Certains virus respiratoires comme rhinovirus semblent favoriser la colonisation par staphylococcus aureus. Cependant, les détails des mécanismes impliqués dans cette synergie n’ont pas été suffisamment élucidés. Le but de cette thèse a été de développer et valider un modèle in vitro mimant la colonisation du vestibule nasal par s. aureus en utilisant les kératinocytes humains hacat. Ce modèle a permis d’étudier (i) les pouvoirs d’adhésion et d’internalisation d’une collection de souche clinique de s. aureus, (ii) l’efficacité intracellulaire des molécules antimicrobiennes utilisées dans le cadre de la décolonisation nasale de s. aureus, (iii) l’effet de la clarithromycine sur l’infection par rhinovirus et (iv) l’impact de l’infection par rhinovirus ou de l’inflammation non spécifique sur la colonisation par s. aureus. ce travail a principalement permis d’identifier un nouveau mécanisme alternatif de l’internalisation de s. aureus à travers la liaison entre la protéine bactérienne eap (extracellular adherence protein) et le récepteur cellulaire icam-1 (intracellular adhesion molecule 1). Cette voie alternative est favorisée en cas d’infection par rhinovirus ou d’inflammation, ce qui pourrait expliquer les observations cliniques de l’augmentation de la charge de s. aureus ou du risque d’infection par cette bactérie lors des infections virales respiratoires ou d’inflammation post-traumatique. Les résultats de cette thèse illustrent la complexité des interactions entre les cellules épithéliales de la muqueuse, s. aureus et les pathogènes viraux et ouvrent les perspectives sur d’autres études nécessaires afin de proposer des stratégies préventives ou thérapeutiques adaptées. / Some respiratory viruses such as rhinoviruses seem to promote staphylococcus aureus colonization. However, the details of the bacterial and cellular mechanisms involved in this synergy have not been sufficiently elucidated. The aim of this thesis was to develop and validate an in vitro model mimicking s. aureus colonization of the nasal vestibule by using hacat human keratinocytes. This model allowed to study (i) the adhesion and internalization capacities of various clinical s. aureus strains, (ii) the intracellular efficiency of the antimicrobial molecules used for s. aureus nasal decolonization, (iii) the effect of clarithromycin on rhinovirus infection, and (iv) the impact of rhinovirus infection and non-specific inflammation on s. aureus colonization. This work has mainly identified a new alternative mechanism for the internalization of s. aureus through the binding between the bacterial protein eap (extracellular adherence protein) and the cell receptor icam-1 (intracellular adhesion molecule 1). This alternative pathway is favored in case of rhinovirus infection or inflammation; which could explain the clinical observations of the increase of the load of s. aureus or the risk of infection by this bacterium during respiratory viral infections or post-traumatic inflammations. The results of this thesis illustrate the complexity of the interactions between the mucosal epithelial cells, s. aureus and viral pathogens and suggest that other studies are needed to propose appropriate preventive or therapeutic strategies.

La squalénisation est la base d’une nouvelle et très prometteuse nanotechnologie. Le concept repose sur l’observation que la conjugaison d’un analogue nucléosidique ayant une activité thérapeutique à une molécule de squalène conduit à la formation spontanée dans l’eau de nanoparticules, de diamètre compris entre 100 et 300 nm, montrant une activité très supérieure à celle de l’analogue nucléosidique seul. Au cours de cette thèse nous avons cherché à comprendre les relations entre la nature de la paire drogue-terpénoide, la structure des nanoparticules et leur activité biologique. Pour cela, d’une part différents nucléosides et analogues nucléosidiques ont été couplés de façon covalente au squalène et d’autre part la gemcitabine a été couplée à des dérivés terpénoides de longueurs croissantes. L’organisation supramoléculaire de ces composés a été déterminée par diffusion des rayons X aux petits angles et cryo-microscopie électronique. L’influence des conditions de nanoprécipitation sur la structure des nanoparticules a été étudiée. L’impact de l’organisation supramoléculaire des nanoparticules sur leur internalisation cellulaire et leur cytotoxicité a été mis en évidence pour certaines lignées. / Squalenoylation is a new and very promising nanotechnology. The concept consists in coupling nucleoside derivatives that have therapeutic activity to a molecule of squalene: whatever the nucleoside, nanoparticles with a diameter around 100 - 300 nm are spontaneously obtained upon nanoprecipitation of the nucleolipid in an aqueous medium. These nanoparticles display an increased biological activity compared with the nucleoside. The aim of this PhD thesis was to understand the link between the nature of the drug-terpenoid pair, the supramolecular structure of nanoparticles and the biological activity.Therefore, in a first part, several nucleosides and nucleoside derivatives were covalently coupled to squalene, and in a second part gemcitabine was coupled to terpenoid chains with increasing length. The supramolecular organization of the nanoparticles was determined by Small Angle X-rays Scattering and cryogenic transmission electronic microscopy. The influence of the condition of nanoprecipitation on the supramolecular structure of nanoparticles was studied. The impact of the supramolecular organization on the cell internalization and cytotoxicity was highlighted for some cell lines.

