No description available.

Neste trabalho, estudamos Loops de Código. Para este estudo, introduzimos os loops de código a partir de códigos pares e depois, provamos que loops de código de posto $n$ podem ser caracterizados como imagem homomórfica de certos loops de Moufang livres com n geradores. Além disso, introduzimos o conceito de vetores característicos associados a um loop de código. Com os resultados da teoria estudada, classificamos todos os loops de código de posto 3 e 4, encontramos todos os grupos de automorfismos externos destes loops e, finalmente, determinamos todas as suas respectivas representações básicas. / This work is about code loops. For this study, we introduce the code loops from even codes and then we prove that code loops of rank n can be characterized as a homomorphic image of a certain free Moufang loops with $n$ generators. Moreover, we introduce the concept of characteristic vectors associated with code loops. With the results of this theory, we classify all the code loops of rank 3 and 4, we find all the groups of outer automorphisms of these loops and finally we determine all their basic representations.

Este trabalho é sobre as geométrias finitas com 3 ou 4 pontos na cada reta e os loops e qiasigrupos relacionados. Em caso de 3 pontos na cada reta descrevemos o loop de Steiner correspondente livre e calculamos o grupo de automorfismos em caso de 3 geradores livres. Além disso descrevemos os loopos de Steiner nilpotentes de clase dois e classificamos estes loopos com 3 geradores. Em caso de 4 pontos na cada reta construimos as geometrias novas atraves de expanção central de um análogo não comutativo do quasigrupo de Steiner. Temos fortes indícios que esta construção é universal em algum sentido. / This work is about finite geometries with 3 or 4 points on every line and related loops and quasigroups. In the case of 3 points on any line we describe the structure of free loops in the variety of corresponding Steiner loops and we calculate the group of automorphisms of free Steiner loop with three generators. We describe the structure of nilpotent class two Steiner loops and classifiy all such loops with three generators. In the case of 4 points on a line we constructe new series of such geometries as central extension of corresponding non-commutative Steiner quasigroups. We conjecture that those geometries are universal in some sense.

Neste trabalho, estudamos Loops de Código. Para este estudo, introduzimos os loops de código a partir de códigos pares e depois, provamos que loops de código de posto $n$ podem ser caracterizados como imagem homomórfica de certos loops de Moufang livres com n geradores. Além disso, introduzimos o conceito de vetores característicos associados a um loop de código. Com os resultados da teoria estudada, classificamos todos os loops de código de posto 3 e 4, encontramos todos os grupos de automorfismos externos destes loops e, finalmente, determinamos todas as suas respectivas representações básicas. / This work is about code loops. For this study, we introduce the code loops from even codes and then we prove that code loops of rank n can be characterized as a homomorphic image of a certain free Moufang loops with $n$ generators. Moreover, we introduce the concept of characteristic vectors associated with code loops. With the results of this theory, we classify all the code loops of rank 3 and 4, we find all the groups of outer automorphisms of these loops and finally we determine all their basic representations.

