O presente trabalho visa compreender o processo de expansão e consolidação do Primeiro Comando da Capital (PCC) no sistema prisional paulista e a figuração social que se constituiu nas prisões como resultado da monopolização das oportunidades de poder pelo PCC. Para tanto, conceitos e concepções teóricas de Norbert Elias são utilizados como ferramentas analíticas para o tratamento do material empírico colhido a partir de fontes diversas. O trabalho é composto por dois eixos de análise: eixo horizontal/processual e eixo vertical/figuracional. O eixo de análise horizontal ou processual aborda o fenômeno de um ponto de vista macrossociológico, em que se focaliza o processo social de desenvolvimento do PCC tendo em vista fatores sociais, políticos e administrativos que direta ou indiretamente estão atrelados a ele. Ainda como parte desse eixo de análise, o processo de expansão do PCC é considerado em termos das várias etapas que o compõem, tendo em vista o papel da violência física direta no exercício do seu poder. O eixo de análise vertical ou figuracional tem como objetivo a compreensão da dinâmica social produzida a partir deste processo. Considerando uma figuração social como ponto de partida da análise, denominada figuração pré-PCC, procurou-se apresentar as transformações ocorridas no universo prisional e que constituíram uma nova figuração social. A nova figuração social produzida a partir da hegemonia do PCC é constituída por uma teia de interdependência individual mais longa e complexa, com uma maior divisão funcional e integração social entre os seus componentes. Diante desta nova forma de dependência, os controles sociais sobre o comportamento individual foram ampliados e centralizados na posição ocupada pelo PCC. A estrutura e organização do PCC, sua dinâmica política e o controle social que adquire a forma de imposição do autocontrole individual, são questões centrais nesta parte do trabalho. O eixo vertical é finalizado com uma discussão sobre a relação de dependência do PCC em face da administração prisional, em que o dispositivo do Regime Disciplinar Diferenciado (RDD) é central na manutenção do equilíbrio de poder que garante a hegemonia do PCC e a estabilidade da ordem social do universo prisional. Uma reflexão que perpassa todo o trabalho e que é desenvolvida no capítulo final coloca em discussão a pacificação social que é vista como o efeito mais expressivo do processo de consolidação do poder do PCC. Neste sentido, a fragilidade deste processo é apontada a partir da sua natureza conjuntural e das bases precárias nas quais está apoiado o poder hegemônico do PCC. / The present work aims to understand the process of expansion and consolidation of the Primeiro Comando da Capital (PCC) in São Paulo prison system and the social figuration that is formed in prisons as a result of the monopolization of the opportunities by the power of PCC. To this end, concepts and theoretical conceptions of Norbert Elias are used as analytical tools for the treatment of empirical data collected from various sources. The work consists of two lines of analysis: axis horizontal / vertical axis and procedural / figurational. The horizontal axis analytical or procedural approaches the phenomenon from a macrosociological point of view, which focuses on the social development of the PCC with a view to social, political and administrative problems that are directly or indirectly linked to it. Also as part of the analysis area, the expansion of the PCC is considered in terms of several steps that compose it, owing to the role of direct physical violence in the exercise of its power. The vertical axis or figurational analysis aims at understanding the social dynamics produced from this process. Whereas a social figuration as a starting point of analysis, called figuration \"pre- PCC\", tried to show the changes in the prison world, which constituted a new social figuration. The new social representation produced from the hegemony of the PCC consists of a web of a longer and more complex individual interdependence, with greater functional division and social integration among its components. Given this new form of dependency, the social controls on individual behavior have been expanded and centralized in the position occupied by the PCC. The structure and organization of the PCC, its political dynamics and social control which takes the form of imposition of individual self-control are central issues in this part of the work. The vertical axis is concluded with a discussion of the dependence of the PCC in the face of the prison administration, where the device Regime Disciplinar Diferenciado (RDD) is central in maintaining the balance of power that ensures the hegemony of the PCC and the stability of the order social of the prison. A reflection that permeates all the work that is developed in the final chapter calls into question the social pacification that is seen as the most significant effect of the consolidation of power of the PCC. In this sense, the fragility of this process is identified from its contextual nature and the precarious foundations on which rests the hegemonic power of the PCC.

