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Yes / Topoisomerase inhibitors are in common use as chemotherapeutic agents although they can display reduced efficacy in chemotherapy-resistant tumours, which have inactivated DNA damage response (DDR) genes, such as ATM and TP53. Here, we characterise the cellular response to the dual-acting agent, Alchemix (ALX), which is a modified anthraquinone that functions as a topoisomerase inhibitor as well as an alkylating agent. We show that ALX induces a robust DDR at nano-molar concentrations and this is mediated primarily through ATR- and DNA-PK- but not ATM-dependent pathways, despite DNA double strand breaks being generated after prolonged exposure to the drug. Interestingly, exposure of epithelial tumour cell lines to ALX in vitro resulted in potent activation of the G2/M checkpoint, which after a prolonged arrest, was bypassed allowing cells to progress into mitosis where they ultimately died by mitotic catastrophe. We also observed effective killing of lymphoid tumour cell lines in vitro following exposure to ALX, although, in contrast, this tended to occur via activation of a p53-independent apoptotic pathway. Lastly, we validate the effectiveness of ALX as a chemotherapeutic agent in vivo by demonstrating its ability to cause a significant reduction in tumour cell growth, irrespective of TP53 status, using a mouse leukaemia xenograft model. Taken together, these data demonstrate that ALX, through its dual action as an alkylating agent and topoisomerase inhibitor, represents a novel anti-cancer agent that could be potentially used clinically to treat refractory or relapsed tumours, particularly those harbouring mutations in DDR genes.

Head and neck squamous cell carcinoma encompasses a complex and heterogeneous group of malignant diseases. Originally, this tumor type was associated with tobacco and alcohol consumption. However, a significantly expanding subset of tumors associated with oncogenic human papillomavirus infection arising in deep tonsillar crypts was identified within the last decades. Due to the essential role of the immune system in antiviral and anticancer immune response, the prognosis of patients is significantly influenced by the volume, composition and functional capacity of the immune infiltrate. The immunosuppressive landscape of head and neck cancer leads to unfavorable outcome of patients and decreased efficacy of immunotherapy. The response rate to standard treatment is high, however, standard therapy is accompanied by considerable toxicity influencing the quality of life. In 2016, the first immunotherapeutics for the treatment of patients with recurrent squamous cell carcinoma of the head and neck were approved - the anti-PD-1 immune checkpoint inhibitors nivolumab and pembrolizumab. This type of therapy, based on mitigation of immunosuppression, shows strong efficacy and less toxicity in combination with other therapies. Therefore, anti-PD-1 immunotherapy was recently approved in the first-line...

STAUFEN1 (STAU1) est une protéine de liaison à l’acide ribonucléique (ARN) double brin jouant un rôle important dans le contrôle post-transcriptionnel de nombreux ARN messager (ARNm). Sa déplétion diminue la prolifération des cellules non cancéreuses en altérant les transitions G1/S et G2/M. En revanche, Ceci n’a aucun impact sur la prolifération des cellules tumorales. La déplétion de STAU1 module le niveau d’expression des transcrits et/ou des protéines impliquées dans la régulation des points de contrôle des transitions de phase. Notamment, STAU1 module le niveau d’expression de la protéine CDK4 ainsi que l’abondance de l’ARNm E2F1, deux régulateurs indispensables de la transition G1/S. Le transcrit de ces deux gènes possède un site de liaison à STAU1 ou STAU1 binding site (SBS) dans la région codante ou coding sequence (CDS) et dans la région non codante en 3’ (3’UTR), respectivement. Cependant, l’importance de la liaison de STAU1 à ces transcrits n’a pas encore été étudiée. Étonnamment, la sensibilité des cellules non tumorales et tumorales à l’expression de STAU1 est inversée lors de la surexpression de STAU1. En effet, sa surexpression altère l’entrée en mitose des cellules cancéreuses et diminue leur prolifération, alors qu’elle n’a aucun effet sur la prolifération des cellules non tumorales. Lors de la mitose, STAU1 s’associe au fuseau mitotique (FM), ce qui lui permet de localiser des ARNm et de contrôler leur séquestration et/ou leur traduction locale. Cependant, le mécanisme qui permet à STAU1 de lier le FM est encore inconnu. Pour ce mémoire, nous avons donc poursuivi deux objectifs. Le premier but est de comprendre la régulation