Níveis elevados de hormônios tireoidianos (HTs) são comumente associados à ativação do sistema renina angiotensina local e ao desenvolvimento da hipertrofia cardíaca. O envolvimento do receptor de angiotensina II tipo 1 (AT1R) nos efeitos hipertróficos dos HTs fora descrito previamente. No entanto, os mecanismos subjacentes a essa interação ainda são desconhecidos. O AT1R pertence à família dos receptores acoplados à proteína G e, portanto, promove a transdução de sinal por mecanismos dependentes e independentes de proteína G. Recentemente, a sinalização dependente de beta-arrestinas (independente de proteína G) tem sido descrita por contribuir com a resposta hipertrófica em diferentes modelos experimentais. Assim, no presente estudo investigou-se o envolvimento da sinalização dependente de beta-arrestinas nos efeitos hipertróficos dos HTs, mediados pelo AT1R, bem como a participação de ERK½ nesse processo. Culturas primárias de cardiomiócitos foram estimuladas com T3 (triiodotironina; 15nM) para indução da hipertrofia. O tratamento dos cardiomiócitos com T3 por tempos rápidos (5-30 min) resultou na ativação transiente de ERK½, a qual foi parcialmente atenuada quando da administração de Losartan (1µM), antagonista do AT1R. A contribuição de ERK½ na hipertrofia dos cardiomiócitos foi verificada através do uso de PD98059 (20µM), inibidor de MEK½, o qual preveniu a transcrição de marcadores hipertróficos. Ensaios de imunoprecipitação revelaram o aumento da interação entre AT1R e beta-arrestina 2 sob estímulo do T3, sugerindo o recrutamento de beta-arrestina 2 e, possível, internalização do AT1R. Através de ensaios de imunofluorescência e fracionamento subcelular, foi demonstrado que o T3 estimula a translocação do AT1R, amentando sua expressão no núcleo dos cardiomiócitos. Além disso, tanto a ativação de ERK½ quanto a hipertrofia cardiomiocítica mostraram-se sensíveis à inibição da endocitose, a qual foi avaliada através de Concanavalina A (0,5µg/ml). Ensaios de silenciamento gênico por RNA de interferência foram eficientes em demonstrar o envolvimento de beta-arrestina 2 na ativação de ERK½ e na hipertrofia cardiomiocítica induzida por T3. Desta forma, os resultados evidenciam o envolvimento da sinalização dependente de beta-arrestina 2 na ativação de ERK½, através do AT1R, a qual contribui com a hipertrofia cardiomiocítica promovida pelo T3. / Elevated levels of thyroid hormones (THs) are commonly associated with activation of the local renin angiotensin system and the development of cardiac hypertrophy. The involvement of the angiotensin II receptor type 1 (AT1R) in the hypertrophic effects of the THs was previously described. However, the mechanisms underlying this interaction are still unknown. AT1R belongs to the G-protein coupled receptor family and promotes its signal transduction by G-protein dependent and independent mechanisms. Recently, beta-arrestin signaling (G-protein independent) has been described as contributing to the hypertrophic response in different experimental models. Thus, the present study investigated the involvement of beta-arrestin signaling in the hypertrophic effects of THs mediated by AT1R, as well as the participation of ERK½ in this process. Primary cardiomyocytes cultures were stimulated with T3 (triiodothyronine; 15nM) for the induction of hypertrophy. Cardiomyocytes acutely treated with T3 (5-30 min) resulted in transient activation of ERK½, which was partially attenuated upon Losartan (1µM) administration, an AT1R antagonist. The contribution of ERK½ to cardiomyocyte hypertrophy was verified by using PD98059 (20µM), a MEK½ inhibitor, which prevented the transcription of hypertrophic markers. Immunoprecipitation assays revealed increased interaction between AT1R and beta-arrestin 2 under T3 stimulation, suggesting the recruitment of beta-arrestin 2 and, possibly, the internalization of AT1R. Through immunofluorescence and subcellular fractionation assays, T3 has been shown to stimulate AT1R translocation, enhancing its expression in the cardiomyocyte nucleus. In addition, both ERK½ activation and cardiomyocyte hypertrophy were sensitive to the inhibition of endocytosis, which was assessed by Concanavalin A (0.5µg/ml). Interfering RNA assays were efficient in demonstrating the involvement of beta-arrestin 2 in ERK½ activation and in T3-induced cardiomyocyte hypertrophy. Therefore, the results evidenced the involvement of beta-arrestin-2-dependent signaling in the activation of ERK½, through the AT1R, which contributes to the cardiomyocyte hypertrophy promoted by T3.

