et les contributions de résultats empiriques de recherche. Enfin, cette recherche conclut sur des voies de recherche futures. / A better comprehension of how consumers interact with travel web site is primordial for its survival as it helps managers improve web site performance to levels that satisfy online travel purchaser, and thus create loyalty intentions resulting in a positive word of mouth and repurchasing behavior. Drawing upon the foundations of marketing literature and particularly the theory of reasoned action of Fishbein and Ajzen (1975), Oliver (1999) and other relevant major works regarding online consumer behavior, this research work aims at developing and test empirically a conceptual model that explains how online leisure traveler develops loyalty intentions towards travel web site. Specifically, this research study investigates the role of consumer’s perceptions and satisfaction on loyalty intentions. In addition, the mediating role of consumer satisfaction between web site attributes perceptions-loyalty intentions relationship is examined. The established theoretical framework is supported by empirical evidence in the online travel settings. Our research study uses quantitative approach leaning on data collected by consumer-based survey targeting online travelers. Our analysis is based from responses of a sample of 200 e-travelers.With regard to the empirical findings, the research brings more knowledge about the consumer’s perceptions-loyalty intentions relationship. Hence, findings indicate the direct impact of perception on loyalty intentions. More precisely, results suggest that consumer’s perception of functional-related and hedonic related attributes of travel web site is likely to affect his loyalty intentions. The empirical findings show as well that the two dimensions of consumers’ perceptions (hedonic and functional-relevant attributes) can potentially enhance consumer satisfaction. However, satisfaction is more driven by functional-related attributes than hedonic-related ones. Furthermore, though consumer satisfaction is deemed to influence consumer loyalty intentions but alone is not sufficient to drive consumer loyalty intentions. Finally, the research study ends with a general conclusion that summarizes the key findings highlighted in this research. It addresses the theoretical, methodological, managerial marketing implications and contributions of empirical findings. Then, it provides a basis for identifying several fruitful directions for future research.

La voie de signalisation Sonic Hedgehog (Shh) joue un rôle fondamental au cours de l’embryogenèse pour la mise en place de nombreux tissus. Elle persiste à l’âge adulte et régulerait notamment le contrôle de fonctions cérébrales. Son activation requiert la liaison d’un peptide Shh sur le récepteur Patched (Ptc) qui réprime l’activité constitutive de Smoothened (Smo), un récepteur apparenté à la famille des récepteurs couplés aux protéines G (RCPG). Récemment, des essais cliniques pour le traitement de médulloblastomes et de diverses tumeurs solides chez l’Homme ont été menés avec des antagonistes de Smo. Cependant, ces molécules ont révélé des limitations à leur utilisation puisque des résistances au traitement sont apparues. Le travail de cette thèse a conduit au développement d’un modèle pharmacophorique des antagonistes de Smo qui a ensuite permis le criblage virtuel d’une banque de molécules et l’identification de nouvelles familles d’antagonistes de Smo. L’acylthiourée MRT-10 et l’acylurée MRT-14 ont été les deux premiers composés caractérisés. Des études de relations structure-activité ont permis l’identification d’une nouvelle famille d’inhibiteurs du récepteur Smo de haute affinité à laquelle l’acylguanidine MRT-83 appartient. Ce composé s’adapte parfaitement au modèle pharmacophorique des antagonistes de Smo. Les modifications structurales que MRT-83 présentes en comparaison avec les deux têtes de séries précédemment caractérisées sont à l’origine du gain d’activité de MRT-83 sur de nombreux tests cellulaires mettant en jeu l’activation de la voie Shh. Le composé MRT-83 inhibe la liaison de la BODIPY-cyclopamine sur le récepteur Smo humain et bloque la prolifération des précurseurs des cellules granulaires de rat avec une affinité de