O presente trabalho visa compreender o processo de expansão e consolidação do Primeiro Comando da Capital (PCC) no sistema prisional paulista e a figuração social que se constituiu nas prisões como resultado da monopolização das oportunidades de poder pelo PCC. Para tanto, conceitos e concepções teóricas de Norbert Elias são utilizados como ferramentas analíticas para o tratamento do material empírico colhido a partir de fontes diversas. O trabalho é composto por dois eixos de análise: eixo horizontal/processual e eixo vertical/figuracional. O eixo de análise horizontal ou processual aborda o fenômeno de um ponto de vista macrossociológico, em que se focaliza o processo social de desenvolvimento do PCC tendo em vista fatores sociais, políticos e administrativos que direta ou indiretamente estão atrelados a ele. Ainda como parte desse eixo de análise, o processo de expansão do PCC é considerado em termos das várias etapas que o compõem, tendo em vista o papel da violência física direta no exercício do seu poder. O eixo de análise vertical ou figuracional tem como objetivo a compreensão da dinâmica social produzida a partir deste processo. Considerando uma figuração social como ponto de partida da análise, denominada figuração pré-PCC, procurou-se apresentar as transformações ocorridas no universo prisional e que constituíram uma nova figuração social. A nova figuração social produzida a partir da hegemonia do PCC é constituída por uma teia de interdependência individual mais longa e complexa, com uma maior divisão funcional e integração social entre os seus componentes. Diante desta nova forma de dependência, os controles sociais sobre o comportamento individual foram ampliados e centralizados na posição ocupada pelo PCC. A estrutura e organização do PCC, sua dinâmica política e o controle social que adquire a forma de imposição do autocontrole individual, são questões centrais nesta parte do trabalho. O eixo vertical é finalizado com uma discussão sobre a relação de dependência do PCC em face da administração prisional, em que o dispositivo do Regime Disciplinar Diferenciado (RDD) é central na manutenção do equilíbrio de poder que garante a hegemonia do PCC e a estabilidade da ordem social do universo prisional. Uma reflexão que perpassa todo o trabalho e que é desenvolvida no capítulo final coloca em discussão a pacificação social que é vista como o efeito mais expressivo do processo de consolidação do poder do PCC. Neste sentido, a fragilidade deste processo é apontada a partir da sua natureza conjuntural e das bases precárias nas quais está apoiado o poder hegemônico do PCC. / The present work aims to understand the process of expansion and consolidation of the Primeiro Comando da Capital (PCC) in São Paulo prison system and the social figuration that is formed in prisons as a result of the monopolization of the opportunities by the power of PCC. To this end, concepts and theoretical conceptions of Norbert Elias are used as analytical tools for the treatment of empirical data collected from various sources. The work consists of two lines of analysis: axis horizontal / vertical axis and procedural / figurational. The horizontal axis analytical or procedural approaches the phenomenon from a macrosociological point of view, which focuses on the social development of the PCC with a view to social, political and administrative problems that are directly or indirectly linked to it. Also as part of the analysis area, the expansion of the PCC is considered in terms of several steps that compose it, owing to the role of direct physical violence in the exercise of its power. The vertical axis or figurational analysis aims at understanding the social dynamics produced from this process. Whereas a social figuration as a starting point of analysis, called figuration \"pre- PCC\", tried to show the changes in the prison world, which constituted a new social figuration. The new social representation produced from the hegemony of the PCC consists of a web of a longer and more complex individual interdependence, with greater functional division and social integration among its components. Given this new form of dependency, the social controls on individual behavior have been expanded and centralized in the position occupied by the PCC. The structure and organization of the PCC, its political dynamics and social control which takes the form of imposition of individual self-control are central issues in this part of the work. The vertical axis is concluded with a discussion of the dependence of the PCC in the face of the prison administration, where the device Regime Disciplinar Diferenciado (RDD) is central in maintaining the balance of power that ensures the hegemony of the PCC and the stability of the order social of the prison. A reflection that permeates all the work that is developed in the final chapter calls into question the social pacification that is seen as the most significant effect of the consolidation of power of the PCC. In this sense, the fragility of this process is identified from its contextual nature and the precarious foundations on which rests the hegemonic power of the PCC.