post-transcriptionnelle médiée par STAU1 des transcrits essentiels à la transition G1/S chez les cellules non tumorales. Notre hypothèse est que STAU1 par sa liaison directe à ses transcrits cibles via le SBS module leur expression. Pour ce faire, des cellules de type sauvage ou déplétées en STAU1 étaient transfectées par des plasmides exprimant les transcrits de CDK4 et d’E2F1 contenant un SBS endogène ou muté de telle sorte qu’il ne reconnait plus STAU1. L’expression des protéines CDK4 et E2F1 est dosée par un essai luciférase ou un immunobuvardage de type western ou western blot (WB). Nous avons observé que STAU1 régule négativement et positivement l’expression endogène de CDK4 et d’E2F1, respectivement, ce qui contribue au passage de la transition G1/S, donc à la prolifération cellulaire non tumorale. Les essais luciférases ont confirmé le rôle de STAU1 dans la régulation positive d’E2F1 lorsque liée au SBS dans le 3’UTR du transcrit E2F1. Malheureusement, les plasmides utilisés pour l’expression de CDK4 se sont avérés non fonctionnels, ce qui nous a forcés à mettre de côté cette expérience. Le deuxième but est d’étudier les déterminants qui régulent la localisation de STAU1 au FM chez les cellules tumorales. Pour ce faire, la localisation de STAU1 ou des mutants au FM est détectée par WB à partir de préparations des FM purifiés. Nos données montrent que le déterminant est composé de plusieurs acides aminés (aa) situés entre le 26ème et 37ème aa du côté N-terminal de la protéine STAU1. En somme, nos résultats montrent les différents rôles de STAU1 dans les cellules tumorales vs cellules non tumorales. De ce fait, STAU1 pourrait être une cible thérapeutique spécifique potentielle dans le traitement du cancer. / STAUFEN1 (STAU1) is a double stranded RNA binding protein that plays an important role in the post-transcriptional control of many mRNAs. Its depletion decreases the proliferation of non-cancer cells by altering G1/S and G2/M transitions. In contrast, this has no impact on the proliferation of tumor cells. The decrease of STAU1 expression modulates the level of transcripts/proteins of several genes involved in phase transition checkpoints, including CDK4 and E2F1, two essential regulators in G1/S transition. In addition, CDK4 and E2F1 transcripts have a STAU1 binding site (SBS) in the coding sequence (CDS) and the non-coding region in 3’ (3’UTR), respectively. However, the molecular consequence of STAU1 association with the SBS is not yet studied. Surprisingly, the sensibility of non-cancer and cancer cells to STAU1 expression is reversed following STAU1 overexpression. Indeed, its overexpression alters the entry into mitosis of cancer cells and decreases their proliferation, while it has no effect on non-cancer cells. During mitosis, STAU1 associates with the mitotic spindle, which allows it to localize mRNAs and other non-coding RNAs. STAU1 likely controls their sequestration and/or local translation during mitosis. However, the molecular determinant involved in STAU1-spindle association is still not known. Therefore, for this master thesis, we had two objectives. The first goal is to understand the post-transcriptional regulation mediated by STAU1 on transcripts that are essential for G1/S transition in non-tumor cells. Our hypothesis is that STAU1, by its direct binding to the SBS of its target transcripts, modulates their expression. To do this, plasmids coding for CDK4 and E2F1 containing a wild-type or mutated SBS that does not recognized STAU1 were transfected in wild-type and STAU1-depleted cells. Expression of CDK4 and E2F1 was detected by dual luciferase assay and western blot (WB). Our results first indicate that STAU1 negatively and positively regulates the endogenous expression of CDK4 and E2F1, respectively, which contributes to the passage of G1/S transition, and therefore to the proliferation non-tumor cells. Then, the luciferase assays confirm the role of STAU1 in E2F1 expression, depending on STAU1 binding to E2F1 SBS in its 3’UTR. Unfortunately, the plasmids used for CDK4 expression turned out to be non-functional. The second goal is to identify the molecular determinants responsible for the localization of STAU1 to the mitotic spindle in tumor cells. To this end, the localization of STAU1 or of several mutants was measured by WB using purified spindle preparations. Our data show that the determinant is composed of several amino acids (aa) located between the 26th and 37th aa at the N-terminal end of STAU1. In summary, our results show the different roles of STAU1 in tumor and non-tumor cells. Therefore, STAU1 could be a potential specific therapeutic target in cancer treatments.