l’ordre du nanomolaire, comparable à celle des antagonistes de référence de Smo tels que le GDC-0449 et le LDE-225. Malgré l’homologie de séquence entre Smo et la famille des récepteurs Frizzled impliqués dans la signalisation Wnt, le composé MRT-83 ne présente aucun effet sur la voie Wnt. MRT-83 bloque la translocation de Smo dans le cil primaire induite par l’activation de la voie Shh dans les cellules NT2, une lignée issue d’un tératocarcinome humain, contrairement à l’antagoniste de Smo de référence, la cyclopamine qui induit l’adressage du récepteur dans le cil primaire. L’injection stéréotaxique dans le ventricule latéral de cerveau de souris adulte de MRT-83, contrairement à celle d’un composé de structure analogue, dépourvu d’activité sur Smo, inhibe l’expression des transcrits de Ptc induite par l’injection de Shh dans la zone sous-ventriculaire, l’une des deux principales aires de neurogenèse adulte. Ces résultats démontrent que les dérivés MRT bloquent également la signalisation Shh in vivo. Ainsi, les composés MRT-10, MRT-14, MRT-83 et les molécules de structure analogues caractérisées sont de puissants antagonistes de Smo. Ces molécules constituent de nouveaux outils pharmacologiques qui pourraient permettre d’améliorer notre compréhension des mécanismes moléculaires et biochimiques régulant la signalisation Hh et permettre le développement de nouvelles molécules en clinique pour le traitement des tumeurs Hh-dépendantes. / The Sonic Hedgehog (Shh) signaling pathway is implicated in multiple physiological responses including the control of brain functions. In mammals, the Shh pathway is expressed at the primary cilium and its activation requires the binding of a Shh peptide to the Patched (Ptc) receptor which represses the constitutive activity of Smoothened (Smo), a proposed member of the G-protein-coupled receptor (GPCR) family. Recently, clinical trials for treating medulloblastoma and various solid tumors in human have been conducted with Smo antagonists such as GDC-0449 or LDE-225. Such molecules may have some limitations leading to treatment resistance. In the present work, the development of a pharmacophoric model of Smo antagonists allowed a virtual screening strategy to identify novel Smo inhibitors. The acylthiourea MRT-10 and the acylurea MRT-14 were the two first leads identified. Structure-activity relationship experiments led to the discovery of new series of Smo inhibitors with high potency and to which the acylguanidine MRT-83 belongs. This inhibitor perfectly fits with the proposed pharmacophoric model for Smo antagonists. The discrete structural differences between MRT-83 and the original leads may account for the increased potency of MRT-83 observed in various in vitro Shh-based assays. MRT-83 inhibits BODIPY-cyclopamine binding to human Smo and Shh-mediated proliferation of rat granule cell proliferation with nanomolar potency similar to GDC-0449 or LDE-225. Despite significant homology of Smo with the Frizzled family of receptors which are involved in the Wnt signaling pathway, MRT-83 displays no significant effect on this pathway. MRT-83 blocks Smo translocation induced by Shh pathway activation to the primary cilia of NT2 cells that derive from a pluripotent testicular carcinoma whereas cyclopamine, a reference Smo antagonist, induces Smo accumulation of Smo signals at the primary cilium. Therefore, it might be anticipated that MRT-83, like GDC-0449 and LDE-225, interacts with Smo in a manner different from that of cyclopamine, suggesting that while their binding sites are overlapping, they are not identical. Stereotaxic injection of MRT-83 into the lateral ventricle of adult mice but not of a structurally-related compound inactive at Smo, abolished upregulation of Ptc transcription induced by Shh in the neighboring subventricular zone, one of the two main neurogenic areas of the adult brain. These data demonstrate that MRT derivatives efficiently antagonize Shh signaling in vivo. Thus, MRT-10, MRT-14, MRT-83 and structurally-related molecules are potent Smo antagonists. These compounds should be useful for clarifying the molecular and biochemical mechanisms underlying the resistance of Smo inhibitors in brain cancer cells and may help develop new therapies against Shh pathway-related brain diseases.

