Este trabalho tem como objetivo auxiliar os institutos de pesquisa, notadamente o IPEN, a melhorar a assertividade do processo de definição de suas linhas de pesquisa. Novas velocidades evolutivas que aumentam exponencialmente exigem maior sincronia e ação múltipla e coordenada dos três elementos fundamentais para o desenvolvimento das sociedades contemporâneas: o governo, a estrutura produtiva e a infra-estrutura científica e tecnológica. Esse ambiente cada vez mais dinâmico e mutante impõe uma maior proximidade com o meio socioeconômico que passa de cliente-consumidor à do co-criador do conhecimento e fornecedor de energia agora contida em um novo padrão de relações sociais, denominado Sociedade em Rede. A diferença nos tempos da Universidade, da Estrutura Produtiva e do Governo é função do tempo de suas atividades centrais: a Ciência, o Mercado e a conquista da Opinião Pública, respectivamente. A equação que harmoniza e encontra sinergias entre as três dimensões é o desafio contemporâneo daqueles que procuram inovar e avançar no conhecimento em prol da sociedade. Neste trabalho procura-se mostrar que a saída para os institutos de pesquisa está em acreditar na frase de Robert Plomin e procurar conectar-se ao diferentes elos das cadeias para fazer uso de uma inteligência coletiva que se expande em velocidade e qualidade superiores a qualquer outro momento na história da humanidade. A comparação dos resultados obtidos com a aplicação de diferentes metodologias de análise permite mostrar os pontos fortes e pontos de atenção, ameaças e oportunidades do IPEN fornecendo subsídios para encontrar o melhor modo para adequar seu desempenho às novas demandas. / This work aims to assist research institutes, notably the IPEN, in order to improve their assertiveness in the process of defining their research lines. New evolutionary speeds have increased exponentially requiring greater synchronism and multiple and coordinated action from the three fundamental elements in order to assure the development of the contemporary society: Government, Productive Structure and Infrastructure in Science and Technology. This environment increasingly dynamic and mutant imposes greater proximity with the socioeconomic environment when former client-consumer has become the co-creator of knowledge and supplier of energy now contained in a new standard of social relations, called Networked Society. The difference in time for the University, the Productive Structure and Government is function of its main activities: Science, Market and the achievement of Public Opinion, respectively. The equation that will harmonize and find synergies between these three dimensions is the contemporary challenge for those who seek to innovate and advance knowledge in order to improve the standard of living of the society. In this work is shown that research institutes must believe in the words of Robert Plomin and start connecting to the several links in different chains in order to make use of a collective intelligence that continuously expands in speed and quality higher than in any other time in human history. The comparison among the results obtained from the different methodologies of analysis proposed in this work allows finding out strengths and weaknesses, threats and opportunities of the IPEN providing subsidies in order to find better ways to tailor its performance to the new demands.

Este trabalho tem como objetivo auxiliar os institutos de pesquisa, notadamente o IPEN, a melhorar a assertividade do processo de definição de suas linhas de pesquisa. Novas velocidades evolutivas que aumentam exponencialmente exigem maior sincronia e ação múltipla e coordenada dos três elementos fundamentais para o desenvolvimento das sociedades contemporâneas: o governo, a estrutura produtiva e a infra-estrutura científica e tecnológica. Esse ambiente cada vez mais dinâmico e mutante impõe uma maior proximidade com o meio socioeconômico que passa de cliente-consumidor à do co-criador do conhecimento e fornecedor de energia agora contida em um novo padrão de relações sociais, denominado Sociedade em Rede. A diferença nos tempos da Universidade, da Estrutura Produtiva e do Governo é função do tempo de suas atividades centrais: a Ciência, o Mercado e a conquista da Opinião Pública, respectivamente. A equação que harmoniza e encontra sinergias entre as três dimensões é o desafio contemporâneo daqueles que procuram inovar e avançar no conhecimento em prol da sociedade. Neste trabalho procura-se mostrar que a saída para os institutos de pesquisa está em acreditar na frase de Robert Plomin e procurar conectar-se ao diferentes elos das cadeias para fazer uso de uma inteligência coletiva que se expande em velocidade e qualidade superiores a qualquer outro momento na história da humanidade. A comparação dos resultados obtidos com a aplicação de diferentes metodologias de análise permite mostrar os pontos fortes e pontos de atenção, ameaças e oportunidades do IPEN fornecendo subsídios para encontrar o melhor modo para adequar seu desempenho às novas demandas. / This work aims to assist research institutes, notably the IPEN, in order to improve their assertiveness in the process of defining their research lines. New evolutionary speeds have increased exponentially requiring greater synchronism and multiple and coordinated action from the three fundamental elements in order to assure the development of the contemporary society: Government, Productive Structure and Infrastructure in Science and Technology. This environment increasingly dynamic and mutant imposes greater proximity with the socioeconomic environment when former client-consumer has become the co-creator of knowledge and supplier of energy now contained in a new standard of social relations, called Networked Society. The difference in time for the University, the Productive Structure and Government is function of its main activities: Science, Market and the achievement of Public Opinion, respectively. The equation that will harmonize and find synergies between these three dimensions is the contemporary challenge for those who seek to innovate and advance knowledge in order to improve the standard of living of the society. In this work is shown that research institutes must believe in the words of Robert Plomin and start connecting to the several links in different chains in order to make use of a collective intelligence that continuously expands in speed and quality higher than in any other time in human history. The comparison among the results obtained from the different methodologies of analysis proposed in this work allows finding out strengths and weaknesses, threats and opportunities of the IPEN providing subsidies in order to find better ways to tailor its performance to the new demands.

