O câncer de colo do útero é o segundo tumor mais frequente entre as mulheres brasileiras, os tratamentos disponíveis trazem complicações de curto a longo prazo e estudos que avaliam a qualidade de vida destas mulheres ainda são escassos no Brasil. Isto é justificado pela falta de instrumentos específicos e validados para esta finalidade em língua portuguesa (Brasil). Neste estudo objetivou-se testar as propriedades psicométricas dos questionários EORTC QLQ-CX24 e FACT-CX em uma amostra de mulheres brasileiras com câncer do colo do útero. O estudo é metodológico e foi realizado com 100 mulheres tratadas no Hospital de Câncer de Barretos, por meio de três avaliações (no início do estudo, 15 dias e 18 a 24 meses após o início). Foi testada a consistência interna (alfa de Cronbach), reprodutibilidade (coeficiente de correlação intraclasse), validade convergente (correlação com o questionário SF-36 e com o questionário EORTC QLQ-C30), a validade discriminante pelo estadiamento, tipo de tratamento e autoclassificação de saúde e a responsividade pelo método de distribuição dos dados, além da análise da facilidade de compreensão das questões e dos questionários. Confirmou-se a confiabilidade do questionário EORTC QLQ-CX24, a reprodutibilidade foi baixa nas escalas de preocupação sexual, atividade sexual e prazer sexual, bons resultados observou-se ao avaliar a validade convergente e discriminante. A análise da responsividade não confirmou todas as hipóteses. Ao avaliar o questionário FACT-CX, por meio da consistência interna, exceto pela escala de bem-estar emocional, as demais apresentaram valores de Alpha de Cronbach superiores a 0,70. A reprodutibilidade foi satisfatória nas cinco escalas que compõem o FACT- CX. Na análise da validade convergente, somente as escalas de bem-estar físico e bem-estar emocional mostrou boa correlação com as escalas do SF-36. Em geral, o questionário revelou boa validade discriminante, principalmente em relação a autoclassificação da saúde. Resultado satisfatório encontrou-se na análise da responsividade. Em geral observou-se um bom grau de entendimento das questões e dos questionário. Concluindo os questionários desenvolvidos para medir a QVRS em mulheres com câncer de colo do útero EORTC QLQ-CX24 e FACT-CX obtiveram resultados aceitáveis recomendando-se que outros estudos testem a responsividade por outros métodos / Cervical cancer is the second most common tumor among Brazilian women. Available treatments bring short and long-term complications, and studies assessing the quality of life of these women are still rare in Brazil. Such situation is warranted by the lack of specific and validated tools in (Brazilian) Portuguese for such a purpose. The goal of this study was to test the psychometric properties of EORTC QLQ-CX24 and FACT-CX questionnaires in a sample of Brazilian women affected by cervical cancer. This is a methodological study and it was conducted on 100 women treated at the Barretos Cancer Hospital by way of three assessments (at baseline, 15 days and 18 to 24 months after the onset). We tested the internal consistency (Cronbach\'s alpha), reproducibility (intraclass correlation coefficient), convergent validity (correlation with the SF-36 questionnaire and the EORTC QLQ-C30 questionnaire), the discriminant validity by way of staging, type of treatment and health self-classification and responsiveness by the method of data distribution, as well as the analysis of how easy it was their understanding of questions and questionnaires. The reliability of the EORTC QLQ-CX24 questionnaire was confirmed, reproducibility was low in the scales of sexual worry, sexual activity and sexual enjoyment, and good results were observed when evaluating the convergent and discriminant validity. The analysis of responsiveness did not confirm all hypotheses. Upon evaluation of the FACT-CX questionnaire through internal consistency, except for the scale of emotional well-being, the others showed Cronbach\'s alpha values above 0.70. Reproducibility was satisfactory in the five scales comprising FACT-CX. In convergent validity analysis, only the scales of physical well-being and emotional well-being showed good correlation with the scales of the SF-36. In general, the questionnaire demonstrated good discriminant validity, especially in relation to the self-ratings of health. Satisfactory result was found in the analysis of responsiveness. In general there was a good degree of understanding of questions and questionnaires. In conclusion, questionnaires developed to measure HRQOL in women with cervical cancer such as EORTC QLQ-CX24 and FACT-CX achieved acceptable results, and we do recommended that further studies are performed to assess responsiveness by other methods

