Au cours de ce projet de thèse, j’ai étudié le lien fonctionnel entre la morphogénèse épithéliale et la signalisation Delta-Notch, dans le cadre de la formation du tube neural chez le poisson-zèbre. La signalisation Delta-Notch est primordiale pour le développement embryonnaire et le maintien de l’homéostasie des tissus adultes. De façon inattendue, j’ai observé suite à la perte-de-fonction de Mib une perte de la polarité apico-basale dans le neuro-épithélium de la moelle épinière embryonnaire. L’analyse plus poussée de ce phénotype m’a ensuite permis de montrer que l’activité de l’intégralité de la signalisation Notch est requise pour l’établissement de la polarité apico-basale dans le tube neural de poisson-zèbre. En effet, l’inhibition des ligands de Notch et des activateurs transcriptionnels situés en aval, Rbpja et Rbpjb, résulte en l’interruption de la polarité apico-basale. De plus, l’activation ectopique de Notch entraîne un sauvetage complet de la polarité apico-basale dans les embryons déplétés pour Mib. Finalement, le mutant Mib échoue à activer la transcription de protéines de polarité apicale Crumbs1 et Crumbs2a au cours de la formation du tube neural, ce qui suggèrerait que la signalisation Notch agit en amont des complexes de polarité. De façon surprenante, nous avons également montré que le composant de la signalisation Notch, Mib, affecte les mouvements de convergence-extension et la division cellulaire orientée, appelée C-divisions, durant la neurulation et la gastrulation à travers la signalisation PCP. Cet effet de Mib sur la PCP est indépendant de son rôle sur la signalisation Notch. Généralement, cette étude révèle un double-rôle de Mib. / In this Ph.D. project, I study the functional link between epithelial polarity and Delta-Notch signaling in the context of zebrafish neural tube morphogenesis. Notch signaling, one of the major signaling pathways and of prime importance in neurogenesis, has been widely studied for its function in cell fate specifications. Surprisingly, I found that the Notch signaling component Mindbomb (Mib) loss-of-function led to a loss of apico-basal polarity in the neuroepithelium of the embryonic spinal cord. I further explored that the activity of the entire Notch signaling pathway is actually required for the earliest steps of establishment of apico-basal polarity in the zebrafish neural tube. Indeed, inhibition of Notch ligands and downstream transcriptional activators Rbpja and Rbpjb resulted in a disruption of apico-basal polarity. Moreover, ectopic activation of Notch ensued to a complete rescue of apico-basal polarity in Mib loss of function embryos. Furthermore, Mib mutant embryos fail to upregulate the transcription of the apical polarity proteins Crumbs1 and Crumbs2a in the course of neural tube formation, suggesting that Notch signalling might act upstream of polarity complexes. Moreover, I found that Mib affects convergent-extension movements and oriented cell divisions during neurulation and gastrulation through an effect on planar cell polarity. Remarkably, this effect of Mib on PCP is independent of its role in Notch signaling. These results indicate a novel role of Mib in the regulation of PCP signaling. Altogether, this study revealed a dual role of Mib in the epithelial morphogenesis of the zebrafish neural tube.

Le modèle des automates cellulaires constitue un des modèles le mieux établi de physique discrète sur espace euclidien. Ils implantent trois symétries fondamentales de la physique: la causalité, l'homogénéité et la densité finie de l'information. Bien que l'origine des automates cellulaires provienne de la physique, leur utilisation est très répandue comme modèles de calcul distribué dans l'espace (machines auto-réplicantes, problèmes de synchronisation,...), ou bien comme modèles de systèmes multi-agents (congestion du trafic routier, études démographiques,...). Bien qu'ils soient parmi les modèles de calcul distribué les plus étudiés, la rigidité de leur structure interdit toute extension triviale vers un modèle de topologie variant dans le temps, qui se trouve être un prérequis fondamental à la modélisation de certains phénomènes biologiques, sociaux ou physiques, comme par exemple la discrétisation de la relativité générale. Les dynamiques causales de graphes généralisent les automates cellulaires aux graphes arbitraires de degré borné et pouvant varier dans le temps. Dans cette thèse, nous nous attacherons à généraliser certains des résultats fondamentaux de la théorie des automates cellulaires. En munissant nos graphes d'une métrique compacte, nous présenterons deux approches différentes du modèle. Une première approche axiomatique basée sur les notions de continuité et d'invariance par translation, et une deuxième approche constructive, où une règle locale est appliquée en parallèle et de manière synchrone sur l'ensemble des sommets du graphe. / Cellular Automata constitute one of the most established model of discrete physical transformations that accounts for euclidean space. They implement three fundamental symmetries of physics: causality, homogeneity and finite density of information. Even though their origins lies in physics, they are widely used to model spatially distributed computation (self-replicating machines, synchronization problems,...), as well as a great variety of multi-agents phenomena (traffic jams, demographics,...). While being one of the most studied model of distributed computation, their rigidity forbids any trivial extension toward time-varying topology, which is a fundamental requirement when it comes to modelling phenomena in biology, sociology or physics: for instance when looking for a discrete formulation of general relativity. Causal graph dynamics generalize cellular automata to arbitrary, bounded degree, time-varying graphs. In this work, we generalize the fundamental structure results of cellular automata for this type of transformations. We endow our graphs with a compact metric space structure, and follow two approaches. An axiomatic approach based on the notions of continuity and shift-invariance, and a constructive approach, where a local rule is applied synchronously on every vertex of the graph. Compactness allows us to show the equivalence of these two definitions, extending the famous result of Curtis-Hedlund-Lyndon’s theorem. Another physics-inspired symmetry is then added to the model, namely reversibility.