Esta dissertação discute o modo como a cidade de São Paulo, marcada pelos ataques do Primeiro Comando da Capital de maio de 2006, é construída em Salve Geral (Sérgio Rezende, 2009), Inversão (Edu Felistoque, 2010) e Os Inquilinos (Sergio Bianchi, 2009). Distantes dos paradigmáticos títulos cariocas que têm abordado violência e crime nas últimas décadas e em consonância com a polifórmica São Paulo do cinema, Salve Geral, Inversão e Inquilinos constroem diferentes cidades na tela. Em suas distintas opções formais e narrativas, encontramos entre os três títulos possiblidades que escapam de um apelo sensacional do evento. De modo instigante, os três filmes inserem a cobertura dos meios de comunicação em suas diegeses, colocando em pauta as interlocuções midiáticas em torno da violência, reforçando a importância das diferentes narrativas na construção do fenômeno e sugerindo uma postura reflexiva sobre a implicação dos filmes nesse conjunto de narrativas. / This dissertation inquiries the ways in which the city of Sao Paulo, marked by the attacks carried out by the criminal organization PCC (First Command of the Capital) in May 2006, is shown on three recent movies: Time of Fear (Salve Geral, Sérgio Resende, 2009),The Tenants - Don\'t Like It, Leave (Os Inquilinos, Sérgio Bianchi, 2009) and Inversão (Edu Felistoque, 2010). All three movies strengthen the multiple filmic representations of Sao Paulo, and not only differ from each other, but also when compared to recent movies that deal with urban violence, specially box-office hits shot in Rio de Janeiro like City of God (Cidade de Deus, Fernando Meirelles, 2002) and Elite Squad (Tropa de Elite, José Padilha, 2007). Through its multiple narrative and formal choices, we see among the three movies possibilities that escape a sensationalistic appeal of the event. In an interesting way the three movies not only include the attacks but also the mediatic reverberations, pointing the implication of the many narratives in the building of the phenomenon of violence and encouraging a reflective thought about is own construction

Esta dissertação discute o modo como a cidade de São Paulo, marcada pelos ataques do Primeiro Comando da Capital de maio de 2006, é construída em Salve Geral (Sérgio Rezende, 2009), Inversão (Edu Felistoque, 2010) e Os Inquilinos (Sergio Bianchi, 2009). Distantes dos paradigmáticos títulos cariocas que têm abordado violência e crime nas últimas décadas e em consonância com a polifórmica São Paulo do cinema, Salve Geral, Inversão e Inquilinos constroem diferentes cidades na tela. Em suas distintas opções formais e narrativas, encontramos entre os três títulos possiblidades que escapam de um apelo sensacional do evento. De modo instigante, os três filmes inserem a cobertura dos meios de comunicação em suas diegeses, colocando em pauta as interlocuções midiáticas em torno da violência, reforçando a importância das diferentes narrativas na construção do fenômeno e sugerindo uma postura reflexiva sobre a implicação dos filmes nesse conjunto de narrativas. / This dissertation inquiries the ways in which the city of Sao Paulo, marked by the attacks carried out by the criminal organization PCC (First Command of the Capital) in May 2006, is shown on three recent movies: Time of Fear (Salve Geral, Sérgio Resende, 2009),The Tenants - Don\'t Like It, Leave (Os Inquilinos, Sérgio Bianchi, 2009) and Inversão (Edu Felistoque, 2010). All three movies strengthen the multiple filmic representations of Sao Paulo, and not only differ from each other, but also when compared to recent movies that deal with urban violence, specially box-office hits shot in Rio de Janeiro like City of God (Cidade de Deus, Fernando Meirelles, 2002) and Elite Squad (Tropa de Elite, José Padilha, 2007). Through its multiple narrative and formal choices, we see among the three movies possibilities that escape a sensationalistic appeal of the event. In an interesting way the three movies not only include the attacks but also the mediatic reverberations, pointing the implication of the many narratives in the building of the phenomenon of violence and encouraging a reflective thought about is own construction