O transplante de células tronco hematopoéticas(TCTH) consiste na infusão intravenosa de células tronco hematopoéticas, destinadas a restabelecer a função medular e imune em pacientes com uma série de doenças malignas e não malignas, herdadas ou adquiridas, sendo considerado um procedimento de alta complexidade, alto custo financeiro e alta morbi-mortalidade . O sucesso do TCTH resultou em um grande número de pacientes sobreviventes livres de doença, trazendo como grande questão colocada pelos candidatos a essa terapêutica como será sua qualidade de vida após o procedimento. O objetivo desse estudo longitudinal consistiu em avaliar a qualidade de vida relacionada à saúde (QVRS) de pacientes submetidos ao TCTH autólogo e alogênico em três momentos distintos: no pré, após 30 e 180 dias pós TCTH e correlacionar com dados clínicos e sócio-demográficos. Para a coleta de dados foram utilizados dois questionários: o primeiro para obtenção de dados clínicos e sócio-demográficos, e o segundo uma escala específica traduzida e validada para o português o Functional Assessment Cancer Therapy (FACT-BMT). A amostra inicial foi constituída por 30 pacientes, 26 avaliados nos três momentos. O conjunto de resultados permitiu visualizar um impacto positivo da QVRS em pacientes com neoplasias e doenças hematológicas submetidos ao TCTH, ao final dos seis meses pós TCTH, apesar de algumas funções se apresentarem mais prejudicadas como a função física, funcional e preocupações adicionais com 30 dias pós TCTH, houve melhora nos escores do FACT-BMT em todos os componentes quando comparado ao do pré TCTH, especialmente nos aspectos físicos, emocionais e relacionamento com o médico.Conhecer essas implicações auxiliam a equipe interdisciplinar e o paciente na decisão de submeter-se a esse procedimento e auxiliam no planejamento de uma assistência que visa a melhora da QVRS desses pacientes. / The Hematopoietic Stem Cells Transplantation (HSCT) consists of infusing stem cells intravenously, aiming to reestablish the spinal cord and immune functions in patients with a series of, inherent or acquired, malignant and nonmalignant diseases. It is considered a highly complex procedure, with high financial costs and morbidity and mortality. The HSCT success resulted in a large number of patients who survived and were healed, which in turn lead potential candidates to question how good quality of life can be after the procedure. This study evaluates the Health- Related Quality of Life (HRQoL) of patients submitted to the autologous and allogenic HSCT in three different points in time: before, 30 and 180 days after the HSCT and correlated clinical and socio-demographic data. Two questionnaires were used for data collection: the first addressed clinical and socio-demographic data and the second was the Functional Assessment Cancer Therapy (FACT-BMT) translated and validated to Portuguese. The initial sample was composed of 30 patients; 26 were evaluated in the three points. The set of results indicated a positive impact on HRQoL in patients with neoplasias and hematologic diseases six months after the HSCT. Despite the fact there were additional concerns and some functions, such as physical and functional, were affected 30 days after the HSCT, the FACT-BMT scores improved in all components reaching levels above those pre HSCT, especially in physical and emotional aspects and relationship with the physician. Knowledge concerning these implications helps patients to decide whether to submit to the procedure and the interdisciplinary team to plan care with a view to improve the HRQoL of these patients.