The increasing complexity of digital circuits forces the use of new technologies. New technologies have the advantage of reducing the circuit size and power consumption coupled with operation speed increasement. Most of signal processing operations migrated to the digital domain, thus, basic blocks like AD converters are needed in mixed-signal systems. Analog-todigital converters based on Sigma-Delta (ΣΔ) modulators stand out among the existing architectures because they cover a wide range of applications. The most common implementation of ΣΔ modulators in CMOS technology is based in switched-capacitor technique (SC), mainly due to its high performance and excellent linearity. However, the continuous reduction in the transistor physical dimensions requires a proportional reduction in the supply voltage levels, making difficult the design of analog circuits with conventional topologies. To overcome this problem, design techniques to analog circuits compatible with these new technologies were developed. This is the case of the technique known as switched-current (SI), which uses samples in the current domain to represent the signal information. This work presents the design of a switched-current Sigma-Delta modulator (SI-ΣΔM) using an architecture oriented to low-distortion applications. The architecture s main characteristic is the reduced sensitivity to integrator nonlinearities, leading to a significant increase in the signal-to-noise ratio (SNR) and dynamic range (DR) values, moreover, it permits the design of high-order modulators intrinsically stable. To demonstrate and verify the performance of the used strategy, based on a combination of circuit techniques and topology, a cascade 2-2 SI-ΣΔM was designed in a CMOS XFAB XC06 technology. Postlayout simulations show that the SNR reaches a maximum value of 80 dB and a dynamic range of approximately 87 dB, implying an effective resolution of 14.15 bits considering 20 kHz bandwidth. The prototype was sent to manufacturing and will be subject to laboratory tests when it returns. / A crescente complexidade dos circuitos digitais força o uso de novas tecnologias de fabricação. A mudança para tecnologias mais avançadas tem como vantagem a redução do tamanho do circuito e a diminuição do consumo de energia aliados ao aumento da velocidade de operação. Grande parte das operações envolvendo processamento de sinais migraram para o domínio digital, portanto, blocos básicos como conversores AD são necessários em sistemas de sinal misto. Conversores AD com base em moduladores do tipo Sigma-Delta (ΣΔ) destacam-se entre as arquiteturas existentes por cobrir uma ampla gama de aplicações. A implementação mais usual de moduladores ΣΔ em tecnologia CMOS baseia-se na técnica de capacitor-chaveado (SC), devido, principalmente, à sua elevada performance e excelente linearidade. Entretanto, a contínua redução das dimensões físicas dos transistores tem exigido uma redução proporcional dos níveis de tensão de alimentação, dificultando o projeto de circuitos analógicos com topologias convencionais. Para contornar este problema, técnicas de projeto de circuitos analógicos compatíveis com essas novas tecnologias foram desenvolvidas. Este é o caso da técnica conhecida como corrente chaveada (SI), que utiliza amostras sob a forma de corrente para a representação de sinais. Neste trabalho é apresentado o projeto de um modulador ΣΔ em modo corrente (SI-ΣΔM) empregando uma arquitetura orientada à aplicações de baixa distorção. Esta arquitetura tem como principal característica a reduzida sensibilidade às não-linearidades do integrador, conduzindo a uma significante melhora no valor da relação sinal-ruído (SNR) e faixa de excursão dinâmica (DR), além de permitir a concepção de moduladores ΣΔ de elevada ordem intrinsecamente estáveis. Para demonstrar e comprovar a performance da estratégia empregada, baseada na combinação de técnicas de circuito e de topologia, projetou-se um modulador SI-ΣΔ cascata 2-2 na tecnologia XFAB CMOS XC06. Simulações elétricas pós-layout revelam que o SNR atinge um valor máximo de 80 dB e uma faixa dinâmica de aproximadamente 87 dB, inferindo uma resolução efetiva de 14,15 bits considerando uma banda de interesse de 20 kHz. Por fim, o protótipo desenvolvido foi enviado para fabricação e será alvo de testes em laboratório quando retornar.