The MA thesis "Minimum Legal Drinking Age in the U.S.: A Reasonable Exception to Age of Majority?" examines the U.S. legal limit for consumption of alcohol from the perspective of policies aimed at controlling drunk driving because the minimum drinking age was set to twenty-one - higher than the age of majority - in order to reduce drunk-driving fatalities. The thesis analyzes different aspects of this issue and concludes that the high minimum legal drinking, which constitutes a severe limitation of personal freedom of those aged eighteen to twenty, did not fulfill the expectations with which it was introduced in 1984. The thesis suggests alternatives to the high age limit, and examines how and if they are implemented or what prevents their frequent use. The thesis has four parts: one provides basic facts about drinking, driving, and drunk driving in the U.S. society including the attitudes of the public toward the issue. The following part looks into the legal developments of the drinking age limits and legal challenges to the law arranging the age limit for its supposed unconstitutionality. The third chapter looks at the results of scientific research and suggests ways to deal with drunk driving more efficiently. The last part examines what prevents these more effective measures from being widely...

OpenMP et MPI sont devenus les outils standards pour développer des programmes parallèles sur une architecture à mémoire partagée et à mémoire distribuée respectivement. Comparé à MPI, OpenMP est plus facile à utiliser. Ceci est dû au fait qu’OpenMP génère automatiquement le code parallèle et synchronise les résultats à l’aide de directives, clauses et fonctions d’exécution, tandis que MPI exige que les programmeurs fassent ce travail manuellement. Par conséquent, des efforts ont été faits pour porter OpenMP sur les architectures à mémoire distribuée. Cependant, à l’exclusion de CAPE, aucune solution ne satisfait les deux exigences suivantes: 1) être totalement conforme à la norme OpenMP et 2) être hautement performant. CAPE (Checkpointing-Aided Parallel Execution) est un framework qui traduit et fournit automatiquement des fonctions d’exécution pour exécuter un programme OpenMP sur une architecture à mémoire distribuée basé sur des techniques de checkpoint. Afin d’exécuter un programme OpenMP sur un système à mémoire distribuée, CAPE utilise un ensemble de modèles pour traduire le code source OpenMP en code source CAPE, puis le code source CAPE est compilé par un compilateur C/C++ classique. Fondamentalement, l’idée de CAPE est que le programme s’exécute d’abord sur un ensemble de nœuds du système, chaque nœud fonctionnant comme un processus. Chaque fois que le programme rencontre une section parallèle, le maître distribue les tâches aux processus esclaves en utilisant des checkpoints incrémentaux discontinus (DICKPT). Après l’envoi des checkpoints, le maître attend les résultats renvoyés par les esclaves. L’étape suivante au niveau du maître consiste à recevoir et à fusionner le résultat des checkpoints avant de les injecter dans sa mémoire. Les nœuds esclaves quant à eux reçoivent les différents checkpoints, puis l’injectent dans leur mémoire pour effectuer le travail assigné. Le résultat est ensuite renvoyé au master en utilisant DICKPT. À la fin de la région parallèle, le maître envoie le résultat du checkpoint à chaque esclave pour synchroniser l’espace mémoire du programme. Dans certaines expériences, CAPE a montré des performances élevées sur les systèmes à mémoire distribuée et constitue une solution viable entièrement compatible avec OpenMP. Cependant, CAPE reste en phase de développement, ses checkpoints et son modèle d’exécution devant être optimisés pour améliorer les performances, les capacités et la fiabilité. Cette thèse vise à présenter les approches proposées pour optimiser et améliorer la capacité des checkpoints, concevoir et mettre en œuvre un nouveau modèle d’exécution, et améliorer la capacité de CAPE. Tout d’abord, nous avons proposé une arithmétique sur les checkpoints qui modélise la structure de leurs données et ses opérations. Cette modélisation contribue à optimiser leur taille et à réduire le temps nécessaire à la fusion, tout en améliorant leur capacité. Deuxièmement, nous avons développé TICKPT (Time-Stamp Incremental Checkpointing) une implémentation de l’arithmétique sur les checkpoints. TICKPT est une amélioration de DICKPT, il a ajouté l’horodatage aux checkpoints pour en identifier l’ordre. L’analyse et les expériences comparées montrent TICKPT sont non seulement plus petites, mais qu’ils ont également moins d’impact sur les performances du programme. Troisièmement, nous avons conçu et implémenté un nouveau modèle d’exécution et de nouveaux prototypes pour CAPE basés sur TICKPT. Le nouveau modèle d’exécution permet à CAPE d’utiliser les ressources