À l'instar de la psychotechnique des industries culturelles, savoir manier l’émotion pour toujours mieux capter l’attention d’un électeur dans la sphère de l'infotainment reste l’un des premiers objectifs d'une stratégie de campagne. Cependant, le Web politique a fait émerger de nouvelles formes de communication dans les méthodes de persuasion électorale : l’impact du capital médiatique d’un candidat se joue en ligne prolongeant celui du terrain. Sur Internet, les politiques, efficacement secondés par des experts de l’image chargés de façonner leur identité, leur réputation et leur influence, ont découvert de nouveaux territoires pour amplifier leur message, se promotionner 24 heures sur 24 ou mobiliser en temps réel des militants et récolter des fonds. Contournant les médias traditionnels pour ne pas être déstabilisé par les éditorialistes, un responsable politique s’exposera plus généreusement sur les réseaux sociaux pour devenir « rédacteur en chef » de sa propre campagne. En immersion de 2011 à 2017 sur le site de microblogging Twitter qui n’utilise que 140 caractères par message, j'essaie au travers de ma thèse de déterminer la place et la fonction de ce « média social », ainsi que son poids dans la construction de l’espace médiatique des prétendants à l’Élysée, notamment lors de la présidentielle française de 2012. Quels sont les enjeux des candidats sur le Web et que nous révèlent-ils sur les mises en scène du pouvoir ? Comment les professionnels des cellules de communication politique ont-ils pris possession de ces nouveaux outils qui accélèrent la temporalité des logiques institutionnelles et qui offrent aux militants un espace de réactivité aussi performant que celui d’un journaliste pour corriger les imprécisions des promesses de campagne ? Quelques éléments de réponses se trouvent dans les mots-clés : défiance, fact-checking, storytelling, Big Data, modélisations prédictives, irrévérence, infotainment, riposte-party et social-TV et dans les chiffres qui leur sont associés. / According to the psycho-technological model of the cultural industries, the ability to manage emotion to get voters’ constant attention in the infotainment sphere, remains one of the first objective in an electoral campaign strategy. However, the political Web contributes to the emergence of new forms of communication in electoral persuasion methods. The impact of a candidate’s media capital plays an important part online and as an extension offline. On the internet, the political class, effectively assisted by technical design experts whose job is specifically to deal with the profile of their identity, their reputation and their influence, have discovered new territories to amplify their message and to promote 24 hours a day, or to mobilize supporters in real time to raise funds. Circumventing traditional media rather than taking the risk of being destabilized by an editorialist, a political manager will choose to be more present on social media to become editor-in-chief of his or her own campaign. Totally immersed from 2011 to 2017 in website Twitter, to practice microblogging (140 characters), I try in my thesis to identify the position and the function of this « social media » as well as its value in the construction of presidential candidates, including during the French 2012 presidential election.What are the issues of the candidates who are present on the web sites and what do they reveal to us about the representation of power? How do the professionals of communication cells (the « cellcoms ») manage to take possession of these new communications tools that accelerate the temporality of institutional logics and offer to supporters an equivalent space to correct the imprecisions of campaign pledges?I suggest some answers to these questions that can be found in these keywords: suspicion, fact-checking, storytelling, Big Data, predictive modeling, irreverence, infotainment, riposte-party and social-TV as well as the associated figures presented in this thesis.