Les cellules sont constamment exposées à des agents endommageant de l'ADN d'origine exogène, notamment les rayons ultraviolets, les irradiations γ, et l'exposition aux agents chimiques génotoxiques, mais également d'origine endogène générés par le métabolisme cellulaire. De plus en plus d'évidences montrent que la transcription est un processus biologique qui peut mettre en péril l'intégrité du génome. Un mécanisme actuellement très étudié qui lie la transcription à l'instabilité génomique est la formation des boucles R (R-loops), des structures hybrides ARN:ADN qui exposent un ADN simple brin déplacé. Ces structures aberrantes se présentent en tant que sous-produits de la transcription et/ou lors de l'interférence entre la réplication et la transcription, et plus récemment ils ont été montrées s'accumuler lorsque la biogénèse de l'ARNm est perturbée. La persistance des boucles R est une source importante d'instabilité génomique car elle peut générer des cassures double brin de l'ADN et favoriser la recombinaison. Pour faire face aux conséquences néfastes des endommagements de l'ADN, les cellules activent une cascade élaborée de voies de signalisation qui permet de coordonner la prolifération cellulaire avec la réparation de l'ADN. L'ensemble de ces acteurs moléculaires constitue un réseau de réponse aux dommages de l'ADN qui est indispensable pour la stabilité génomique. Récemment chez la levure, l'activation transitoire de ce réseau a été également proposée être important dans la coordination de la transcription et de la réplication, afin d'éviter d'une part des contraintes topologiques et d'autre part la formation de structures aberrantes générées lors de conflits entre ces deux processus cellulaires essentiels. Dans la perspective d'identifier des nouveaux gènes impliqués dans ce réseau de signalisation, un crible fonctionnel in vitro précédemment établi au laboratoire a conduit à l'identification de Ddx19, une hélicase à motif DEAD-box, en tant que nouvel élément répondant à l'endommagement de l'ADN. Ddx19 interagit avec le pore nucléaire via CAN/Nup214, et il est impliqué dans l'export des ARNm grâce à son activité hélicase et ATPase, stimulé par les facteurs IP6 et Gle1. Le présent travail de thèse dévoile une nouvelle fonction de Ddx19 distincte de son rôle connu dans l'export de l'ARNm. Je pu montrer que, lors de l'induction des dommages à l'ADN par les rayons UV, Ddx19 se relocalise transitoirement de la face cytoplasmique du nucléopore vers le noyau de façon dépendant d'ATR. L'inactivation de Ddx19 entraîne des endommagements spontanées dépendant de la prolifération, démontré par l'activation de la voie de signalisation d'ATM-Chk2 et la formation de foyers nucléaires de γH2AX et 53BP1. Ces phénotypes sont concomitants avec le ralentissement des fourches de réplication qui ne peuvent plus redémarrer après leur blocage par la camptothécine. En outre, les cellules déplétées de Ddx19 présentent une forte accumulation des boucles R nucléaires, enrichi dans le compartiment nucléolaire, et aussi autour de la périphérie nucléaire. Par ailleurs, ces cellules présentent une viabilité réduite et une létalité synthétique lorsque la déplétion de Ddx19 est combinée avec l'inhibition de l'expression de la topoisomérase I. Je propose Ddx19 comme deuxième hélicase nécessaire pour la résolution des boucles R, et qui fonctionne à côté mais de façon indépendante de la Senataxin, l'hélicase précédemment connue pour résoudre ces structures in vivo chez les cellules de mammifères. Je démontre que cette nouvelle fonction de Ddx19 ne dépend pas de son interaction avec le pore nucléaire, mais plutôt de son activité hélicase et d'un résidu de sérine phosphorylée par Chk1 qui stimule sa relocalisation vers le noyau. Ces données proposent Ddx19 en tant que nouvelle ARN hélicase qui facilite la coordination de la réplication et la transcription, médiée par ATR à travers de la résolution des boucles R, préservant ainsi l'intégrité du génome. / Cells are continuously challenged by DNA damage resulting from external cues as UV light, γ-irradiation and exposure to genotoxic chemicals, as well as from endogenous stress caused by cellular metabolism. Growing evidence points to transcription as a biological process that could adversely affect genome integrity. One currently highly investigated mechanism by which transcription can induce genome instability is through the formation of R-loops, RNA:DNA hybrid structures exposing a displaced single-stranded DNA tract. These aberrant structures occur as byproducts of transcription and/or upon interference between replication and transcription, and more recently were also shown to accumulate upon disruption of mRNA biogenesis and processing. Persistent unresolved R-loops are a potent source of genomic instability as they ultimately generate double strand breaks and promote recombination events. To deal with the deleterious consequences of DNA damage, cells activate elaborate DNA damage response (DDR) pathways to delay cell division and stimulate repair of lesions, thus preserving genome stability. Recently in yeast transient DDR activation has also been proposed to be important in the coordination of transcription and replication, in order to avoid topological constraints and the formation of aberrant structures generated upon collision of their machineries. By means of an in vitro screen aimed at identifying new DDR genes, we isolated Ddx19, a DEAD-Box helicase known to be involved in mRNA export, as a novel DNA damage responsive gene. Ddx19 interacts with the nucleopore complex via nucleoporin CAN/Nup214, and is involved in mRNA remodelling and export through its ATPase and helicase activities, stimulated by IP6 and the Gle1 factor. My present thesis work unravels a novel function of Ddx19 in preserving genome stability in mammalian cells, distinct from its known role in mRNA export. I show that upon UV-induced damage, Ddx19 transiently relocalizes from the cytoplasmic face of the nucleopore to the nucleus in an ATR-dependent manner. Downregulation of Ddx19 gives rise to spontaneous, proliferation-dependent DNA damage, as determined by the specific activation of the ATM-Chk2 pathway and formation of γH2AX and 53BP1 nuclear foci. This is concomitant with the slowing down of replication forks that are unable to restart after being stalled with camptothecin. In addition, cells depleted of Ddx19 display strong accumulation of nuclear R-loops, enriched in the nucleolar compartment, and around the nuclear periphery. Moreover, these cells show low viability and exhibited synthetic lethality when combined with inhibition of topoisomerase I expression. I propose Ddx19 as a second helicase required for R-loops resolution, functioning alongside but independently of Senataxin, the first known RNA helicase to resolve these structures in vivo in mammalian cells. I provide evidence that this new function of Ddx19 does not depend on its interaction with the nuclear pore, but rather on its helicase activity and on a serine residue phosphorylated by Chk1 which promotes its relocalization into the nucleus upon damage. These data put forward Ddx19 as a novel RNA helicase that facilitates ATR-dependent coordination of DNA replication and transcription through R-loops resolution, thus preserving genome integrity.