Made available in DSpace on 2016-07-27T13:53:04Z (GMT). No. of bitstreams: 1 MARIZETH FERREIRA FARIAS.pdf: 3346122 bytes, checksum: e8bbaa85b80d9529551d0cc8daa4e59a (MD5) Previous issue date: 2013-09-12 / The purpose of this research is to study the object of the process of expansion and internalization of Higher Education in the State of Tocantins, more specifically the Arraias campus. It has as time frame the effective date of the Federal University of Tocantins-UFT, in 2003, to the present day, 2013. At the core of these policies is highlighted the effectiveness of one of its campuses, the campus of Arraias City, explaining their specificities, the nature, the character, the history and current perspectives of the process of expansion and restructuring of this campus. The objectives of this research is to understand, from the history of the creation of the Federal Public University in the city of Arraias, its consolidation as a public space and integrated federal system of higher education; to analyze if the UFT, campus Arraias, has provided to the professionals who are graduated in it a more expanded form of the reality in which they operate; as well as to identify which changes the performance of the university has brought to the city of Arraias and region, the contributions and punctual difficulties during 2003-2013. Accordingly, the results of the research show that there are important contributions of undergraduate courses in pedagogy and mathematics campus Stingrays, the opportunity for a graduate qualification and the lower classes and working in the region, through the dissemination of knowledge, training of teachers to act basic education in regional and encouraging research. The relevance of this study becomes evident by the concern focused on understanding the strategic importance of this campus to the political and social development in Southeastern Tocantins, with the driving shaft of the National Regional Development, the investment in education and public higher education, internalization and Reuni. To carry out this research, we adopted the methodology of the case study with qualitative approach, using multiple data collection procedures, such as documentary sources, a field notebook and semi-structured interviews and the analysis of several documents is here understood as the possibility of joint between the empirical and the theoretical. / A pesquisa tem por objeto o processo de expansão e interiorização do Ensino Superior no Estado do Tocantins, mais especificamente o campus da cidade de Arraias. Tem como recorte temporal a data da efetivação da Universidade Federal do Tocantins-UFT, em 2003, aos dias atuais, 2013. No bojo dessas políticas, ganha destaque a efetivação de um dos seus campi, o campus da cidade de Arraias, explicitando suas especificidades, a natureza, o caráter, a história e as perspectivas atuais do seu processo de expansão e reestruturação. Os objetivos da pesquisa são: compreender, a partir da história da criação do campus da universidade pública federal na cidade de Arraias, sua consolidação como espaço público e integrado ao sistema federal de ensino superior; analisar se a UFT, campus de Arraias tem proporcionado aos profissionais que nela se formam um conhecimento mais ampliado da realidade em que atuam; e identificar quais mudanças a atuação da universidade tem trazido para a cidade de Arraias e região, as contribuições efetivadas e as dificuldades pontuais no decorrer de 2003 a 2013. Nesse sentido, os resultados da pesquisa apontam que há contribuições importantes dos cursos de licenciaturas de pedagogia e matemática do campus de Arraias, oportunizando uma graduação e qualificação às classes mais desfavorecidas e trabalhadoras da região, através da disseminação de conhecimento, formação de professores para atuar na educação básica regional e incentivo à pesquisa. A relevância desse estudo se evidencia pela preocupação voltada para o entendimento da importância estratégica deste campus para o desenvolvimento político e social da região sudeste do Tocantins, tendo como veio condutor da Política Nacional de Desenvolvimento Regional-PNDR, o investimento na educação e no ensino superior, a interiorização das universidades públicas e o Reuni. Para a realização dessa pesquisa, adotamos a metodologia do estudo de caso de abordagem qualitativa, utilizando de múltiplos procedimentos de coleta de dados, tais como fontes documentais, caderno de campo e entrevistas semiestruturadas. A análise dos documentos diversos é aqui compreendida como possibilidade de articulação entre o trabalho empírico e o teórico.