Submitted by Fabio Sobreira Campos da Costa (fabio.sobreira@ufpe.br) on 2016-07-26T13:51:20Z No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) JORGE MARTINS FILHO.pdf: 3510444 bytes, checksum: 5186219c8dea84ee4dce1542def0855b (MD5) / Made available in DSpace on 2016-07-26T13:51:20Z (GMT). No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) JORGE MARTINS FILHO.pdf: 3510444 bytes, checksum: 5186219c8dea84ee4dce1542def0855b (MD5) Previous issue date: 2014-12-18 / CAPEs / O turismo tem-se revelado como atividade capaz de efetuar a inserção e a reabilitação econômica de espaços deprimidos. O resultado desse processo envolve profundas transformações no espaço e na sociedade, criando territórios para atender aos interesses do mercado turístico e objetos estranhos ao lugar. De forma planejada e por meio de estratégias voltadas para o crescimento econômico, o espaço é transformado em palco de ações que reforçam seu caráter imaginário, onde tudo está relacionado à condição de mercadoria, seja por meio da criação de projetos hoteleiros e empreendimentos imobiliários destinados à segunda residência, ou pela formação de mão de obra especializada, ou até mesmo, por conta do surgimento de empreendimentos comerciais. Essas ações são novas formas de produção capazes de introduzir ideias e valores, além de uma grande quantidade de objetos estranhos à paisagem, todos integrados na relação lugar - mundo, ainda que de forma segregadora e seletiva. Neste sentido, o propósito desta tese é compreender as transformações do espaço do litoral piauiense em função da introdução e desenvolvimento dos serviços ligados ao turismo. A metodologia consta de análise documental e pesquisa bibliográfica; observação; entrevista semiestruturada/aberta e questionários fechados, aplicados a gestores e trabalhadores, respectivamente, dos estabelecimentos de hospedagem e alimentação e questionários fechados aplicados a moradores dos municípios do Polo Costa do Delta. A aceleração das transformações de caráter territorial decorrentes do turismo em certos pontos do litoral do Nordeste brasileiro tem produzido novas formas de organização do espaço geográfico, com amplas repercussões socioeconômicas, políticas e culturais, que devem ser objeto da preocupação dos agentes responsáveis pelo planejamento e gestão do turismo. Esta tese é, pois, oriunda de uma reflexão sobre caminhos seguidos pelos órgãos público e privado, enquanto agentes do turismo, responsáveis pelo desenvolvimento de projetos nos municípios do litoral piauiense e que devem agir a partir de ações que dinamizem (e privilegiem) os interesses dos moradores locais, oportunizando sua inserção no mercado de trabalho mediante a qualificação da mão de obra local, bem como direcionando projetos para romper os fatores que limitam a inserção do litoral piauiense no mercado do turismo nacional e no internacional, com a dinamização dos fluxos, criação de novas conectividades e melhoria da infraestrutura. Este trabalho recomenda algumas proposições, como valorização do desenvolvimento pela justiça social para a conquista de melhores condições de vida e atendimento das necessidades da população local e a valorização do turismo de eventos para suprir os efeitos da sazonalidade do turismo de lazer. Assim, esta tese constitui documento geográfico que se esforça em apresentar a empirização de conceitos atinentes ao turismo, na modalidade Sol e Praia, que se realiza no litoral do Piauí. / Tourism has been set up as an activity able to perform the insertion and economic rehabilitation of depressed areas. The result of this process involves profound changes in environment and society, creating territories to meet the interests of the tourist market and unusual objects of the place. In a planned way and through strategies for economic growth, the space is transformed into a place of actions that strengthen its imaginative character, where everything is related to the condition of merchandise, either through the creation of hotel projects and real estate developments designed for second residences, or by the formation of skilled labor, or even because of the emergence of business ventures. They are new forms of production able to introduce ideas and values, besides a lot of unusual objects of the landscape, all integrated in the interaction experience, even though in a segregated and selective way. In this sense, the purpose of this thesis is to understand the transformations of the environment of the Piauí coast due to the introduction and development of services related to tourism. The methodology consists of document analysis and bibliographic research; observation; semi-structured/ open interview and multiple-choice questionnaires applied to managers and workers, respectively, of the lodging and food establishments and multiple-choice questionnaires applied to inhabitants of the towns of Polo Costa do Delta. The acceleration of the territorial transformations as a result of tourism in certain costal parts of the Brazilian Northeast has produced new forms of organization of the geographical environment, with broad socio-economic, political and cultural repercussions that should be the object of concern of the agents responsible for the planning and management of tourism. This thesis is, therefore, derived from a reflection about initiatives of public and private agencies, as tourism agents, responsible for developing projects in towns of the Piauí coast, and who should act based on actions that stimulate (and prioritize) the interests of local inhabitants, providing opportunities for their integration into the labor market through the qualification of local labor, as well as directing projects to break factors that limit the insertion of the Piauí coast into the national and international tourist market, with the stimulation of the tourist flow, creation of new connectivity and improvement of infrastructure. This study recommends a number of propositions, such as enhancement of development through social justice for the achievement of better living conditions and addressing the needs of the local population and the use of events to supply the effects of seasonality of leisure tourism. Thus, this thesis is considered as a geographical document that strives to present the empiricization of concepts concerning tourism, in the Sun and Sand modality, which takes place on the coast of Piauí.