efficacement, d’éviter les risques de goulots d’étranglement et de satisfaire à l’exigence des les conditions de Bernstein. Au final, ces approches améliorent significativement les performances de CAPE, ses capacités et sa fiabilité. Le partage des données implémenté sur CAPE et basé sur l’arithmétique sur des checkpoints est ouvert et basé sur TICKPT. Cela démontre également la bonne direction que nous avons prise et rend CAPE plus complet / OpenMP and MPI have become the standard tools to develop parallel programs on shared-memory and distributed-memory architectures respectively. As compared to MPI, OpenMP is easier to use. This is due to the ability of OpenMP to automatically execute code in parallel and synchronize results using its directives, clauses, and runtime functions while MPI requires programmers do all this manually. Therefore, some efforts have been made to port OpenMP on distributed-memory architectures. However, excluding CAPE, no solution has successfully met both requirements: 1) to be fully compliant with the OpenMP standard and 2) high performance. CAPE stands for Checkpointing-Aided Parallel Execution. It is a framework that automatically translates and provides runtime functions to execute OpenMP program on distributed-memory architectures based on checkpointing techniques. In order to execute an OpenMP program on distributed-memory system, CAPE uses a set of templates to translate OpenMP source code to CAPE source code, and then, the CAPE source code is compiled by a C/C++ compiler. This code can be executed on distributed-memory systems under the support of the CAPE framework. Basically, the idea of CAPE is the following: the program first run on a set of nodes on the system, each node being executed as a process. Whenever the program meets a parallel section, the master distributes the jobs to the slave processes by using a Discontinuous Incremental Checkpoint (DICKPT). After sending the checkpoints, the master waits for the returned results from the slaves. The next step on the master is the reception and merging of the resulting checkpoints before injecting them into the memory. For slave nodes, they receive different checkpoints, and then, they inject it into their memory to compute the divided job. The result is sent back to the master using DICKPTs. At the end of the parallel region, the master sends the result of the checkpoint to every slaves to synchronize the memory space of the program as a whole. In some experiments, CAPE has shown very high-performance on distributed-memory systems and is a viable and fully compatible with OpenMP solution. However, CAPE is in the development stage. Its checkpoint mechanism and execution model need to be optimized in order to improve the performance, ability, and reliability. This thesis aims at presenting the approaches that were proposed to optimize and improve checkpoints, design and implement a new execution model, and improve the ability for CAPE. First, we proposed arithmetics on checkpoints, which aims at modeling checkpoint’s data structure and its operations. This modeling contributes to optimize checkpoint size and reduces the time when merging, as well as improve checkpoints capability. Second, we developed TICKPT which stands for Time-stamp Incremental Checkpointing as an instance of arithmetics on checkpoints. TICKPT is an improvement of DICKPT. It adds a timestamp to checkpoints to identify the checkpoints order. The analysis and experiments to compare it to DICKPT show that TICKPT do not only provide smaller in checkpoint size, but also has less impact on the performance of the program using checkpointing. Third, we designed and implemented a new execution model and new prototypes for CAPE based on TICKPT. The new execution model allows CAPE to use resources efficiently, avoid the risk of bottlenecks, overcome the requirement of matching the Bernstein’s conditions. As a result, these approaches make CAPE improving the performance, ability as well as reliability. Four, Open Data-sharing attributes are implemented on CAPE based on arithmetics on checkpoints and TICKPT. This also demonstrates the right direction that we took, and makes CAPE more complete