Submitted by Silvana Teresinha Dornelles Studzinski (sstudzinski) on 2015-07-03T17:40:01Z No. of bitstreams: 1 AndreCarvalhoLindemam.pdf: 929527 bytes, checksum: 60b2d11de24543bd40bd55f690859780 (MD5) / Made available in DSpace on 2015-07-03T17:40:01Z (GMT). No. of bitstreams: 1 AndreCarvalhoLindemam.pdf: 929527 bytes, checksum: 60b2d11de24543bd40bd55f690859780 (MD5) Previous issue date: 2011 / Nenhuma / A partir da aplicação do conceito de empreendedorismo à organização surge a orientação empreendedora (OE), que se refere ao processo empreendedor no nível organizacional. A orientação empreendedora focaliza-se nos métodos, práticas e estilos de tomada de decisão usados para agir de forma empreendedora. Uma das formas de se perceber a OE de uma organização é através das suas dimensões: inovação, propensão ao risco e proatividade. Esta dissertação busca analisar a OE no contexto internacional. Neste sentido, destaca que as empresas interessadas em operar no mercado internacional precisam de criatividade, proatividade e cálculo de risco, para conseguir superar as dificuldades impostas pelo mercado. Em relação às operações no mercado internacional, a inserção das empresas brasileiras nesse mercado é considerada tardia em comparação às suas concorrentes de nações desenvolvidas. Realizar operações internacionais requer o desenvolvimento de estratégias deliberadas, que permitam o ingresso de produtos, tecnologias, gestão, recursos humanos, entre outros recursos de uma empresa, em país estrangeiro. Também envolve escolher a melhor estratégia, seja por exportação, contratual ou por investimentos, e requer da empresa ações pertinentes à superação de barreiras existentes à internacionalização, seja para entrada e/ou operações. Esta pesquisa, de natureza qualitativa, analisa, através de estudo de caso único, como o empreendedorismo no nível organizacional - aqui especificado como orientação empreendedora (OE) através de suas dimensões inovação, propensão ao risco e proatividade, bem como os seus elementos constitutivos - contribui no contexto de internacionalização de um grupo vinícola brasileiro, representado pelo Miolo Wine Group (MWG). Os dados foram coletados por meio de entrevistas em profundidade e análise documental. Os principais resultados encontrados destacam que a OE contribui no processo de internacionalização do MWG através: da entrada em mercados estratégicos, na redução da barreira da falta de associação entre Brasil e o vinho de qualidade, na diferenciação dos seus produtos em relação aos demais produtos brasileiros na competição internacional, tecnologia avançada, qualidade dos produtos, no aproveitamento do potencial de algumas regiões ainda não exploradas, sendo benchmarking internacional, aumentando o volume de vendas, na identificação de ameaças e planejamento global, na identificação de inovações e através do fortalecimento da marca. / By applying the concept of entrepreneurship to the organization comes to entrepreneurial orientation (EO), which refers to the entrepreneurial process, at the organizational level. The entrepreneurial orientation refers to the methods, practices and styles of decision making used to act in an entrepreneurial way. One way to realize the OE of an organization is through its dimensions: innovation, risk propensity and proactivity. Companies interested in operating in international markets, need creativity, proactivity and risk calculation, to help them to overcome the difficulties imposed by the market. Regarding operations in the international market, Brazilian companies are considered late for its inclusion in comparison to its competitors from developed nations. International operations requires determination of strategies that could allow the inflow of products, technologies, management, human resources and other resources of a company in a foreign country. It also involves choosing the best strategy, whether for export or investment contract and requires the company, appropriate actions to overcome barriers to internationalization, both for entry and / or operations. This research is qualitative in nature and examines, through a single case study, how entrepreneurship at the organizational level, here specified as entrepreneurial orientation (EO) through its dimensions, which are: innovation, risk propensity and proactivity, and their constituent elements, contribute in the context of internationalization of Brazilian wine group, represented by Inside Wine Group. Data were collected through in-depth interviews and documentary analysis. The main findings highlight the OE helps in the process of internationalization of the MWG through: strategic market entry, reducing the barrier of lack of association between Brazil and wine quality, to differentiate their products in relation to other Brazilian products in international competition, advanced technology, product quality, in harnessing the potential of some unexplored regions, and international benchmarking, increasing the volume of sales, in identifying threats and overall planning, identification of innovation and by strengthening the brand.