Verificou-se a ocorrência dos teores totais e disponíveis de mercúrio nos sedimentos de fundo e em suspensão, e de mercúrio total em amostras de lambari (Astianax altiparanae) capturadas no ribeirão Guamium, bacia do rio Piracicaba, S.P. As concentrações foram correlacionadas aos diferentes usos dos solos limítrofes à bacia; pequena ocupação urbana com uso agrícola no distrito de Tanquinho (à montante), agrícola (médio-Guamium) e industrial (à jusante). Para tanto, foram conduzidas amostragens representativas do sedimento e da ictiofauna da bacia de drenagem nos períodos de seca e de chuva; (sedimento de fundo julho de 2008 e março de 2009) (sedimento em suspensão mar/2009); (peixes setem/2005 e fever/2006). As amostras de sedimentos de malha inferior a 0,063 mm foram solubilizadas em água-régia (3HCl + 1HNO3), as amostras de peixe foram liofilizadas e digeridas em solução nitro-sulfo-perclórica, em sistemas abertos de decomposição. A determinação de Hg nos extratos foi conduzida por espectrometria de fluorescência atômica (AFS), estando o intervalo de concentração de Hg total nos sedimentos de fundo, para o período de seca, entre 0,040 a 0,105 mg kg-1 Hg e disponível entre 0,018 e 0,064 mg kg-1. Neste mesmo substrato, para o período de chuvas, esse teor apresentou concentrações entre 0,54 a 0,13 mg kg-1 Hg e disponível de 0,010 a 0,052 mg kg-1. Em relação aos sedimentos em suspensão (época chuvosa), os teores de Hg estiveram entre 0,040 a 0,120 mg kg-1 e o disponível em 0,028 a 0,081 mg kg-1. Para a ictiofauna, cujo comprimento variou de 44 a 135 mm, o teor de Hg esteve entre 0,18 e 1,90 mg kg-1 Hg. Os valores de Hg encontrados nos substratos peixe e sedimentos (total e biodisponível) foram correlacionados com parâmetros físico-químicos do meio como, temperatura, pH, condutividade e oxigênio dissolvido da água. Para o sedimento, através dos valores de Eh e pH, construiu-se diagrama de estabilidade para o elemento mercúrio. Complementa-se a abordagem biogeoquímica do estudo, avaliando-se a influência do uso do solo no meio hídrico, através da determinação de \'delta\'13C nos sedimentos amostrados ao longo da bacia hidrográfica / There was the occurrence of total and available mercury in bottom sediments, suspended and total mercury in samples Astyanax altiparanae seizure in the river Guamium, Piracicaba river basin, SP. Concentrations were correlated to different uses land adjacent to the basin, a small urban and agricultural use, the district of Tanquinho (upstream) of the city of Piracicaba, agriculture (medium Guamium) and industrial (downstream). Representative sampling, of the sediment and the fish fauna of the drainage basin were conducted during periods of drought and rain, (bottom sediment in july 2008 and march 2009) (suspended sediment mar/2009) (fish septem/2005 and feb/2006). Samples of sediment less than 0.063 mm mesh were dissolved in 3HCl with 1HNO3, the fish samples were freeze dry and digested in solution, sulfo-nitro-perchloric, in open systems. The determination of Hg in the extracts was conducted by atomic fluorescence spectrometry (AFS), while the concentration range of total Hg in bottom sediments for the period of drought between 0.040 to 0.105 mg kg-1 Hg and available between 0,018 and 0.064 mg kg-1. In the same substrate, for the rainy season, this level showed concentrations between 0.54 to 0.13 mg kg-1 Hg and available from 0.010 to 0.052 mg kg-1. Regarding the suspended sediments (rainy season), the concentrations of Hg were between 0.040 to 0.120 mg kg-1 and available in 0.028 to 0.081 mg kg-1. For the fishes, whose length ranged 44-135 mm Hg content was between 0.18 and 1.90 mg kg-1 Hg. Values of Hg found in fish and sediment substrates (total and bioavailable), were correlated with physicochemical parameters of the medium as, temperature, pH, conductivity and dissolved oxygen from the water. For the sediment through the values of Eh and pH, was constructed diagram of stability for the element mercury. Evaluating the influence of land use on the aquatic environment, through the determination of \'delta\'13C in sediments sampled along the river basin

The activity of Delta-Aminolevulinate Dehydratase (d-ALA-D) was analyzed in patients suffering from diabetes mellitus and primary hypothyroidism. Five groups of patients were studied: compensated diabetes mellitus, non-compensated diabetes mellitus, compensated hypothyroidism, non-compensated hypothyroidism and control group. The analysis of d-ALA-D in these groups showed the following results: the activity of d-ALA-D on non-compensated diabetes mellitus decreased comparing to the control group, to the compensated diabetes mellitus group. The activity of d-ALA-D on non-compensated hypothyroidism increased compared to the control group and also to non-compensated hypothyroidism. In vitro analyses of the drugs used by the patients suffering diabetes mellitus (metformin, chlorpropamide, glibenclamide, glimepiride) and