Synechococcus elongatus PCC 7942 is a model organism used to study the circadian rhythm, a process that is driven by an endogenous biological clock that can be modulated by external cues such as light and temperature. Some proteins have been identified that are involved in circadian signal transduction in S. elongatus. Of them, KaiA, KaiB and KaiC comprise the central oscillator components, which are essential for internal timekeeping. SasA is an important protein in the output pathway, which passes the information from central oscillator to downstream components, and thus controls metabolic and behavioral processes. CikA is a major component in the input pathway, which maintains synchrony of the oscillator with the environment. CikA is an unusual phytochrome-like histidine protein kinase. It has a pseudo receiver domain which can not accept a phosphoryl group. CikA is thought to be located at the poles of the cell through interaction between PsR and some protein or protein complex that is also localized at the poles. One of the potential CikA-interacting proteins identified through a yeast two hybrid screen is called hypothetical protein 1. It specifically recognizes a PsR bait in a yeast two hybrid assay. A bioinformatics analysis showed that there are predicted signal peptide and transmembrane domains at the N-terminal and a cytochrome C homolog domain at the C-terminal of Hyp1. Elucidating the features and function of Hyp1 will provide us with useful information to understand the function and working mechanism of CikA, and therefore will help us to clarify the signal transduction in the clock. In this research, I used genetic, cell biological and biochemical approaches to study the features and function of this newly identified clock component Hyp1. To confirm the interaction between PsR and Hyp1 and complement the yeast two hybrid data, I truncated Hyp1 (Thyp1) and purified soluble Thyp1. At the same time, I obtained purified PsR. I tried to copurify the PsR and 6-histidine-tagged Hyp1 on a nickel affinity column. However, PsR non-specifically bound to the column, which eliminated the utility of this approach to study their interaction. In addition to using a biochemical approach to study Hyp1, I constructed three hyp1 overexpression alleles for genetic analysis and two hyp1-yfp overexpression fusion alleles for subcellular localization studies. All of them will help us to understand the features and function of Hyp1.

Many multicellular cyanobacteria produce specialized nitrogenfixing heterocysts. During diazotrophic growth of Anabaena (Nostoc) sp. strain PCC 7120, a regulated developmental pattern of single heterocysts separated by about 10 to 20 photosynthetic vegetative cells is maintained along filaments. Heterocyst structure and metabolic activity function together to accommodate oxygensensitive nitrogen fixation, catalyzed by nitrogenase. In this work, we show that the promoter of the nifHDK genes that encode nitrogenase, lies upstream from the intergenic region between nifH and nifU. Excision of the fdxN element is required for transcription of the nifHDK genes. Fluorescence microscopy of reporter strain PnifHDgfp, in the chromosomal nif locus indicated that expression of nifHDK is blocked in mutants that are unable to excise the fdxN element after nitrogen deprivation. We proposed that a promoter upstream of the element, likely PnifB, is required for transcription of the nifHDK genes. Indeed, the PnifHDgfp reporter at an ectopic site did not show GFP fluorescence. A PnifBgfp reporter was expressed specifically in heterocysts indicating that a promoter for the nifB gene lies in the intergenic region upstream of nifB. A stem loop structure located in the intergenic region between nifH and nifU may act as a processing site for production of nifHDK transcripts. We also provide evidence that DevH, a transcriptional regulator, is involved in regulating the nifBfdxNnifSUHDK genes. DevH is a protein belonging to the cAMP receptor protein (CRP) family of proteins that are widespread in bacteria and regulate genes in response to a gamut of physiological conditions. We show that DevH binds specifically to the nifB upstream region but not to the immediate upstream region of nifH. We predict that DevH binds to an NtcAlike binding site upstream of nifB and functions as an activator of the nifBfdxNnifSUHDK genes. Finally, we show that sigE, which is expressed at 16 hours after nitrogen deprivation, is required for normal expression of some heterocyst specific genes, including nifHDK. A sigE mutant shows delayed and reduced expression of nifHDK and some middle and late genes. We hypothesize that DevH in concert with SigE upregulates the expression of nifHDK in heterocysts after nitrogen deprivation.