Les R-loops générés durant la transcription sont impliqués dans de nombreuse fonctions incluant la réplication, la recombinaison et l’expression génique tant chez les procaryotes que chez les eucaryotes. Plusieurs études ont montré qu’un excès de supertours négatifs et des séquences riches en bases G induisent la formation de R-loops. Jusqu’à maintenant, nos résultats nous ont permis d’établir un lien direct entre les topoisomérases, le niveau de surenroulement et la formation de R-loops. Cependant, le rôle physiologique des R-loops est encore largement inconnu. Dans le premier article, une étude détaillée du double mutant topA rnhA a montré qu’une déplétion de RNase HI induit une réponse cellulaire qui empêche la gyrase d’introduire des supertours. Il s’agit ici, de la plus forte évidence supportant les rôles majeurs de la RNase HI dans la régulation du surenroulement de l’ADN. Nos résultats ont également montré que les R-loops pouvaient inhiber l’expression génique. Cependant, les mécanismes exacts sont encore mal connus. L’accumulation d’ARNs courts au détriment d’ARNs pleine longueur peut être causée soit par des blocages durant l’élongation de la transcription soit par la dégradation des ARNs pleine longueur. Dans le deuxième article, nous montrons que l’hypersurenroulement négatif peut mener à la formation de R-loops non-spécifiques (indépendants de la séquence nucléotidique). La présence de ces derniers, engendre une dégradation massive des ARNs et ultimement à la formation de protéines tronquées. En conclusion, ces études montrent l’évidence d’un lien étroit entre la RNase HI, la formation des R-loops, la topologie de l’ADN et l’expression génique. De plus, elles attestent de la présence d’un nouvel inhibiteur de gyrase ou d’un mécanisme encore inconnu capable de réguler son activité. Cette surprenante découverte est élémentaire sachant que de nombreux antibiotiques ciblent la gyrase. Finalement, ces études pourront servir également de base à des recherches similaires chez les cellules eucaryotes. / R-loops generated during transcription elongation are implicated in many DNA reactions, including replication, recombination and gene expression both in prokaryotes and in eukaryotes. Many studies have shown that negative supercoils excess and G-rich sequences induce the formation of R-loops. Up to now, our results allow us to establish a direct link between topoisomerases, supercoiling level, and the formation of R-loops. However, what the physiological significance, if any, of R-loops is still largely unknown. In the first article, a detailed study on double topA rnhA mutants showed that the depletion of RNase HI activity induces a cellular response which renders gyrase unable to perform supercoils. This is the first evidence implicating RNase HI as a major player in DNA supercoiling regulation. Our results also show that R-loops formation can lead to the inhibition of gene expression. However, the exact mechanism(s) leading to the inhibition of gene expression are not yet understood. The accumulation of shorter than full length RNAs could be caused by road-blocks during transcription elongation or by the degradation of full length RNAs. In the second article, we show that hypernegative supercoiling can lead to sequence independent R-loop formation. The physiological consequence is extensive RNA degradation which ultimately culminates in the formation of truncated proteins. In conclusion, this study clearly shows a close link between RNase HI activity, R-loop formation, DNA topology and gene expression. In addition, this study also provides some evidence for the synthesis of a gyrase inhibitor that can regulate gyrase activity directly or indirectly via unidentified mechanisms. This surprising observation is still preliminary taking into consideration that many antibiotics target gyrase. Finally results from this study could open up avenues for research in eukaryotes.