the drug used by the patients suffering primary hypothyroidism (thyroxine) were fulfilled to verify some change in the activity of d-ALA-D, and the findings showed that there was not any changes on d-ALA-D activity. Metals may interfere in the action of d-ALA-D. Consequently,the quantity of metals (lead, zinc, copper) present in the patients blood was measured. One observed that the amount of those metals was not different, from a statistical, among the groups. Therefore, we can conclude that the activity of d-ALA-D increased in the group of non-compensated hipothyroidism and decreased in the non-compensated diabetes, and may be it could be related to the complications observed in such pathologies / A atividade da delta-aminolevulinato desidratase (d-ALA-D) foi analisada em pacientes com diabetes mellitus e pacientes com hipotireoidismo primário. Foram estudados cinco grupos de pacientes: diabetes mellitus compensado, diabetes mellitus descompensado, hipotireoidismo compensado, hipotireoidismo descompensado e grupo controle. A análise da d-ALA-D nesses grupos mostrou os seguintes resultados: a atividade da d-ALA-D nos pacientes com diabetes mellitus descompensados encontrava-se diminuída em relação ao grupo controle, ao grupo dos diabéticos compensados. Observamos que nos pacientes com hipotireoidismo descompensado, a atividade da d-ALA-D encontrava-se aumentada em relação ao controle e também em relação ao grupo dos hipotireoideos compensados. Foram realizadas análises in vitro das medicações utilizadas pelos pacientes diabéticos (metformina, glibenclamida, clorpropamida, glimepirida) e hipotireoideos (tiroxina), com o objetivo de verificar se havia alteração na atividade da d-ALA-D e como resultados obtivemos que as medicações não alteraram a atividade da referida enzima. Os metais podem interferir na atividade da d-ALA-D. Por isso foi medida a quantidade de metais (chumbo, zinco, cobre) presentes no sangue destes pacientes. Observamos que a quantidade dos referidos metais não foi diferente, do ponto de vista estatístico, entre os grupos. Desta forma, concluímos que a atividade da d-ALA-D estava aumentada no grupo de pacientes hipotireoideos descompensados e diminuída no dos diabéticos descompensados, podendo este fato ter relação com o desenvolvimento das complicações nestas doenças

Ce travail doctoral traite de l’influence du contrat de rémunération du dirigeant, et plus particulièrement des caractéristiques incitatives de la rémunération en titres, sur les décisions prises par l’entreprise. Nous nous proposons en particulier d’apprécier l’effet de l’articulation des incitations financières à la prise de risque et à la performance boursière sur le niveau de risque de l’entreprise. Le travail, essentiellement empirique, s’appuie sur un échantillon d’entreprises américaines issu des bases de données Compustat et Execucomp sur la période 1992-2005. Quatre dimensions du risque de l’entreprise sont successivement abordées. Un premier chapitre se propose de définir de manière exploratoire un lien possible entre les caractéristiques incitatives de la rémunération du dirigeant et le niveau de contrainte de financement auquel l’entreprise fait face. Un deuxième chapitre se propose d’analyser empiriquement l’influence des caractéristiques incitatives de la rémunération du dirigeant sur le risque d’investissement notamment appréhendé par la R&D. Dans un troisième chapitre, nous nous intéressons aux déterminants du niveau d’endettement recherché par l’entreprise. Nous utilisons, pour ce faire, un modèle d’ajustement dynamique. Enfin dans un quatrième et dernier chapitre, nous analysons les déterminants du risque de défaut de l’entreprise mesuré par l’indicateur de distance au défaut. Le résultat essentiel de ce travail doctoral est que les caractéristiques incitatives à la prise de risque ne conduisent le dirigeant à prendre du risque que si, simultanément, la sensibilité de sa rémunération à la valeur créée est suffisante. / The purpose of this work is to analyze the influence of CEO’s compensation package on the risk taking behavior of the firm. We focus on the financial incentives contained in equity based compensation and their interaction. Our sample consists of US firms for the period 1992-2005. The data come from the Compustat and Execucomp databases. The purpose of the first chapter explores the link between CEO’s compensation and the financial constraints of the firm. In a second chapter, we empirically analyze the effect of financial incentives on the risk of investment. We use Research and Development expenses level as a proxy of the risk of investment. In a third chapter, we focus on target debt leverage level determinants using a dynamic adjustment model. In the last chapter we analyze default risk determinants. The main result of this work is that the efficiency of risk incentive is highly dependent of CEO’s performance incentive reaching a given threshold.