Este trabalho analisa teórica e empiricamente a pretensão de legitimidade do agrupamento autodenominado Primeiro Comando da Capital (PCC) nos distritos periféricos do município de São Paulo (MSP) onde tem adquirido forte territorialização. Legitimidade aqui entendida enquanto um processo dinâmico travado no âmbito de relações de poder que envolve, de um lado, as autojustificações do PCC no exercício de suas práticas, especialmente no âmbito da regulação de condutas e resolução de conflitos, e, de outro, a possibilidade de seu reconhecimento pelos moradores e profissionais dessas localidades. No que concerne à operacionalização dessa regulação e arbitragem de conflitos, aborda-se centralmente a pretensão ao direito de matar acionado pelo PCC por meio dos debates ou tribunais do crime, a fim de evidenciar que o uso da força física é um dos pilares fundamentais de sustentação desse poder. De forma mais ampla, essa problemática é situada no contraponto aos limites do Estado em promover o monopólio legítimo do uso da força física na sociedade brasileira, seja devido à sua incompletude na promoção da segurança pública ou por sua atuação historicamente arbitrária e abusiva. Consiste em um estudo qualitativo que procura ressaltar a multiplicidade de efeitos produzidos pela presença de grupos criminosos (sob a normatividade do PCC) nessas localidades e as possibilidades de reconhecimento dos moradores e profissionais diante das práticas desses grupos. Considerando-se as ambiguidades que perpassam as relações entre o PCC, as forças de segurança estatais e os moradores e profissionais desses locais, sustenta-se que não é possível afirmar que o PCC é uma instância legítima perante a população e sim que há possibilidades de reconhecimento (em diferentes gradações) constituídas constantemente por meio dessas relações, o que tensiona, mas não desconstrói a legitimidade estatal enquanto expectativa sempre reatualizada. Nessa perspectiva, delimitam-se para fins analíticos três possibilidades, entendidas em suas interconexões: ausência de reconhecimento, atrelada ao medo e às situações de coação produzidas pelas práticas dessa instância de poder; reconhecimento situacional constituído nas brechas e limites da atuação estatal; e situação de reconhecimento, na qual se verifica uma maior consonância entre as concepções da população e as práticas de fazer justiça do PCC. No que concerne a esse último aspecto, ganha relevo as seletividades operantes no uso da força física no interior dos mecanismos de punição do PCC, conformando esse próprio uso como aspecto importante nas ponderações sobre a possibilidade de reconhecimento dessa instância de poder. Possibilidade que encerra conjuntamente às práticas de violência estatais extralegais (mas igualmente com pretensões de legitimidade) limites à constituição de um Estado democrático de Direito no país. / This study analyses theoretically and empirically the pretension of legitimacy of the criminal group self-titled Primeiro Comando da Capital (PCC) in peripheral districts of the city of Sao Paulo, places where the group is rooted. Legitimacy here is understood as a dynamic process that takes place within power relations that involves on the one hand the self-justification of PCC in the exercise of their practices, especially in the context of regulation of conduct and conflict resolution and on the other hand, the possibility of their recognition by residents and professionals in these locations. Regarding the operationalization of this regulation and arbitration of conflicts, the study focuses mainly the pretension of the \"right to kill\" claimed by the PCC through debates or criminal courts in order to show that the use of physical force is one of the sustaining pillars of this power. Broadly, this issue lays on the state limitation in promoting legitimate monopoly on the use of physical force in Brazilian society whether due to its incompleteness in promoting public safety or on its historically arbitrary and abusive action. It consists in a qualitative study that tries to highlight the multiplicity of effects produced by the presence of criminal groups (in the normativity of PCC) in these locations and the possibilities of recognition by residents and professionals on the practices of these groups. Taking into account the ambiguities that pervade the relations between the PCC, the state security forces, the residents and the professionals of these locations, it is argued that if it is not possible to say that the PCC is a legitimate instance to the population, it is possible to say that