La 5-azacytidine (AZA) est un médicament approuvé pour le traitement des leucémies myéloïdes aiguës des patients qui ne sont pas éligibles à une greffe de cellules souches hématopoïétiques. Bien que l’AZA est augmenté significativement le pronostic des patients, le mécanisme d’action précis de l’AZA demeure nébuleux. En plus de son activité d’hypométhylation, il a été montré que l’AZA a aussi des effets immunologiques. Des études précédentes suggèrent que ces réponses immunitaires sont causées par des modifications du répertoire de peptides présentés par le CMH-I (MAPs), dont l’expression de MAPs dérivés de rétroéléments endogènes (EREs) et des cancer-testis antigens (CTAs). Ces gènes sont généralement réprimés par la méthylation de l’ADN. Dans cette thèse, nous avons testé cette hypothèse à l’aide de séquençage à haut débit et de spectrométrie de masse appliqués à quatre lignées cellulaires d’AML différentes. Notre approche protéogénomique d’avant-garde a révélé que l’AZA induit la présentation de MAPs dérivés de CTAs, mais pas d’EREs, malgré le fait que ces deux groupes de séquences soient surexprimés au niveau transcriptomique. Ces résultats indiquent que les réponses des lymphocytes T observées chez les patients suite au traitement à l’AZA dépendent probablement des MAPs dérivés des CTAs, et non pas des EREs. Les EREs stimulés par l’AZA ont tout de même un impact sur la réponse immunitaire en formant des ARN double-brins menant à une activation de l’immunité innée. L’incorporation de l’AZA et l’inhibition subséquente de la DNMT2 mène cependant à des agrégats protéiques et à l’autophagie, qui dégrade les transcrits EREs et limite leur surexpression. Nous avons démontré que les effets immunologiques de l’AZA peuvent être amplifiés par un traitement combiné de l’AZA et d’inhibiteurs de l’autophagie. De plus, le travail contenu dans cette thèse a montré que bien qu’elles soient un modèle expérimental pratique, les lignées cellulaires ont des limitations et doivent être utilisés avec prudence. Des différences majeures ont été observées entre des lignées cellulaires supposément identiques provenant de fournisseurs établis. Nos analyses ont permis de démontrer quelle lignée cellulaire était la plus similaire à la lignée parentale. Ainsi, ce travail fourni des recommandations pour améliorer les lignes directrices d’utilisation des lignées cellulaires en recherche. / 5-azacytidine (AZA) is approved for the treatment of acute myeloid leukemia (AML) patients ineligible for hematopoietic cell transplantation. Although AZA treatment has substantially improved patient outcomes, there remains a lack of clear understanding of the mechanisms driving these responses. In addition to its hypomethylating activity, AZA has been shown to have immunological effects. Previous reports suggest that these immune responses occur due to alterations in the repertoire of MHC-I-associated peptides (MAPs), including the expression of MAPs deriving from endogenous retroelements (EREs) and cancer-testis antigens (CTAs). These genes are typically silenced by methylation. With this thesis, we aimed to test this hypothesis using high-coverage RNA sequencing and mass spectrometry in four different AML cell lines. Our state-of-the-art proteogenomic approach uncovered that AZA treatment induced MAPs deriving from CTAs, but not EREs, despite both being upregulated at the RNA level. This indicates that T-cell responses post-AZA treatment are more likely to be dependent on CTA- than ERE-derived MAP presentation. AZA-induced EREs produced at the RNA level still contributed to immune responses by forming double-stranded RNA leading to a state of viral mimicry. However, AZA incorporation into RNA and subsequent DNMT2-inhibition led to protein aggregation and autophagy responses. These responses were responsible for degrading EREs, which limited their upregulation. We further demonstrate that the immune effects of AZA can be enhanced by the combination of AZA with autophagy inhibitors. Additionally, the work in this thesis has shown that although a practical model, cell lines have their caveats and must be used with caution. This work has highlighted the grave discrepancies between supposedly identical cell lines supplied by established repositories. Moreover, our analyses determine which of the two is closer to the parental cell line. Finally, this work provides recommendations for improving the current guidelines for cell line-based research.