The Red River Delta in Vietnam is one of the regions whose quaternary aquifers are polluted by arsenic. Chronic toxification by arsenic can cause severe illnesses such as cancer, skin lesions, developmental defects, cardiovascular and neurological diseas-es, and diabetes. In this study, a food processing craft village in the Red River Delta was investigated regarding the potential risk faced by the population due to arsenic. The potential sources of arsenic are the groundwater, the crops grown in the sur-roundings, and animal products from local husbandry. However, the occurrence of arsenic in nature is variable, and its bioavailability and toxicity depend very much on its specification: trivalent compounds are more toxic and often more mobile than pen-tavalent compounds, while inorganic species are generally more toxic than organic ones. Local conditions, such as the redox potential, strongly influence its specification and thus potential bioavailability. The introduction to this work elucidates the key factors which potentially cause human exposure to arsenic: the geological setting of the study area, land and water use pat-terns, and the current state of research regarding the mobilization, bioavailability and plant uptake of arsenic. Although the study area is located in a region where the groundwater is known to be moderately contaminated by arsenic, the level of arsenic in the groundwater in the village had not previously been determined. In this study, water use in the village was examined by a survey among the farmers and by water analyses, which are present-ed in the following chapters. Four main water sources (rain, river, tube well and a pub-lic municipal waterworks) are used for the different daily activities; the highest risk to human health was found to be the bore well water, which is pumped from the shallow Holocene aquifer. The water from the bore wells is commonly used for cleaning and washing as well as to feed the animals and for food processing. Products like noodles and rice wine were examined as well as local pork and poultry. Vegetables from the gardens and rice plants from the surrounding paddy fields were sampled and ana-lyzed. All plants were found to have accumulated arsenic, leafy vegetables showing the highest arsenic concentrations. The results are discussed and compared, and conclusions are drawn in the last part. The reducing conditions in the paddy fields are likely to have a strong influence on arsenic uptake in rice plants and on transport to the aquifer. The installation of a wastewater treatment plant under the research project INHAND, which was funded by the BMBF German Ministry of Education and Research, led to lower arsenic concen-trations in the groundwater. Soaring industrialization, the growing population, and the consumers’ changing behav-ior will widely affect land and water use and hence the potential mobilization of arse-nic. In order to mitigate further human exposure to arsenic, wastewater needs to be treated and the reducing conditions in the rice fields need to be decreased by means of enhanced cultivation methods.

Le virus de l'hépatite Delta (HDV) est un agent infectieux transmissible satellite du virus de l'hépatite B (HBV), induisant des maladies du foie plus sévères que la mono–infection par le HBV. Aucun traitement totalement efficace n'est disponible contre l'HDV et les 15 millions de personnes infectées par le HDV dans le monde sont exposées a un risque élevé de cirrhose et de carcinome hépatocellulaire. HDV est un virus unique qui ne code pas pour une polymérase virale contrairement aux autres virus a ARN. La réplication de l'ARN HDV s'effectue par un double mécanisme de cercle roulant générant des brins d'ARN de longueur génomique ou antigénomiques unitaires. La synthèse de l'ARN génomique est sensible à de faibles concentrations d'alpha–amanitine, ce qui suggère qu'elle soit médiée par l'ARN polymérase II (ARN Pol II) classiquement ADN dépendante. Ce processus repose sur la petite protéine du HDV (S–HDAg), qui doit être acétylée sur l'acide amine K72 pour activer la synthèse de l'ARN génomique. Nous avons récemment identifié la protéine BAZ2B (Bromodomain Associated Zinc finger protein 2B) comme un interactant majeur de S–HDAg par capture par affinité, couplée à la spectrométrie de masse à partir de l'expression de S– HDAg étiqueté par un double motif Strep–TagR dans les cellules HepaRG différentiées. La fonction biologique de BAZ2B est inconnue. Cependant, en comparant avec des protéines apparentées BAZ (BAZ–1A/1B/2A), on postule que BAZ2B représente la sous–unité accessoire d'un nouveau complexe de remodelage de chromatine de type ISWI, qui régule le positionnement des nucléosomes par hydrolyse de l'ATP. Des études récentes ont révélé que le bromodomaine de BAZ2B (BRD) reconnait la signature épigénétique spécifique K14ac–X–X–R sur l'histone H3. Cela pourrait impliquer le mode d'action du complexe de remodelage de la chromatine dont BAZ2B représente l'unité régulatrice reconnaissant des marques spécifiques d'acétylation des histones propagées séquentiellement modifiant la dynamique de la chromatine et favorisant le recrutement de l'ARN Pol II pour activer la transcription. Nous émettons l'hypothèse que