there are different degrees of recognition constantly formed by these relationships, which can damage but not tear down the state legitimacy as an expectation always updated. In this perspective, for analytical purposes we delimit three possibilities, understood in their interconnections: no recognition, linked to the fear and duress situations produced by the practices of this instance of power; situational recognition made in the gaps and limitations of state action; and situation of recognition, in which we can see a greater consonance between the views of the population and the practices of \"doing justice\" of the PCC. Regarding this last aspect, we should highlight the selectivity in the use of physical force within the PCC punishment mechanisms, since this use is an important aspect of the weightings of the possibility of recognition of this power instance. Possibility that appears, next to extra-legal state violence practices (but which also have the pretension of legitimacy), as a limit to the establishment of a democratic Rule of Law in the country.

O presente trabalho, baseado em pesquisa etnográfica desenvolvida em uma instituição de controle social, a Fundação Centro de Atendimento Socioeducativo ao Adolescente (Fundação CASA), debruça-se sobre o deslocamento do universo institucional ao longo do tempo, tendo como ponto de partida a criação da Fundação Nacional do Bem-Estar do Menor (FUNABEM), em pleno contexto de ditadura militar. Trata-se de etnografar o movimento ininterrupto da instituição, isto é, de vê-la a partir de uma perspectiva processual, atentando para as figurações sociais que emergem das relações estabelecidas entre os atores que circulam pelas distintas unidades de medida socioeducativa de internação. Tendo como base a reconstituição de três trajetórias, procura-se desvelar a dinâmica de funcionamento dos distintos espaços institucionais, iluminando as tensões que os caracterizam, bem como os incessantes embates travados entre os atores sociais que se movimentam em tal contexto. Se em um primeiro momento, nos defrontamos com os antigos espaços de internação, caracterizados, entre outros traços, pelas acentuadas disparidades de força entre os adolescentes e os funcionários, com o reordenamento do universo institucional, veremos que em algumas Unidades de Internação, conhecidas como cadeias dominadas, os internos tornam-se os principais responsáveis pela gestão da operação cotidiana de tais unidades. Espaços institucionais em que os adolescentes orientam as suas ações de acordo com os preceitos do Primeiro Comando da Capital (PCC), que, vale notar, também operam no sistema prisional, bem como nas periferias de São Paulo, o que torna evidente que tais territórios, ainda que hajam particularidades, encontram-se conectados, isto é, na mesma sintonia. / The present study is based on an etnographic research developed in a Social Control Institution known as Fundação Centro de Atendimento Socioeducativo ao Adolescente (Fundação CASA). It focuses on the shift in the institutional universe over time, considering the building of the Fundação Nacional do Bem-Estar do Menor (FUNABEM), amid the Military Dictatorship, its starting point. The ethnography aims to register the constant displacement in the institution, in other words, it looks at this movement from a process-like perspective, taking into account the social figurations that emerge from the relationship established among the social actors who roam through the social and educational measures at the Juvenile Detention Units. Based on the reconstitution of three trajectories, it seeks to reveal the dynamic and functioning of these distinct institutional spaces, bringing into the light the tensions which characterize them, as well as the unceasing disputes among the social actors who move in such context. If, at first, we are faced with the same old detention places characterized, among other features, by the wide contrast of power between teenagers and staff, leading to a rearrangement in the institutional universe, we also perceive that in some of those Juvenile Detention Units, known as cadeias dominadas, the inmates have become primarily responsible for managing the Units everyday operation. Institutional places where these teenagers guide their actions according to the rules of PCC (Primeiro Comando da Capital), which also operates in the jail system, as well as in the outskirts of São Paulo. This shows that those areas, although different and with their own specificities, are connected. In other words, they are on the same wavelength.