Made available in DSpace on 2016-04-25T19:20:41Z (GMT). No. of bitstreams: 1 Tese Maria Cecilia Domezi.pdf: 3205443 bytes, checksum: b2955c8bbf069403b05fedd8d135d450 (MD5) Previous issue date: 2006-06-21 / ADVENIAT / The force of devotion lived on the dividing line between traditional and popular catholicism and basic christian communities (CEBs), within the plurality of different forms of brazilian catholicism is the central point of this study. The empirical research limits itself to some networks of brazilian CEBs in the state of São Paulo. The starting point was a suspicion that allowing for the necessity to make credible certain existential situations, many of the members of the CEBs would preserve fragments of the old devotions in a parallelism with the theology of liberation. One questions the possibilities of this theology recovering and resignifying in its rational coherency, these fragments of belief and traditional rituals. In the CEBs persists a devotional "continuum" from early popular traditional catholicism. This "continuum" transmits itself from generation to generation, in a selective and recreative manner through rearrangements, translations, resignifications and constant reelaborations of images and concepts. The subjects preserve traditional religious values, the sacredness of images and a complex web of relations with the saints, crediting them with cultural recourses of the popular universe such as indetermination, ambiguity and ambivalence. The devotion to the Virgin Mary, resignified in the obligation with the praxis of the transformation of society, guards the mythical space of intimacy with the "Great Mother", clement, compassionate, and almost goddess, in equality with God the Father. The form of intelligibility of these subjects is more situated in "concrete thoughts" that are made up and remade through bricolage. The evidence that the devotional "continuum" preserves the central part of it's meaning, wherein the new attitudes encounter vital nourishment, turns the question in reverse: What is the force of the CEBs, looking from the central part of it's meaning, that preserve the mythical universe, the sacred cosmic order and the dynamic interventions of the saints? It is the very members of the CEBs, from within the brazilian popular culture, while being social and ecclesiastical subjects, assume the fragments of being "libertarians" of the theology of liberation, and the projects of a new sociaty defended by the social movements, and resignify them. Mythical space and historical reality are complemented, opening new perspectives when faced with contemporary problems in the encounter between tradition and modernity. / A força da devoção, vivida na fronteira entre o catolicismo tradicional popular e as CEBs, dentro da pluralidade de formas do catolicismo brasileiro, é o foco deste estudo. A pesquisa empírica delimita-se em algumas redes de CEBs brasileiras, situadas no Estado de São Paulo. O ponto de partida foi uma suspeita de que, pela necessidade de tornar plausíveis certas situações existenciais, muitos membros de CEBs preservariam fragmentos da antiga devoção, num paralelismo com a teologia da libertação. Indagava-se, de início, das possibilidades desta teologia resgatar e ressignificar, dentro da sua coerência racional, esses fragmentos de crenças e rituais tradicionais. Nas CEBs persiste um "continuum" devocional, desde o catolicismo tradicional popular. Esse "continuum" transmite-se de geração a geração, de maneira seletiva e recriativa; passa por rearranjos, traduções, ressignificações e constante reelaboração de imagens e conceitos. Os sujeitos preservam valores religiosos tradicionais, a sacralidade das imagens e a teia complexa de relações com as santas e os santos, valendo-se de recursos culturais do universo popular, como indeterminação, ambigüidade e ambivalência. A devoção a Nossa Senhora, ressignificada no compromisso com a práxis de transformação da sociedade, guarda o espaço mítico de intimidade com a "Grande Mãe", misericordiosa, compassiva e quase-deusa, a par com Deus Pai. A forma de inteligibilidade destes sujeitos está mais situada no "pensamento concreto", que se compõe e recompõe através da bricolagem. A constatação de que o "continuum" devocional preserva o seu núcleo de sentido, no qual as novas atitudes encontram um alimento vital, fez a pergunta inverter-se: Qual é a força das CEBs, a partir desse núcleo de sentido que preserva o universo mítico, a ordem cósmica sagrada e as intervenções dinamizadoras dos santos? São os próprios membros de CEBs que, no interior da cultura popular brasileira, enquanto sujeitos sociais e sujeitos eclesiais, apropriam-se de fragmentos "libertários", da teologia da libertação e dos projetos de nova sociedade defendidos pelos movimentos sociais, e os ressignificam. Espaço mítico e realidade histórica complementam-se, abrindo novas perspectivas frente às problemáticas contemporâneas, no encontro entre tradição e modernidade.