L'ADN de chaque cellule est constamment soumis à des stress pouvant compromettre son intégrité. Les bris double-brins sont probablement les dommages les plus nocifs pour la cellule et peuvent être des sources de réarrangements chromosomiques majeurs et mener au cancer s’ils sont mal réparés. La recombinaison homologue et la jonction d’extrémités non-homologues (JENH) sont deux voies fondamentalement différentes utilisées pour réparer ce type de dommage. Or, les mécanismes régulant le choix entre ces deux voies pour la réparation des bris double-brins demeurent nébuleux. Le complexe Mre11-Rad50-Xrs2 (MRX) est le premier acteur à être recruté à ce type de bris où il contribue à la réparation par recombinaison homologue ou JENH. À l’intersection de ces deux voies, il est donc idéalement placé pour orienter le choix de réparation. Ce mémoire met en lumière deux systèmes distincts de phosphorylation du complexe MRX régulant spécifiquement le JENH. L’un dépend de la progression du cycle cellulaire et inhibe le JENH, tandis que l’autre requiert la présence de dommages à l’ADN et est nécessaire au JENH. Ensembles, nos résultats suggèrent que le complexe MRX intègre différents phospho-stimuli pour réguler le choix de la voie de réparation. / The genome of every cell is constantly subjected to stresses that could compromise its integrity. DNA double-strand breaks (DSB) are amongst the most damaging events for a cell and can lead to gross chromosomal rearrangements, cell death and cancer if improperly repaired. Homologous recombination and non-homologous end joining (NHEJ) are the main repair pathways responsible for the repair of DSBs. However, the mechanistic basis of both pathways is fundamentally different and the regulation of the choice between both for the repair of DSBs remains largely misunderstood. The Mre11-Rad50-Xrs2 (MRX) complex acts as a DSB first responder and contributes to repair by both homologous recombination and NHEJ. Being at the crossroads of both DSB repair pathways, the MRX complex is therefore in a convenient position to influence the repair choice. This thesis unravels two distinct phosphorylation systems modifying the MRX complex and specifically regulating repair by NHEJ. The first relies on cell cycle progression and inhibits NHEJ, while the second requires the presence of DNA damage and is necessary for efficient NHEJ. Together, our results suggest a model in which the MRX complex would act as an integrator of phospho-stimuli in order to regulate the DSB repair pathway choice.

Alzheimer's disease (AD) is the most common form of dementia. As the prevalence of AD increases with age, population aging will inevitably lead to an exponential increase in the proportion of older persons suffering from this disease. According to 2005 WHO estimate, 26.6 million people (approximately 0.55% of the general population) suffered from this disease. AD not only affects intellectual and functional abilities, it is also associated with significant neuropsychiatric disturbances. The pathogenesis of AD is characterized by widespread cerebral atrophy, abnormal deposition of amyloid plaques and tau protein in the central nervous system. While the classical histopathological features of AD are well recognized, exact physiological mechanisms that initiate the cascade of neural degeneration are still under active investigation. / As mentioned, the telomere length studies focused on ethically Chinese subjects recruited from two independent samples. The first clinical sample consisted of 411 older people and the other sample from healthy aging study, 976 community dwelling men were recruited. All subjects were assessed with the Cantonese version of the Mini-mental State Examination (CMMSE) for global cognitive function. Genomic DNA of the subjects was extracted from the peripheral whole blood sample. Lengths of the telomere were measured with Quantitative Real-Time PCR and the Ct ratio of the telomere and a control gene (36B4) of each sample was compared with the standard curve constructed with 4 selected sample's telomere lengths measured previously by Southern blotting. / For the first association study of the cell cycle checkpoint genes and AD, sample was recruited from a prospective study of cognitive function and risk factors for development of AD. 701 elderly were clinically evaluated for diagnosis of AD by psychiatrists. For this sample, genotyping of tagging SNPs of the 10 cell-cycle checkpoint genes were carried out by Restriction Fragment Length Polymorphism (RFLP) analysis. All tagging SNPs were selected from HapMap database and 5000bp upstream and downstream regions of each gene was also included. / For the results, the association study with cell cycle checkpoint genes, there was no SNPs found to be associated with diagnosis of clinical AD. We also found out that telomere length was associated with age in both two healthy aging men and clinical samples. There was no association between education and telomere lengths. For subjects in the healthy aging study, participants with CMMSE scores fell into the lowest 25% were found to have shorter telomere lengths. Similar result was found in the clinical AD sample. / In the study, telomere lengths were negatively associated with age. As the telomere will be shortened for each cell cycle, this finding correlated with physiological function at a cellular level. Statistical analysis also showed that shorter telomere lengths were found in subjects with poorer cognitive function. However, as