Les phéochromocytomes (PCC) et les paragangliomes (PGL) sont des tumeurs neuroendocrines rares, pour lesquelles le déterminisme génétique est très important, avec 16 gènes de prédisposition identifiés à ce jour. Au cours de ce travail de thèse, je me suis plus particulièrement intéressée aux conséquences des mutations du gène SDHB, car il avait été préalablement démontré qu’elles constituaient un facteur de risque de mauvais pronostic, associé à un phénotype métastatique et à une réduction de la survie des patients. Grâce à l’analyse du transcriptome d’une large cohorte de 188 échantillons de PCC/PGL humains, j’ai pu mettre en évidence que la voie de la transition épithélio-mésenchymateuse (EMT) était spécifiquement activée dans les tumeurs métastatiques SDHB-dépendantes. En effet, j’ai observé, dans ce sous-groupe de tumeurs, une surexpression de facteurs de transcription et de régulateurs précoces de l’EMT, comme TWIST1, TFC3, ou LOXL2 ; une perte d’expression de marqueurs de jonctions cellulaires, comme CDH2 et KRT19 ; ou encore une induction de gènes codant pour des enzymes pro-invasives, comme MMP1 et MMP2. Dans ces tumeurs, j’ai par ailleurs validé l’induction transcriptionnelle de l’EMT en mettant en évidence la rétention nucléaire de la protéine SNAIL (un facteur de transcription clé de l’EMT) sur des coupes de tissus. Dans cette même cohorte, l’analyse des données de méthylation globale de l’ADN nous a permis d’observer un phénotype hyperméthylateur dans les tumeurs SDHx, qui est expliqué par une inhibition de déméthylases de l’ADN et des histones par le succinate, qui s’accumule dans ces tumeurs où la succinate déshydrogénase est inactivée. Nous avons ainsi pu démontrer que le succinate est un oncométabolite qui induit des modifications épigénétiques impliquées dans l’extinction de nombreux gènes, et en particulier des gènes associés à l’EMT, comme le gène KRT19 (l’un des plus hyperméthylés dans les tumeurs SDHB-malignes, comparativement aux autres). J’ai ensuite caractérisé le premier modèle cellulaire de PCC/PGL porteur d’une inactivation complète du gène Sdhb, dans lequel j’ai confirmé l’activation de l’EMT, au niveau transcriptionnel et au niveau protéique. La caractérisation fonctionnelle de ces cellules m’a ensuite permis de mettre en évidence des propriétés migratoires, invasives, et adhésives spécifiques des cellules chromaffines Sdhb -/-. J’ai par la suite focalisé mon étude sur le gène Krt19, qui code pour une protéine du cytosquelette, la kératine 19 et qui est éteint dans les tumeurs et dans les cellules Sdhb -/-. La réintroduction de ce gène dans les cellules Sdhb -/- et son inhibition dans les cellules sauvages m’ont permis de conclure à l’implication de la kératine 19 dans les processus d’adhésion, de migration et d’invasion. Cependant je n’ai pas pu expliquer l’ensemble du phénotype par la seule modulation de ce gène, ce qui démontre l’implication d’autres acteurs dans la mise en place du phénotype invasif décrit. Mes travaux de thèse ont ainsi permis de démontrer que l’activation de l’EMT est responsable du caractère métastatique et invasif observé dans les tumeurs porteuses d'une mutation sur le gène SDHB et que cette activation est notamment secondaire aux modifications épigénétiques induites par l’inactivation de la succinate déshydrogénase. / Pheochromocytomas (PCC) and paragangliomas (PGL) are rare neuroendocrine tumors for which there is a major impact of genetic determinism with 16 identified predisposition genes to date. During this PhD training, I was particularly interested in the consequences of SDHB gene mutations because it was previously demonstrated that they constitute a high risk factor of poor prognosis, associated with metastatic phenotype and reduced survival. During my thesis, thanks to the analysis of transcriptomic data of a large cohort of 188 human PCC/PGL samples, I identified epithelial to mesenchymal transition (EMT) as activated in SDHB-metastatic tumors. Indeed, I observed a transcriptional induction of TWIST1, TCF3 and LOXL2, which are transcription