A partir da década de 1970, os impactos da sociedade de consumo industrial sobre o meio ambiente tornaram-se amplamente reconhecidos e debatidos em diversos setores da sociedade, inserindo-se nas agendas de lideranças mundiais. Central para o debate sobre meio ambiente e crescimento econômico tem sido o papel das empresas que, tendo sido historicamente parte do problema, passaram a incluir o meio ambiente em suas atividades e na gestão de seus negócios. Grandes acidentes envolvendo usinas nucleares e contaminações e outros de menor porte aumentaram a percepção pública quanto aos riscos decorrentes de um processo de produção predatório que ignora os limites da natureza. O objetivo do trabalho é discutir as estratégias de internalização da gestão ambiental à estrutura da empresa Suzano de Papel e Celulose nos últimos 30 anos, com enfoque na gestão hídrica da empresa. Para tanto, adotou-se uma metodologia baseada em análise documental e em um estudo de caso na empresa Suzano de Papel e Celulose. A revisão bibliográfica foi realizada em materiais obtidos na CETESB, na sede da Empresa Suzano e na Associação Brasileira de Papel e Celulose (ABTCPBRACELPA), além de teses e dissertações. Os dados para análise foram levantados em revistas setoriais com foco em gestão ambiental e em papel e celulose e nos relatórios de Sustentabilidade da empresa Suzano dos últimos 10 anos. Nesta etapa buscou-se avançar na compreensão das alternativas tecnológicas do setor de papel e celulose com foco na gestão da água, conhecer os participantes no mercado de papel e celulose e suas iniciativas voltadas ao tema da sustentabilidade. Foram ainda realizadas visitas à fábrica e à sede da empresa Suzano, com realização de entrevistas com a gerência de meio ambiente e qualidade. Os resultados alcançados revelam que três fatores têm sido determinantes para as mudanças na gestão hídrica na empresa, a saber: a legislação, que estabelece padrões de emissão de efluentes hídricos em corpos dágua; a pressão da opinião pública, notadamente a partir de meados da década de 1980 com relação à presença de compostos organoclorados (dioxinas) em efluentes de papel e celulose; e as exigências dos mercados importadores, como, por exemplo, quanto à certificação ambiental dos processos produtivos. Os resultados dessa pesquisa indicam que a empresa Suzano de Papel e Celulose nos últimos 30 anos passou de uma estratégia passiva com relação ao meio ambiente para uma estratégia proativa incorporando as exigências ambientais da legislação e de seus mercados no exterior. Conclui-se, portanto, que o meio ambiente tornou-se elemento-chave de competitividade e permanência no mercado para a empresa Suzano de Papel e Celulose. / Since the 1970s, the impacts of the industrial production on the environment have become highly recognized and debated by ample sectors of society and taken over the agendas of leaders all over the world. Central to the debate between environmental protection and economic growth has been the role played by the business sector in the search for solutions to the environmental crisis by internalizing environmental demands. The aim of this paper is to discuss the strategies adopted by the Companhia Suzano de Papel e Celulose when interiorizing environmental concerns. Emphasis will be given to the industrial management of water resources in the last 30 years. To this effect, a case study method has been adopted. The bibliographic research was carried out through the use of materials, obtained at The State of São Paulo Environmental Agency), at ABTCP-BRACELPA (The Brazilian official Pulp and Paper Organization), and other studies on the pulp and paper sector. The data used in the analysis in environmental management magazines focused on the pulp and paper sector and the companys annual sustainability reports of the last 10 years. The aim was to acquire deeper understanding of the pulp and paper sector technological alternatives for cleaner production. In addition, interviews with the company´s Environment and Quality manager of the Suzano plant were also carried out. The results suggest that the company´s water management strategies have been determined by three key factors: the regulation, which sets the standards for effluent discharges; the pressure of public opinion, in the mid 1980s, particularly public demands for the elimination of the use of chlorine compounds (the dioxins); and the environmental demands of external markets such as those related to the environmental certification of production processes. The results reveal that, in the last 30 years, Companhia Suzano de Papel e Celulose has shifted from a passive strategy towards its environmental impacts to a proactive by interiorizing both the demands of the regulation and the demands of its overseas markets. In conclusion, the environment has become a key element both for the companys competitiveness and survival.

Les infections ostéo-articulaires (IOA) regroupent plusieurs entités cliniques hétérogènes ayant en commun l'invasion et la destruction progressive des tissus osseux et cartilagineux par un ou plusieurs micro-organismes. Le genre Staphylococcus, impliqué dans plus de 65% des IOA, représente la première étiologie dans ces infections particulièrement sévères et difficiles à traiter. Les Staphylococcus non-aureus (SNA) incluant des espèces tels que Staphylococcus epidermidis sont responsables de près de 40% de certaines formes cliniques notamment les IOA sur matériels. Contrairement à S. aureus, pour lequel les mécanismes physiopathologiques incluent : (i) la capacité d'internalisation dans les cellules de l'hôte et (ii) la formation de biofilm, peu de données sont disponibles concernant ceux impliqués dans les IOA dues aux SNA. Dans ce contexte, mon travail de doctorat s'est attaché à caractériser les mécanismes physiopathologiques impliqués dans la genèse des IOA causées par différentes espèces de SNA. A l'aide d'une approche in silico puis in vitro conduite dans un modèle d'invasion d'ostéoblastes humains, nos travaux ont mis en évidence une capacité d'internalisation et de persistance dans les cellules osseuses pour seulement deux espèces (S. pseudintermedius et S. delphini) sur les 17 testées. De façon similaire à S. aureus, le processus