Aplicações podem apresentar laços perfeitamente aninhados que demandam um alto poder de processamento. Diversas aplicações científicas contêm laços aninhados em suas estruturas. Tais laços podem processar computações heterogêneas. Uma solução para reduzir o tempo de execução desta classe de aplicações é a paralelização destes laços. A heterogeneidade dos tempos de execução de computações presentes nas iterações de laços perfeitamente aninhados demanda uma paralelização adequada visando uma distribuição de carga homogênea entre os recursos computacionais para reduzir a ociosidade de tais recursos. Esta heterogeneidade implica em um número ideal de recursos computacionais a partir do qual, o seu aumento não impactaria no ganho de desempenho, uma vez que, o tempo mínimo possível é o tempo de execução da tarefa que consome o maior tempo de processamento. Neste trabalho é proposta uma metodologia e ferramentas para paralelização de laços perfeitamente aninhados sem dependência de dados e com processamento heterogêneo em sistemas paralelos e distribuídos. A implementação da metodologia proposta em aplicações melhora o desempenho da execução e reduz a ociosidade dos recursos de processamento. Na metodologia proposta, alguns procedimentos são apoiados por ferramentas desenvolvidas para auxiliá-los. O sistema de processamento poderá ser: um computador Multicore, um Cluster real ou virtual alocado na nuvem. Resultados experimentais são apresentados neste trabalho. Tais resultados mostram a viabilidade e eficiência da metodologia proposta. / Applications may have nested perfectly loops that require a high processing power. Various scientific applications contain nested loops in their structures. Such loops can process heterogeneous computations. A solution to reduce the execution time of this class of applications is the parallelization of these loops. The heterogeneity of the execution times of computations present in the iterations of nested perfectly loops demands an adequate parallelization aiming at a homogeneous load distribution among the computational resources to reduce the idleness of such resources. This heterogeneity implies an ideal number of computational resources which, its increase would not impact the performance gain, since the minimum possible time is the execution time of the task that consumes the longest processing time. In this work is proposed a methodology and tools for parallelization of loops perfectly nested with heterogeneous processing in parallel and distributed systems. The implementation of proposed methodology in application improves execution performance and reduce idles of the processing resources. In the methodology proposed, some procedures are supported by tools developed to assist them. The processing system can be: a computer multicore, a cluster real or virtual allocated in cloud. Experimental results are presented in this work. These results show the feasibility and efficiency of the proposed methodology.

Aplicações podem apresentar laços perfeitamente aninhados que demandam um alto poder de processamento. Diversas aplicações científicas contêm laços aninhados em suas estruturas. Tais laços podem processar computações heterogêneas. Uma solução para reduzir o tempo de execução desta classe de aplicações é a paralelização destes laços. A heterogeneidade dos tempos de execução de computações presentes nas iterações de laços perfeitamente aninhados demanda uma paralelização adequada visando uma distribuição de carga homogênea entre os recursos computacionais para reduzir a ociosidade de tais recursos. Esta heterogeneidade implica em um número ideal de recursos computacionais a partir do qual, o seu aumento não impactaria no ganho de desempenho, uma vez que, o tempo mínimo possível é o tempo de execução da tarefa que consome o maior tempo de processamento. Neste trabalho é proposta uma metodologia e ferramentas para paralelização de laços perfeitamente aninhados sem dependência de dados e com processamento heterogêneo em sistemas paralelos e distribuídos. A implementação da metodologia proposta em aplicações melhora o desempenho da execução e reduz a ociosidade dos recursos de processamento. Na metodologia proposta, alguns procedimentos são apoiados por ferramentas desenvolvidas para auxiliá-los. O sistema de processamento poderá ser: um computador Multicore, um Cluster real ou virtual alocado na nuvem. Resultados experimentais são apresentados neste trabalho. Tais resultados mostram a viabilidade e eficiência da metodologia proposta. / Applications may have nested perfectly loops that require a high processing power. Various scientific applications contain nested loops in their structures. Such loops can process heterogeneous computations. A solution to reduce the execution time of this class of applications is the parallelization of these loops. The heterogeneity of the execution times of computations present in the iterations of nested perfectly loops demands an adequate parallelization aiming at a homogeneous load distribution among the computational resources to reduce the idleness of such resources. This heterogeneity implies an ideal number of computational resources which, its increase would not impact the performance gain, since the minimum possible time is the execution time of the task that consumes the longest processing time. In this work is proposed a methodology and tools for parallelization of loops perfectly nested with heterogeneous processing in parallel and distributed systems. The implementation of proposed methodology in application improves execution performance and reduce idles of the processing resources. In the methodology proposed, some procedures are supported by tools developed to assist them. The processing system can be: a computer multicore, a cluster real or virtual allocated in cloud. Experimental results are presented in this work. These results show the feasibility and efficiency of the proposed methodology.