O câncer de colo do útero é o segundo tumor mais frequente entre as mulheres brasileiras, os tratamentos disponíveis trazem complicações de curto a longo prazo e estudos que avaliam a qualidade de vida destas mulheres ainda são escassos no Brasil. Isto é justificado pela falta de instrumentos específicos e validados para esta finalidade em língua portuguesa (Brasil). Neste estudo objetivou-se testar as propriedades psicométricas dos questionários EORTC QLQ-CX24 e FACT-CX em uma amostra de mulheres brasileiras com câncer do colo do útero. O estudo é metodológico e foi realizado com 100 mulheres tratadas no Hospital de Câncer de Barretos, por meio de três avaliações (no início do estudo, 15 dias e 18 a 24 meses após o início). Foi testada a consistência interna (alfa de Cronbach), reprodutibilidade (coeficiente de correlação intraclasse), validade convergente (correlação com o questionário SF-36 e com o questionário EORTC QLQ-C30), a validade discriminante pelo estadiamento, tipo de tratamento e autoclassificação de saúde e a responsividade pelo método de distribuição dos dados, além da análise da facilidade de compreensão das questões e dos questionários. Confirmou-se a confiabilidade do questionário EORTC QLQ-CX24, a reprodutibilidade foi baixa nas escalas de preocupação sexual, atividade sexual e prazer sexual, bons resultados observou-se ao avaliar a validade convergente e discriminante. A análise da responsividade não confirmou todas as hipóteses. Ao avaliar o questionário FACT-CX, por meio da consistência interna, exceto pela escala de bem-estar emocional, as demais apresentaram valores de Alpha de Cronbach superiores a 0,70. A reprodutibilidade foi satisfatória nas cinco escalas que compõem o FACT- CX. Na análise da validade convergente, somente as escalas de bem-estar físico e bem-estar emocional mostrou boa correlação com as escalas do SF-36. Em geral, o questionário revelou boa validade discriminante, principalmente em relação a autoclassificação da saúde. Resultado satisfatório encontrou-se na análise da responsividade. Em geral observou-se um bom grau de entendimento das questões e dos questionário. Concluindo os questionários desenvolvidos para medir a QVRS em mulheres com câncer de colo do útero EORTC QLQ-CX24 e FACT-CX obtiveram resultados aceitáveis recomendando-se que outros estudos testem a responsividade por outros métodos / Cervical cancer is the second most common tumor among Brazilian women. Available treatments bring short and long-term complications, and studies assessing the quality of life of these women are still rare in Brazil. Such situation is warranted by the lack of specific and validated tools in (Brazilian) Portuguese for such a purpose. The goal of this study was to test the psychometric properties of EORTC QLQ-CX24 and FACT-CX questionnaires in a sample of Brazilian women affected by cervical cancer. This is a methodological study and it was conducted on 100 women treated at the Barretos Cancer Hospital by way of three assessments (at baseline, 15 days and 18 to 24 months after the onset). We tested the internal consistency (Cronbach\'s alpha), reproducibility (intraclass correlation coefficient), convergent validity (correlation with the SF-36 questionnaire and the EORTC QLQ-C30 questionnaire), the discriminant validity by way of staging, type of treatment and health self-classification and responsiveness by the method of data distribution, as well as the analysis of how easy it was their understanding of questions and questionnaires. The reliability of the EORTC QLQ-CX24 questionnaire was confirmed, reproducibility was low in the scales of sexual worry, sexual activity and sexual enjoyment, and good results were observed when evaluating the convergent and discriminant validity. The analysis of responsiveness did not confirm all hypotheses. Upon evaluation of the FACT-CX questionnaire through internal consistency, except for the scale of emotional well-being, the others showed Cronbach\'s alpha values above 0.70. Reproducibility was satisfactory in the five scales comprising FACT-CX. In convergent validity analysis, only the scales of physical well-being and emotional well-being showed good correlation with the scales of the SF-36. In general, the questionnaire demonstrated good discriminant validity, especially in relation to the self-ratings of health. Satisfactory result was found in the analysis of responsiveness. In general there was a good degree of understanding of questions and questionnaires. In conclusion, questionnaires developed to measure HRQOL in women with cervical cancer such as EORTC QLQ-CX24 and FACT-CX achieved acceptable results, and we do recommended that further studies are performed to assess responsiveness by other methods