d'invasion cellulaire pour ces espèces fait intervenir une liaison tripartite entre les adhésines bactériennes liant la fibronectine (FnBPs), la fibronectine de la matrice extracellulaire et l'intégrine cellulaire α5β1. Un autre point essentiel de ce travail est la mise en évidence du phénotype hautement cytotoxique de l'espèce S. pseudintermedius après internalisation dans les cellules hôtes. Nous démontrons ici que cette cytotoxicité est, au moins en partie, médiée par une action combinée de (i) la leucocidine Luk-I (toxine homologue de la leucocidine Panton-Valentine de S. aureus) qui cible spécifiquement les cellules immunitaires exprimant le récepteur CXCR2 (récepteur 2 à l'interleukine 8) et (ii) les phénol-soluble modulins (PSMs) qui perturbent les membranes des cellules immunes et non immunes. Sachant que les SNA sont les agents infectieux les plus incriminés dans les IOA sur matériel, une technique d'étude du biofilm sur biomatériaux orthopédiques (acier inoxydable, titane et polyéthylène) a été mise au point pour étudier le biofilm mature formé par les six espèces SNA les plus prévalentes dans les IOA (S. epidermidis, S. lugdunensis, S. heamolyticus, S. warneri, S. caprae, S. capitis). A l'exception de S. epidermidis qui forme plus de biofilm sur le polyéthylène, constituant placé à l'interface des pièces métalliques et/ou des os dans les prothèses orthopédiques, aucune différence significative n'a été observée entre les trois biomatériaux orthopédiques pour l'ensemble des espèces de SNA testées. Néanmoins, nos observations indiquent une forte hétérogénéité au sein des SNA en matière de capacité à former un biofilm mature. Les espèces telles que S. capitis et S. lugdunensis se distinguent significativement de S. haemolyticus et S. warneri par leurs aptitude à former plus de biofilm. La grande diversité des phénotypes observés vis-à-vis des mécanismes physiopathologiques impliqués lors des IOA par les différentes espèces de SNA testées démontre qu'il ne faut pas considérer les SNA comme une entité clinique unique. L'amélioration des connaissances apportées au cours de ce travail devraient contribuer à l'optimisation de la prise en charge chirurgicale, médicale, et thérapeutique des patients / Bone and joint infections (BJI) include several heterogeneous clinical entities that share the invasion and the progressive destruction of bone and cartilage tissue by one or more microorganisms. The genus Staphylococcus, involved in over 65% of the BJI, represents the first etiology in these particularly severe and difficult-to-treat infections. Staphylococcus non-aureus (SNA), including species such as Staphylococcus epidermidis, are responsible for nearly 40% of some clinical forms, including device-associated BJI. In contrast to S. aureus, for which pathophysiological mechanisms include (i) internalization capacity in host cells and (ii) biofilm formation, few data are available regarding those involved in BJIs due to SNA. In this context, my PhD work focused on characterizing the pathophysiological mechanisms involved in the genesis of BJI caused by different SNA species. Using an in silico together with an in vitro approach conducted in a human osteoblast invasion model, our work revealed an ability to internalize and persist in bone cells for only two species of SNA out of the 17 tested. Indeed, we have been able to demonstrate that only S. pseudintermedius and S. delphini have the ability to invade the cytoplasmic compartment of the host cells. Similar to S. aureus, the cellular invasion process for these species involves a tripartite association between bacterial adhesins fibronectin-binding proteins (FnBPs), fibronectin of the extracellular matrix, and α5β1 cell integrin. Another key point of this work is the demonstration of the highly cytotoxic phenotype of the S. pseudintermedius species after internalization in the host cells. We demonstrate here that this cytotoxicity is, at least in part, mediated by a combined action of (i) the Leukocidin Luk-I (homologous to S. aureus Panton-Valentine Leukocidin) that specifically targets immune cells expressing the CXC chemokine receptor 2 (CXCR2) with (ii) phenol-soluble modulins (PSMs) that disrupt the membranes of immune and non-immune cells. Knowing that SNA are the most incriminated infectious agents in device-associated BJI, a technique for studying biofilm on orthopedic biomaterials (stainless steel, titanium and polyethylene) has been developed to study the mature biofilm formed by the six SNA species with the highest prevalence in BJI (S. epidermidis, S. lugdunensis, S. heamolyticus, S. warneri, S. caprae, S. capitis). With the exception of S. epidermidis, which forms more biofilm on polyethylene (constituting at the interface of metal parts and / or bone in orthopedic prostheses), no significant difference was observed between the three orthopedic biomaterials for all the SNA species tested. The great diversity of phenotypes observed with respect to the pathophysiological mechanisms involved in BJI by the different SNA species tested demonstrates that SNA should not be considered as a single clinical entity. Improved knowledge provided during this work should contribute to the optimization of the surgical management, medical and therapeutic patient