Les R-loops générés durant la transcription sont impliqués dans de nombreuse fonctions incluant la réplication, la recombinaison et l’expression génique tant chez les procaryotes que chez les eucaryotes. Plusieurs études ont montré qu’un excès de supertours négatifs et des séquences riches en bases G induisent la formation de R-loops. Jusqu’à maintenant, nos résultats nous ont permis d’établir un lien direct entre les topoisomérases, le niveau de surenroulement et la formation de R-loops. Cependant, le rôle physiologique des R-loops est encore largement inconnu. Dans le premier article, une étude détaillée du double mutant topA rnhA a montré qu’une déplétion de RNase HI induit une réponse cellulaire qui empêche la gyrase d’introduire des supertours. Il s’agit ici, de la plus forte évidence supportant les rôles majeurs de la RNase HI dans la régulation du surenroulement de l’ADN. Nos résultats ont également montré que les R-loops pouvaient inhiber l’expression génique. Cependant, les mécanismes exacts sont encore mal connus. L’accumulation d’ARNs courts au détriment d’ARNs pleine longueur peut être causée soit par des blocages durant l’élongation de la transcription soit par la dégradation des ARNs pleine longueur. Dans le deuxième article, nous montrons que l’hypersurenroulement négatif peut mener à la formation de R-loops non-spécifiques (indépendants de la séquence nucléotidique). La présence de ces derniers, engendre une dégradation massive des ARNs et ultimement à la formation de protéines tronquées. En conclusion, ces études montrent l’évidence d’un lien étroit entre la RNase HI, la formation des R-loops, la topologie de l’ADN et l’expression génique. De plus, elles attestent de la présence d’un nouvel inhibiteur de gyrase ou d’un mécanisme encore inconnu capable de réguler son activité. Cette surprenante découverte est élémentaire sachant que de nombreux antibiotiques ciblent la gyrase. Finalement, ces études pourront servir également de base à des recherches similaires chez les cellules eucaryotes. / R-loops generated during transcription elongation are implicated in many DNA reactions, including replication, recombination and gene expression both in prokaryotes and in eukaryotes. Many studies have shown that negative supercoils excess and G-rich sequences induce the formation of R-loops. Up to now, our results allow us to establish a direct link between topoisomerases, supercoiling level, and the formation of R-loops. However, what the physiological significance, if any, of R-loops is still largely unknown. In the first article, a detailed study on double topA rnhA mutants showed that the depletion of RNase HI activity induces a cellular response which renders gyrase unable to perform supercoils. This is the first evidence implicating RNase HI as a major player in DNA supercoiling regulation. Our results also show that R-loops formation can lead to the inhibition of gene expression. However, the exact mechanism(s) leading to the inhibition of gene expression are not yet understood. The accumulation of shorter than full length RNAs could be caused by road-blocks during transcription elongation or by the degradation of full length RNAs. In the second article, we show that hypernegative supercoiling can lead to sequence independent R-loop formation. The physiological consequence is extensive RNA degradation which ultimately culminates in the formation of truncated proteins. In conclusion, this study clearly shows a close link between RNase HI activity, R-loop formation, DNA topology and gene expression. In addition, this study also provides some evidence for the synthesis of a gyrase inhibitor that can regulate gyrase activity directly or indirectly via unidentified mechanisms. This surprising observation is still preliminary taking into consideration that many antibiotics target gyrase. Finally results from this study could open up avenues for research in eukaryotes.

No description available.