La transplantation d’îlots pancréatiques est une des thérapies proposées aux diabétiques de type 1. Cependant, la perte d’un nombre considérable d’îlots durant le processus est un frein à l’expansion de la thérapie (en culture : anoïkis et hypoxie ; lors de la greffe : réactions inflammatoires intenses déclenchées lors de l’infusion intra-portale). L’objectif de ce travail était de valider un biomatériau permettant d’optimiser la transplantation d’îlots. Nous avons pu démontrer l’efficacité du plasma réticulé sur la survie des îlots en culture via une diminution drastique de l’anoïkis. Nous avons également mis au point une technique de greffe intra-tissulaire à l’aide d’HPMC combinée à du plasma, permettant de reverser le diabète de manière semblable à la greffe hépatique. Ces travaux ont donc permis de valider l’importance d’un support de culture adapté, mais aussi du site receveur de la greffe et placé l’omentum comme site de choix pour ce type de greffe. / Pancreatic islet transplantation is one of the therapies proposed to type 1 diabetic patients. However, the considerable loss of islets during the process is an obstacle to the expansion of this therapy (culture: anoïkis and hypoxia; at graft time: intense inflammatory reactions triggered by intra-portal islet infusion). The objective of this work was to validate a biomaterial that can optimize islet transplantation. We were able to demonstrate the effectiveness of cross-linked plasma on the islet survival in culture through a drastic reduction of anoikis. We also design a new intra-tissular grafting technique using HPMC combined with plasma, which reversed diabetes in a manner similar to the liver. This work allowed validating the importance of an adapted culture support, but also the one of the recipient site. Also, this work placed the omentum as an excellent recipient site for this kind of transplant.

FundaÃÃo Cearense de Apoio ao Desenvolvimento Cientifico e TecnolÃgico / O Riacho Pajeà à um recurso hÃdrico de fundamental importÃncia histÃrica e ambiental para a cidade de Fortaleza que foi aos poucos apagado do espaÃo fÃsico e simbÃlico. Tal riacho foi objeto de monografia de graduaÃÃo desta pesquisadora como conclusÃo do curso em Arquitetura e Urbanismo (2003), a partir de um viÃs de urbanismo ecossistÃmico. ApÃs mais de dez anos desse trabalho, a presente pesquisa à uma retomada daquele corpus de estudo a partir do campo das Artes, pela compreensÃo desse lugar como um campo potente para problematizaÃÃo e atuaÃÃo simbÃlica. Diante do apagamento do riacho e das possibilidades de ampliaÃÃo do espaÃo atuais, colocam-se as questÃes: como apropriar-se das possibilidades de ampliaÃÃo da realidade criadas pelas mÃdias locativas para discutir o apagamento no contexto especÃfico do riacho Pajeà (ou como, pela adiÃÃo de camadas, falar da subtraÃÃo do espaÃo)? Como somar as virtualidades desses dispositivos Ãs virtualidades do espaÃo para construir um Parque ampliado do PajeÃ? Esta dissertaÃÃo tem como objetivo geral investigar as possibilidades de apropriaÃÃo pela arte das chamadas prÃticas Locative media para gerar um espaÃo desviante no contexto especÃfico do riacho Pajeà como espaÃo ampliado, tendo o site-specific como mÃtodo. / The Pajeà creek is a watercourse of fundamental historical and environmental rele-vance in Fortaleza, Brazil, which has been gradually erased from the cityâs physical and symbolic space. The creek was the subject of investigation of this researcherâs degree in Architecture and Urbanism (2003), from the standpoint of ecosystemic ur-banism. More than ten years later, this research is a return to the previous corpus of study, but now with a renewed perspective from the field of the Arts, in the under-standing of the creek as a field of potential for both problematization and symbolic action. In face of the creekâs erasure and its current possibilities of spatial expan-sion, questions emerge: how to take hold of the possibilities of augmented reality, enabled by locative media, in order to discuss the process of erasure in the specific context of the Pajeà creek (or how to talk about space subtraction by adding layers)? How to add the virtualities of devices to the virtualities of space to create an aug-mented park for the Pajeà creek? Using the site-specific method, this Masterâs thesis aims to investigate the possibilities of artistic appropriation of the so-called practices of locative media, in order to generate a deviant space in the specific context of the Pajeà creek as an augmented space.