Humane Zytomegalieviren (HCMV) etablieren nach einer Primärinfektion eine lebenslange latente oder persistierende Infektion. Es wird allgemein angenommen, daß hieran die Manipulation der humanen Immunantwort durch das Virus beteiligt ist. Hierzu zählen die Hemmung von zytotoxischen CD8+ T-Zellen durch das Genprodukt US11 und die Beeinträchtigung der Leukozytenwanderung durch die Hemmung des Chemokinsystems durch den Chemokinrezeptor US28. Die Effizienz der US11-vermittelten Hemmung der T-Zell-Aktivierung wurde in einem rekombinanten Modell zur MHC-Klasse-I-vermittelten T-Zell-Aktivierung untersucht. Obwohl die Expression der MHC-Klasse-I-Moleküle durch US11 in dendritische Zellen (DCs) um bis zu 60% vermindert war, konnte keine Hemmung der T-Zell-Proliferation beobachtet werden. US28 ist der einzige funktionelle Rezeptor für die inflammatorischen Chemokine MCP-1, MCP-3, RANTES, MIP-1(, MIP-1( sowie Fraktalkine. Er kann sowohl Liganden-abhängig die Aktivierung von MAPK als auch die konstitutive Aktivierung von NF-(B vermitteln. In der vorliegenden Arbeit konnte mit Hilfe einer Rezeptormutante der Argininrest an Position 129 des DRY-Motivs als Voraussetzung für die Aktivierung der Signalwegen identifiziert werden. Ferner bewirkt die Expression des US28-Rezeptors die Entfernung inflammatorischer Chemokine aus der Umgebung infizierter Zellen. Molekulare Grundlage der Liganden-Depletion stellt die Endozytose des US28-Liganden-Komplexes dar. Es konnte gezeigt werden, daß der US28-Rezeptor eine Umlagerung von (-Arrestin-Molekülen in Vesikel vermittelt, jedoch unabhängig von Arrestin-Molekülen endozytiert wird. Die Endozytose des US28-Rezeptors war abhängig von der GTP-ase Dynamin. Ebenso konnte die Beteiligung des Lipid-Raft-Weges an der US28-Endozytose gezeigt werden. Die Hemmung des Clathrinweges bewirkte jedoch eine zweifach stärkere Verminderung der US28-Endozytose, kann der Clathrin-abhängige Weg als der Hauptweg der US28-Endozytose angesehen werden. / Primary infections of the human cytomegalovirus (HCMV) are followed by a lifelong infection in the state of latency or persistence. It is believed that the virus employs a number of immunomodulatory mechanisms to establish latent infections. Among these are the inhibition of cytotoxic CD8+ T-cells by US11 and the impairment of leukocyte migration by US28. The potency of US11 to mediate the inhibition of T-cell activation was analysed in a model of MHC class I mediated T-cell activation. Surface expression of MHC class I molecules was reduced by 60 % after expression of US11 in murine dendritic cells. In contrast, there was no reduction in the capacity of the dendritic cells to induce T-cell proliferation. The US28 gene product has been characterized as a functional receptor for the inflammatory chemokines RANTES, MCP-1, MCP-3, MIP-1?? MIP-1? and fractalkine.Upon ligand stimulation US28 mediates the activation of MAPK and additionally a constitutive activation of NF-?B. By generating site directed receptor mutant it was shown that the arginine at position 129 represents a structural requirement for both the ligand-induced and the constitutive signaling by US28. Moreover, it was suggested that the US28 dependent sequestration of chemokines from the environment of infected cells hinders leukocytes from the recruitment to sites of viral infection. A molecular mechanism for the ligand depletion is provided by the endocytosis of US28-ligand complexes. Studies revealed that US28 expression induced a redistribution of ?-arrestin molecules into vesicular structures but was dispensable for the endocytosis of the US28 receptor. However, US28 internalization was dependent on the small GTPase dynamin and by impaired receptor endocytosis after inhibition of the lipid raft pathway. Since inhibition of the clathrin dependent pathway resulted in a two-fold stronger reduction of US28 endocytosis, the clathrin-dependent pathway can be considered as the major route of US28 endocytosis.

The aim of this thesis is to illuminate which role theories of music education can have in the dialectic between discourse and competence in the practice of music pedagogy. The thesis stems from a problem-oriented project that resulted in the formulation of the following research question: how can the connection between music education theory and the power of definition be described and problematized from a cultural-historical perspective using Vygotsky's thesis of Semiotic Thinking? In his research on the dual function of language Vygotsky makes a distinction between the usage of concepts and conceptualization. In this study this distinction has been crucial to determining the relationship between music education theory and the power of definition as practised in music pedagogy. The research project comprised a background study and three sub-studies. The focus of the background-study was the conditions for musical learning and development in persons with severe cognitive dysfunctions. The first sub-study dealt with how social workers in this area of special education conceptualise their view of music in relation to their understanding of music activities in their own practice. The second sub-study aimed to explore which concepts music-therapists use in their meta-reflections on musical situations in this area of special education. The purpose of the third sub-study was to formulate a theoretical perspective on the relationship between music education theory and the power of definition using Vygotsky's hypothesis of semiotic thinking. The main conclusions are: first, that music education theory can be understood as a structural coupling between the power of definition that is embedded in music-pedagogical discourse as a whole, and the power of definition possessed by music pedagogues; second, that the development of the power of definition in the practice of music pedagogy is a creative process that in turn entails a critical questioning of music education theory.