l'acétylation, médiée par p300, du motif K72–X–X–R conserve dans les S–HDAg interagissant avec l'ARN antigénomique pseudo double brin, mimerait l'acétylation des histone H3 en K14 permettant de recruter le complexe de remodelage de la chromatine BAZ2B associée et de lancer la réplication HDV. Brièvement, pour confirmer la pertinence fonctionnelle du recrutement BAZ2B pour la réplication HDV, nous avons transfecté des lignées cellulaire Huh–7 exprimant de façon stable, soit la protéine sauvage S–HDAg ou le mutant R75A pour étudier la réplication HDV à partir plasmide pSVLD2m défectif pour l'expression de S–HDAg. Nos résultats indiquent que la synthèse de l'ARN génomique est fortement réduite dans les cellules exprimant le mutant R75A S–HDAg par rapport aux cellules exprimant le type sauvage S–HDAg, alors que la quantité d'ARN antigénomique est restée le même dans les deux cas. Des expériences de co–cristallisation et de siRNA sont actuellement menées afin de mieux caractériser au niveau moléculaire l'association entre BAZ2B BRD et des peptides dérivés de la séquence de S–HDAg et d'étudier les conséquences de l'inhibition par siRNA de BAZ2B. L'implication des BAZ2B dans la réplication de HDV pourra ouvrir des possibilités de développement de médicaments anti–HDV, basées sur l'optimisation des inhibiteurs émergents de BAZ2B–BRD / Hepatitis Delta Virus (HDV) is a satellite of Hepatitis B Virus (HBV), leading to more severe life threatening liver diseases than HBV mono–infection. No efficient therapy is available against HDV and the estimated 15 million HDV infected individuals worldwide are at a high risk of cirrhosis and hepatocellular carcinoma. HDV is a unique RNA virus as it does not encode a viral polymerase. HDV RNA replication occurs via a double rolling circle mechanism generating unit–length genomic or antigenomic RNA strands. The synthesis of the genomic RNA is sensitive to low concentrations of α–amanitin, suggesting that the RNA–dependent RNA synthesis is mediated by DNA–dependent RNA polymerase II (RNA Pol II). This process relies on the HDV encoded Small Hepatitis Delta antigen (S–HDAg), which must be acetylated at K72 to activate the synthesis of the genomic RNA. We recently identified BAZ2B (Bromodomain Associated to Zinc finger protein 2B) as a major interactant of S–HDAg by affinity capture coupled to mass spectrometry in differentiated HepaRG cells. The biological function of BAZ2B is however unknown. In comparison with related BAZ proteins (BAZ–1A/1B/2A), it is postulated that BAZ2B is the accessory subunit of a new chromatin remodeling complex of ISWI–type, which regulates nucleosome positioning through ATP hydrolysis. Recent studies revealed that the BAZ2B bromodomain (BRD) recognizes the distinct epigenetic signature K14ac–X–X–R on histone H3. This suggests that the mode of action of BAZ2B associated chromatin remodeling complex involves recognizing propagated specific histone acetylation marks to subsequently alter the chromatin dynamic and recruit the RNA Pol II for transcriptional activation. We hypothesized that the p300–mediated acetylation of the conserved K72–X–X–R motif in S–HDAg mimics acetylated histones on the pseudo–double stranded antigenomic RNA, to recruit the BAZ2B associated chromatin remodeling complex to initiate RNA Pol II mediated synthesis of HDV genome. To confirm the functional relevance of BAZ2B recruitment for HDV replication, we transfected Huh 7 cells stably expressing either wild–type S–HDAg or R75A mutant S–HDAg with the HDV replication defective plasmid pSVLD2m. Our results indicate that the synthesis of genomic RNA was greatly reduced in cells expressing the R75A mutant S–HDAg in comparison to cells expressing wild–type S–HDAg, whereas the amount of antigenomic RNA remained the same in both cases. Co–crystallization experiments are currently being carried out to better characterize at the molecular level the association between BAZ2B BRD and S–HDAg derived peptides. Furthermore, siRNA experiments directed against the BAZ2B gene are expected to reveal the consequences of BAZ2B inhibition on HDV viral replication. The involvement of BAZ2B in HDV replication may open anti–HDV drug development opportunities, based on the optimization of emerging BAZ2B–BRD inhibitors

La matière organique continentale déposée dans les bassins profonds est peu décrite et représente un intérêt certain pour l'industrie pétrolière. Comprendre les processus sédimentaires qui permettent le dépôt et la préservation de cette matière organique d'origine terrestre dans les bassins profonds est alors fondamental. Durant le Paléogène, période de transition climatique greenhouse à icehouse, le Delta de Mackenzie, situé dans le Bassin Arctique, reçoit de la matière organique continentale du continent et en préserve une partie. Quel est le contexte stratigraphique et climatique qui a rendu possible l'export de la matière organique continentale. Dans un premier temps, l'étude sédimentaire du bassin a montré un delta mixte dominé par des processus fluviatiles, avec une influence moindre des processus de tempêtes et de marées. Ce modèle de faciès associé à l'étude des diagraphies des puits disponibles dans la zone a permis de proposer un modèle d'électrofaciès des puits du bassin