age is a major determinant for cognitive impairments, further studies are recommended to evaluate the interaction effects of age in this association. Telomere shortening will cause cell senescence, and may be associated with faster neuronal degeneration, thus affecting cognitive function. Further studies should be conducted to examine its usefulness as an adjuvant biomarker for risk stratification of AD intervention trials. / Recent researches begin to unfold the physiological significance of telomere. A telomere is a repetitive region at the end of a chromosome. Basic functions of telomeres are involved with protection of the chromosome during replication and preventing chromosomal rearrangement or fusion. Abnormal telomere lengthening may be related to cancerous conditions. At a cellular level, telomere may also be related to aging and limitation in cell lifespan. In my study, I aimed to evaluate the association between the lengths of telomere and global cognitive function in community dwelling Chinese older persons in Hong Kong. As the length of telomere is also determined by the turnover rates of cells, apart from association study of telomere lengths and cognitive function, I also tried to study the association of genes related to cell cycles and AD. Polymorphisms of ten cell-cycle checkpoint genes, i.e. RB1, CDKN1A, CDK5R1, CDK2AP1, CDKN2A, CDKN2C, MDM2, P53, GSK3B, TPND1 and CDKN1B genes, were chosen in my project. / The thesis comprised of three studies. The first study was an association study of cell cycle checkpoint gene single nucleotide polymorphisms (SNPs) with clinical diagnosis of AD. The second study was an association study of telomere lengths and clinical diagnosis of AD in a clinical sample of patients suffering from the disease. The third study was an association study of the telomere lengths and global cognitive status in a group of active community dwelling older men who participated in a healthy aging study. / Lau, San Shing. / Adviser: Linda C.W. Lam. / Source: Dissertation Abstracts International, Volume: 73-01, Section: B, page: . / Thesis (Ph.D.)--Chinese University of Hong Kong, 2010. / Includes bibliographical references (leaves 101-124). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [201-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.

L'ADN de chaque cellule est constamment soumis à des stress pouvant compromettre son intégrité. Les bris double-brins sont probablement les dommages les plus nocifs pour la cellule et peuvent être des sources de réarrangements chromosomiques majeurs et mener au cancer s’ils sont mal réparés. La recombinaison homologue et la jonction d’extrémités non-homologues (JENH) sont deux voies fondamentalement différentes utilisées pour réparer ce type de dommage. Or, les mécanismes régulant le choix entre ces deux voies pour la réparation des bris double-brins demeurent nébuleux. Le complexe Mre11-Rad50-Xrs2 (MRX) est le premier acteur à être recruté à ce type de bris où il contribue à la réparation par recombinaison homologue ou JENH. À l’intersection de ces deux voies, il est donc idéalement placé pour orienter le choix de réparation. Ce mémoire met en lumière deux systèmes distincts de phosphorylation du complexe MRX régulant spécifiquement le JENH. L’un dépend de la progression du cycle cellulaire et inhibe le JENH, tandis que l’autre requiert la présence de dommages à l’ADN et est nécessaire au JENH. Ensembles, nos résultats suggèrent que le complexe MRX intègre différents phospho-stimuli pour réguler le choix de la voie de réparation. / The genome of every cell is constantly subjected to stresses that could compromise its integrity. DNA double-strand breaks (DSB) are amongst the most damaging events for a cell and can lead to gross chromosomal rearrangements, cell death and cancer if improperly repaired. Homologous recombination and non-homologous end joining (NHEJ) are the main repair pathways responsible for the repair of DSBs. However, the mechanistic basis of both pathways is fundamentally different and the regulation of the choice between both for the repair of DSBs remains largely misunderstood. The Mre11-Rad50-Xrs2 (MRX) complex acts as a DSB first responder and contributes to repair by both homologous recombination and NHEJ. Being at the crossroads of both DSB repair pathways, the MRX complex is therefore in a convenient position to influence the repair choice. This thesis unravels two distinct phosphorylation systems modifying the MRX complex and specifically regulating repair by NHEJ. The first relies on cell cycle progression and inhibits NHEJ, while the second requires the presence of DNA damage and is necessary for efficient NHEJ. Together, our results suggest a model in which the MRX complex would act as an integrator of phospho-stimuli in order to regulate the DSB repair pathway choice.