La diffusion des Fake News sur les réseaux sociaux est devenue un problème central ces dernières années. Notamment, hoaxy rapporte que les efforts de fact checking prennent généralement 10 à 20 heures pour répondre à une fake news, et qu'il y a un ordre de magnitude en plus de fake news que de fact checking. Le fact checking automatique pourrait aider en accélérant le travail humain et en surveillant les tendances dans les fake news. Dans un effort contre la désinformation, nous résumons le domaine de Fact Checking Automatique basé sur le contenu en 3 approches: les modèles avec aucune connaissances externes, les modèles avec un Graphe de Connaissance et les modèles avec une Base de Connaissance. Afin de rendre le Fact Checking Automatique plus accessible, nous présentons pour chaque approche une architecture efficace avec le poids en mémoire comme préoccupation, nous discutons aussi de comment chaque approche peut être appliquée pour faire usage au mieux de leur charactéristiques. Nous nous appuyons notamment sur la version distillée du modèle de langue BERT tinyBert, combiné avec un partage fort des poids sur 2 approches pour baisser l'usage mémoire en préservant la précision. / The spreading of fake news on social media has become a concern in recent years. Notably, hoaxy found that fact checking generally takes 10 to 20 hours to respond to a fake news, and that there is one order of magnitude more fake news than fact checking. Automatic fact checking could help by accelerating human work and monitoring trends in fake news. In the effort against disinformation, we summarize content-based automatic fact-checking into 3 approaches: models with no external knowledge, models with a Knowledge Graph and models with a Knowledge Base. In order to make Automatic Fact Checking more accessible, we present for each approach an effective architecture with memory footprint in mind and also discuss how they can be applied to make use of their different characteristics. We notably rely on distilled version of the BERT language model tinyBert, combined with hard parameter sharing on two approaches to lower memory usage while preserving the accuracy.

Recently, the Description Logic (DL) SHIQ has found a large number of applications. This success is due to the fact that SHIQ combines a rich expressivity with efficient reasoning, as is demonstrated by its implementation in DL systems such as FaCT and RACER. One weakness of SHIQ, however, limits its usability in several application areas: numerical knowledge such as knowledge about the age, weight, or temperature of real-world entities cannot be adequately represented. In this paper, we propose an extension of SHIQ that aims at closing this gap. The new Description Logic Q-SHIQ, which augments SHIQ by additional, 'concrete domain' style concept constructors, allows to refer to rational numbers in concept descriptions, and also to define concepts based on the comparison of numbers via predicates such as < or =. We argue that this kind of expressivity is needed in many application areas such as reasoning about the semantic web. We prove reasoning with Q-SHIQ to be EXPTIME-complete (thus not harder than reasoning with SHIQ) by devising an automata-based decision procedure.

Submitted by Filipe dos Santos (fsantos@pucsp.br) on 2018-04-06T12:55:35Z No. of bitstreams: 1 Desirèe Luíse Lopes Conceição.pdf: 2748185 bytes, checksum: c467bc5ad86bb59233d0a5e34244958c (MD5) / Made available in DSpace on 2018-04-06T12:55:35Z (GMT). No. of bitstreams: 1 Desirèe Luíse Lopes Conceição.pdf: 2748185 bytes, checksum: c467bc5ad86bb59233d0a5e34244958c (MD5) Previous issue date: 2018-02-21 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / This dissertation aims to analyze the political information produced and disseminated by the digital platform “Truco!”, which is Agência Pública’s fact-checking project developed for the 2014 election in order to identify and ascertain the political debate taking place. The methodology adopted is based on the network policy concept of the author Manuel Castells, and consists of an elaboration for primary data collection, defined from the interactions and linked to the initial proposal