et de caractériser les séquences sédimentaires du delta évoluer au cours du temps et mettre en évidence sa migration au début du Paléogène en réponse à la mise en place de la chaîne des Brooks et des Rocheuses. Malgré des contraintes biostratigraphiques contradictoires qu'il a fallu réévaluer et des données sismiques de mauvaise qualité et fortement impactés par la déformation contemporaine de la chaîne de Brooks, il a été possible de proposer le long de deux transects terre-mer un découpage stratigraphique et sédimentologique des séries paléogènes du Delta de Mackenzie. L'étude sédimentaire du bassin a montré la présence d'influence de processus de marée en zone interne du Bassin Arctique. La présence conjointe de pollens d'Avicennia et de Nypa a montré l'existence d'une mangrove bien installée en domaine Arctique durant le Paléogène avec des températures associées d'au moins 18-20 °C. Les dépôts de matière organique sont dans la quasi-totalité d'origine continentale du Delta de Mackenzie. Cette matière organique est de deux types : 1) des dépôts de charbon déposés durant la période où la mangrove se développe et 2) des dépôts formés d'association de débris végétaux et de matière organique amorphe et déposés en condition réductrice sous l'interface eau-sédiment. Ces dépôts de matière organique sont les plus importants à la fin des séquences progradantes dans les faciès de plaine deltaïque. Il a été montré une corrélation positive entre l'augmentation des TOC et l'augmentation des apports détritiques dans le delta, ainsi qu'entre les dépôts de charbon et illite. En revanche, aucune corrélation entre le second type (débris végétaux + MO amoprhe) de matière organique et le cortège argileux n'a pu être mise en évidence. A partir de la comparaison des dépôts de matière organique dans le Delta de Mackenzie et sur la Ride de Lomonosov, le taux de sédimentation et l'anoxie semblent être des paramètres clefs dans les conditions de sédimentation et surtout de préservation de la matière organique selon l'oxygénation du milieu. De plus, la Ride de Lomonosov semble semble avoir présenté un retard dans sa subsidence ce qui lui a permis de rester en position semi-émergée durant le Paléogène. / The continental organic matter deposited in the deep basins is little described and represents a definite interest for the petroleum industry. Understanding the sedimentary processes that allow the deposit and preservation of this organic material of terrestrial origin in the deep basins is fundamental. During the Palaeogene, a period of glacial transition to icehouse, the Mackenzie Delta, located in the Arctic Basin, receives and maintains continental organic matter from the continent. What is the stratigraphic and climatic context that made possible the export of continental organic matter? Initially, the sedimentary study of the basin showed a mixed mixture dominated by the fluviatile process, with less influence of the process of storms and tides. This model of facies associated with the study of the logs of wells available in the zone made it possible to propose a model of electrical appliances of the wells of the basin and to characterize the sedimentary sequences of the delta to evolve over time and to demonstrate its migration to Beginning of the Paleogene in response to the establishment of the Brooks and Rocky Ranges. Despite the contradictory biostratigraphic constraints that had to be re-evaluated and poor quality seismic data and strongly impacted by the contemporary deformation of the Brooks chain, it is possible to propose a stratigraphic and sedimentological division along two land-sea transects. Paleogeographic series of the Mackenzie Delta. The sedimentary study of the basin showed the presence of influence of the tidal process in the internal zone of the Arctic Basin. The common presence of pollen from Avicenna and Nypa showed the existence of a mangrove well established in the Arctic domain during the Palaeogene with associated temperatures of at least 18-20 ° C. The deposits of organic matter are in the Almost all of continental origin of the Mackenzie Delta. This organic matter is of two types: (1) deposits of coal deposited during the period when the mangrove develops and (2) deposits formed by association of plant debris and amorphous organic matter and deposited under reducing conditions under the water interface -sediment. These deposits of organic matter are the most important at the end of the prograding sequences in the facies of the deltaic plain. A positive correlation was found between the increase in OCD and the increase in detrital inputs in the delta, as well as between deposits of coal and illite. On the other hand, no correlation between the second type (organic debris + MO amoprhe) of organic matter and the clayey cortege could not be demonstrated. From the comparison of organic matter deposits in the Mackenzie Delta and Lomonosov Ridge, the sedimentation rate and anteriority appear to be key parameters in sedimentation conditions and especially in the preservation of organic matter according to l Oxygenation of the medium. Moreover, Lomonosov's Ride presents itself as a guest in a home where it is permitted to remain in semi-emerged position during the Paleogene.