factors or early regulators of EMT; a loss of expression of cellular junction components such as CDH2 and KRT19; and an up regulation of genes encoding pro-invasive proteases, such as MMP1 and MMP2. In these tumors, I validated the transcriptional induction of EMT by showing a nuclear retention of SNAIL protein, the master EMT transcription factor. In the same cohort, global DNA methylation data allowed us to describe a hypermethylator phenotype in SDHx related tumors, explained by the inhibition of DNA and histones déméthylases by succinate, which accumulates massively in cells inactivated for succinate dehydrogenase. We thus demonstrated that succinate is an oncometabolite responsible for epigenetic modifications implicated in gene extinction, including EMT-related genes such as KRT19 (one of the most hypermethylated genes in SDHB-metastatic samples). Following these observations, I characterized the first PCC/PGL cellular model displaying a complete Sdhb inactivation, in which I confirmed EMT activation, at transcriptional and protein levels. Functional characterization of these cells allowed me to show Sdhb-specific migratory, invasive and adhesive properties. I thus focused my study on Krt19, which encodes keratin 19, a cytoskeleton protein, lost in Sdhb -/- cells and in human SDHB-related tumors. Krt19 rescue in Sdhb -/- cells or Krt19 inhibition in wild-type cells allowed me to conclude that keratin 19 is implicated in adhesion, migration and invasion. However I was not able to explain the whole phenotype observed, demonstrating the implication of other actors in the establishment of the invasive phenotype. The main result of my PhD work is the discovery that EMT is a molecular pathway responsible for the metastatic and invasive phenotype observed in SDHB-mutated tumors as a result of epigenetic alterations due to succinate dehydrogenase inactivation.

Dans ce travail, une configuration laminaire stratifiée est utilisée afin d’étudier les caractéristiques de la pyrolyse et de l’oxydation du charbon pulvérisé dans un mélange de flux réactif à la fois dans les conditions atmosphériques conventionnelles et dans des conditions de combustion enrichie en oxygène. Deux diagnostics optiques, la spectroscopie d’émission de flamme et la mesure de l’émission spontanée sont utilisés pour caractériser la structure de la flamme. Les profiles de concentration de trois radicaux excités, OH*, CH* and C*2 sont mesurés et analysés.Des simulations 1-D utilisant la cinétique détaillée y compris des sous-mécanismes de OH*, CH* and C*2 et de combustion de charbon sont effectuées et comparées avec des données expérimentales. La comparaison qualitative a montré que la configuration numérique actuelle était appropriée pour la prédiction des émissions de OH*, CH* and C*2. Les résultats prédits par l’approche numérique diffèrent avec les modifications apportées aux sous-modèles de charbon et aux paramètres cinétiques. Le modèle de pyrolyse et les matières volatiles semblent jouer des rôles plus importants. / In the present work, a laboratory-scale laminar strained configuration is used to investigate the characteristics of pulverized coal devolatilization and oxidation in a mixture of CH4/O2/N2 reactive flow both in conventional air conditions and in oxygen-enriched combustion conditions. Two optical diagnostics, Flame Emission Spectroscopy and measurement of spontaneous emission, are employed for the characterization of flame structure. The spatial concentration evolution of three excited radicals, OH*, CH*and C*2 , are measured and analyzed.1-D simulations using detailed gas-phase kinetics including OH*, CH*, and C*2 sub-mechanisms and coal combustion submodels are performed and compared with experimental data. Qualitative comparison with experiments showed that the current numerical configuration was suitable for the prediction of OH*, CH* and C*2 emission. The predicted results differed with changes to the coal sub-models and kinetic parameters. The devolatilization model and volatile matters seem to play more important roles.