of this research. The results recognize qualitative investigative journalism work with political participation activities, and it’s possible to relate them to the idea that the internet has elements to contribute to citizen education / A dissertação tem por objetivo analisar a produção e divulgação de informação política na plataforma digital “Truco!”, um projeto de fact-checking da Agência Pública desenvolvido para as eleições de 2014, além de identificar e averiguar o debate político ocorrido por meio da iniciativa. A metodologia adotada é baseada no conceito de política em rede do autor Manuel Castells. A técnica metodológica consistiu na elaboração de indicadores para a coleta de dados primários, definidos a partir de uma análise piloto e da identificação de padrões de interação relacionados à proposta inicial da pesquisa. Os resultados permitem identificar um trabalho de jornalismo investigativo qualitativo, além da presença de atividades de colaboração e participação política, o que aponta à concepção de que a internet contém elementos para contribuir com a formação para a cidadania

Made available in DSpace on 2016-08-19T18:16:05Z (GMT). No. of bitstreams: 1 Dissertacao Karla.pdf: 856285 bytes, checksum: fcc2f4b0c80fa2c3867dcc02058c15a5 (MD5) Previous issue date: 2012-06-18 / The effects of the treatment of breast cancer on the quality of life have been widely discussed in the literature. However, little is known about the subject in northeastern Brazil. The purposewasto evaluatethequality of life of patients treated for breast cancer in Sao Luis, MA. We conducted a cross-sectional study with 197 women Who underwent breast surgery and were attended in a Oncology Reference Hospital in Maranhao. The study included women treated unilaterally, regardless of adjuvant therapy conducted or in progress, no other malignancy. The sociodemographic variables studied were: age, education, marital status, ethnicity and number of children. Variables related to treatment were type of surgery, time since surgery and neo-adjuvant and adjuvant therapy. Quality of life was assessed using the FACT-B, applied in one step by a team of trained researchers. The variables were presented as Mean and Standard Deviation. For the classification groups with more than three classes, we used the ANOVA orKruskal Wallis. For those with only two classes, we applied Student's t test when there was a normal distribution or Mann-Whitney test for nonparametric variables. To check the correlation between them and the scores of the domains, we applied the Pearson linear correlation test. The significance level adopted for all tests was &#945; less than or equal to 0,05.Withanaverage age of 53.02 years (SD ± 11,71), white (44,67%), school (46,19%), married or in consensual union (57,87%) and average of 3,17 children (SD±2,73), women underwent mastectomy (63,46%) or breast conserving surgery (36,54 %), less than 6 years of surgery (92,90%). Neo-adjuvant therapies were not adopted in the majority (86,30%), but 92,38% received adjuvant therapies. The average values through the FACT-B showed a tendency to good quality of life, and the Functional Domain was the most committed and the total score, the less committed. Age, education, marital status, ethnicity, type and duration of surgery and adjuvant therapies influenced the quality of life in at least one Domain or Score of questionnaire, and the relationships were more marked with the sub-scale breast cancer (p=0,0001) and the FACT-B total score (p=0,0001) and adjuvant therapy with sub-scale breast cancer (p<0,0001). Pearson said there was a positive correlation between Domains and the questionnaire Scores. Qualityoflifewas relatively good, but was negatively influenced by mastectomy, the shortest time since the surgery and adjuvant therapies. / Os efeitos do tratamento do câncer de mama sobre a qualidade de vida têm sido amplamente discutidos na literatura, entretanto, pouco se conhece sobre o assunto no Nordeste do Brasil. O objetivo deste estudo foi avaliar a qualidade de vida das pacientes tratadas de câncer de mama no município de São Luís-MA. Foi realizado um estudo de corte transversal com 197 mulheres submetidas a tratamento cirúrgico para o câncer de mama, assistidas no Instituto Maranhense de Oncologia Hospital Aldenora Bello. Foram incluídas no estudo, mulheres tratadas unilateralmente, independente da terapia coadjuvante realizada ou em andamento, sem outra neoplasia As variáveis sócio-demográficas estudadas foram: idade, escolaridade, estado civil, etnia e número de filhos. As variáveis relacionadas ao tratamento foram tipo de cirurgia, tempo desde a cirurgia e terapias neo-adjuvantes e adjuvantes. A qualidade de vida foi avaliada através do FACT-B, aplicado em etapa única por uma equipe de pesquisadores treinados. Para os grupos de variáveis com mais de três classes, foi utilizada a Anova ou Kruskal Wallis. Para aqueles de apenas duas classes, aplicou-se Teste t de Student quando houve distribuição normal ou Mann-Whitney para as variáveis não-paramétricas. Para verificação de Correlação entre si dos Domínios e dos Escores, foi aplicado o teste de Correlação Linear de Pearson. Os níveis de significância adotados para todos os testes foi de &#945; menor ou igual a 0.05. As mulheres apresentaram média de 53,02 anos (DP±11,71), tinham cor branca (44,67%), estavam no ensino fundamental (46,19%), eram casadas ou em união consensual (57,87%) e com uma média de 3,17 filhos (DP±2,73). Quanto à cirurgia, a maioria realizou tratamento radical (mastectomia) (63,46%) e um terço, cirurgia conservadora (36,54%) há menos de 6 anos (92,90%). Terapias neo-adjuvantes não foram adotadas na maioria (86,30%), porém 92,38% receberam tratamento adjuvante. Os valores médios encontrados através do FACT-B demonstram uma tendência para boa qualidade de vida, sendo que o Domínio Funcional foi o mais comprometido e o Escore Total, menos comprometido. Idade, escolaridade, estado civil, etnia, tipo e tempo de cirurgia e terapias adjuvantes influenciaram a qualidade de vida em pelo menos um Domínio ou Escore do questionário, sendo que as relações mais marcantes foram idade com a sub-escala câncer (p=0,0001) e com o escore total FACT-B (p=0,0001) e das terapias adjuvantes com a subescala câncer de mama (p<0,0001). A qualidade de vida encontrada foi relativamente boa, mas foi influenciada negativamente pela mastectomia, pelo menor tempo desde a cirurgia e pelas terapias adjuvantes.

FACT est une protéine clé, qui joue de multiples rôles, y compris dans la transcription et la réparation de l'ADN endommagé. Néanmoins, comment FACT participe à la réparation et à la transcription de la chromatine n'est pas élucidé. Dans ce travail nous avons tout d'abord étudié le rôle de FACT dans le processus de réparation par excision de base (BER). Nous avons utilisé des nucléosomes reconstitués avec de l'ADN à uracile incorporé au hasard. Nous avons trouvé que l'enzyme UDG est capable d'enlever les uraciles localisés du côté de la solution et pas les uraciles se trouvant en face de l'octamère d'histone. La présence simultanée de FACT et de RSC (facteur de remodelage de la chromatine, impliqué dans la réparation) permet un enlèvement efficace des uraciles localisés du côté de l'octamère d'histone par l'UDG. De plus, l'action concertée de FACT et RSC contribue à l'enlèvement de la lésion oxidative 8-oxoG, autrement inaccessible, de la matrice nucléosomale par l'enzyme OGG1. Ce résultat est obtenu grâce à une activité « co-remodelatrice » de la protéine FACT. Dans ce travail nous décrivons pour la première fois cette nouvelle propriété de FACT et nous montrons par une série d'expériences biochimiques que FACT est capable de stimuler l'activité de remodelage du RSC. Nos expériences montrent que la présence de FACT augmente l'efficacité de RSC à transformer l'énergie libérée par l'hydrolyse de l'ATP en travail « mécanique ». Les données obtenues suggèrent une nature stochastique du BER in vivo, FACT étant un facteur clé dans le processus de réparation. Nous avons également investigué l'implication de l'activité co-remodelatrice de FACT dans la fixation de NF-kB aux matrices nucléosomales. La production de nucléosomes remodelés, mais non - mobilisés (remosomes) n'est pas suffisante pour promouvoir la fixation de NF-kB. Pourtant, la mobilisation des nucléosomes par l'intermédiaire de RSC permet une interaction efficace entre NF-kB et l'ADN nucléosomal. Toutes ces données sont essentielles pour le décryptage du mécanisme moléculaire par lequel FACT agit dans le BER et dans la transcription médiée par NF-kB. / FACT is a vital protein which has multiple roles including one in transcription and repair of damaged DNA. However, how FACT assists repair and transcription remains elusive. In this work, we have first studied the role of FACT in Base Excision Repair (BER). We used nucleosomes containing DNA with randomly incorporated uracil. We found that the enzyme UDG is able to remove uracils facing the solution and not the uracils facing the histone octamer. The simultaneous presence of FACT and RSC (a chromatin remodeler involved in repair) allows, however, a very efficient removal of uracil facing the histone octamer by UDG. In addition, the concerted action of FACT and RSC permits the removal of the otherwise un-accessible oxidative lesion 8-oxoG from nucleosomal templates by OGG1. This was achieved thanks to the co-remodeling activity of FACT. Here we described for the first time this novel property of FACT and we show in a series of biochemical experiments that FACT is able to boost the remodeling activity of RSC. The experiments reveal that the presence of FACT increases the efficiency of RSC to transform the energy freed by ATP hydrolysis into “mechanical” work. The presented data suggest a stochastic nature of BER functioning in vivo, FACT being a key factor in the repair process. The implication of the co-remodeling activity of FACT in NF-kB factor binding to nucleosomal templates was also investigated. The generation of remodeled, but not mobilized nucleosomes (remosomes), was not sufficient to promote NF-kB binding. However, the RSC-induced nucleosome mobilization allows efficient NF-kB interaction with nucleosomal DNA. Our data are instrumental in deciphering the molecular mechanism of FACT implication in BER and NF-kB mediated transcription.

L’intégrase (IN) du VIH-1 est une enzyme clé du cycle viral catalysant l’insertion stable de l’ADN viral dans le génome de la cellule infectée. L’IN participe également à de nombreuses étapes du cycle viral telles que la transcription inverse ou la maturation virale. Ainsi, la compréhension des mécanismes régulant l’intégration du VIH-1 représente un enjeu majeur dans le cadre notamment d’approches thérapeutiques. En effet, les études montrent que ces mécanismes sont finement régulés dans la cellule par des facteurs viraux et cellulaires agissant à différentes étapes du cycle viral. C’est donc dans ce contexte que nous avons étudié les facteurs à la fois viraux et cellulaires régulant ce processus. Dans un premier temps, les déterminants viraux modulant l’intégration dans la chromatine ont été analysés dans le cas de plusieurs modèles rétroviraux. Puis, dans un second temps, nous avons étudié l’impact de facteurs cellulaires, identifiés au laboratoire, sur les mécanismes d’insertion de l’ADN viral dans le génome cellulaire. Mon travail de thèse s’est ainsi articulé en trois axes majeurs aboutissant à : ● La démonstration de la régulation de l’intégration rétrovirale par la structure chromatinienne de l’hôte ● L’identification de nouveaux cofacteurs cellulaires participant à la régulation de l’intégration dans la chromatine dont le complexe de remodelage FACT « Facilitates Chromatin Transcription » ● L’identification d’une nouvelle interaction fonctionnelle entre l’IN du VIH-1 et la queue amino-terminale de l’histone humaine H4 et de son rôle dans la sélectivité de l’intégration / HIV-1 integrase (IN) is a key enzyme of the viral cycle that catalyzes the stable insertion of viral DNA into the genome of the infected cell. IN also participates in many stages of the viral cycle such as reverse transcription or viral maturation. Thus, an understanding of the mechanisms regulating the integration of HIV-1 is a major challenge, particularly in the context of therapeutic approaches. Indeed, studies show that these mechanisms are finely regulated in the cell by viral and cellular factors acting at different stages of the viral cycle. It is in this context that we studied both viral and cellular factors regulating this process. Initially, the viral determinants modulating the integration in chromatin were analyzed in the case of several retroviral models. Then, we studied the impact of cellular factors, identified in the laboratory, on the mechanisms of insertion of the viral DNA in the cellular genome. My thesis work has thus been articulated in three major axes leading to: • The demonstration of the regulation of retroviral integration by the chromatin structure of the host • The identification of new cellular cofactors participating in the regulation of chromatin integration, including the FACT remodeling complex "Facilitates Chromatin Transcription" • The identification of a new functional interaction between the HIV-1 IN and the amino-terminal tail of human H4 histone and its role in the selectivity of integration.