Dans cette thèse, nous nous sommes intéressés aux problèmes d'ordonnancement et d'optimisation dans des contextes probabilistes. Les contributions de cette thèse se déclinent en deux parties. La première partie est dédiée à l’optimisation de différents mécanismes de tolérance aux pannes pour les machines de très large échelle qui sont sujettes à une probabilité de pannes. La seconde partie est consacrée à l’optimisation du coût d’exécution des arbres d’opérateurs booléens sur des flux de données.Dans la première partie, nous nous sommes intéressés aux problèmes de résilience pour les machines de future génération dites « exascales » (plateformes pouvant effectuer 1018 opérations par secondes).Dans le premier chapitre, nous présentons l’état de l’art des mécanismes les plus utilisés dans la tolérance aux pannes et des résultats généraux liés à la résilience.Dans le second chapitre, nous étudions un modèle d’évaluation des protocoles de sauvegarde de points de reprise (checkpoints) et de redémarrage. Le modèle proposé est suffisamment générique pour contenir les situations extrêmes: d’un côté le checkpoint coordonné, et de l’autre toute une famille de stratégies non-Coordonnées. Nous avons proposé une analyse détaillée de plusieurs scénarios, incluant certaines des plateformes de calcul existantes les plus puissantes, ainsi que des anticipations sur les futures plateformes exascales.Dans les troisième, quatrième et cinquième chapitres, nous étudions l'utilisation conjointe de différents mécanismes de tolérance aux pannes (réplication, prédiction de pannes et détection d'erreurs silencieuses) avec le mécanisme traditionnel de checkpoints et de redémarrage. Nous avons évalué plusieurs modèles au moyen de simulations. Nos résultats montrent que ces modèles sont bénéfiques pour un ensemble de modèles d'applications dans le cadre des futures plateformes exascales.Dans la seconde partie de la thèse, nous étudions le problème de la minimisation du coût de récupération des données par des applications lors du traitement d’une requête exprimée sous forme d'arbres d'opérateurs booléens appliqués à des prédicats sur des flux de données de senseurs. Le problème est de déterminer l'ordre dans lequel les prédicats doivent être évalués afin de minimiser l'espérance du coût du traitement de la requête. Dans le sixième chapitre, nous présentons l'état de l'art de la seconde partie et dans le septième chapitre, nous étudions le problème pour les requêtes exprimées sous forme normale disjonctive. Nous considérons le cas plus général où chaque flux peut apparaître dans plusieurs prédicats et nous étudions deux modèles, le modèle où chaque prédicat peut accéder à un seul flux et le modèle où chaque prédicat peut accéder à plusieurs flux. / In this thesis, we are interested in scheduling and optimization problems in probabilistic contexts. The contributions of this thesis come in two parts. The first part is dedicated to the optimization of different fault-Tolerance mechanisms for very large scale machines that are subject to a probability of failure and the second part is devoted to the optimization of the expected sensor data acquisition cost when evaluating a query expressed as a tree of disjunctive Boolean operators applied to Boolean predicates. In the first chapter, we present the related work of the first part and then we introduce some new general results that are useful for resilience on exascale systems.In the second chapter, we study a unified model for several well-Known checkpoint/restart protocols. The proposed model is generic enough to encompass both extremes of the checkpoint/restart space, from coordinated approaches to a variety of uncoordinated checkpoint strategies. We propose a detailed analysis of several scenarios, including some of the most powerful currently available HPC platforms, as well as anticipated exascale designs.In the third, fourth, and fifth chapters, we study the combination of different fault tolerant mechanisms (replication, fault prediction and detection of silent errors) with the traditional checkpoint/restart mechanism. We evaluated several models using simulations. Our results show that these models are useful for a set of models of applications in the context of future exascale systems.In the second part of the thesis, we study the problem of minimizing the expected sensor data acquisition cost when evaluating a query expressed as a tree of disjunctive Boolean operators applied to Boolean predicates. The problem is to determine the order in which predicates should be evaluated so as to shortcut part of the query evaluation and minimize the expected cost.In the sixth chapter, we present the related work of the second part and in the seventh chapter, we study the problem for queries expressed as a disjunctive normal form. We consider the more general case where each data stream can appear in multiple predicates and we consider two models, the model where each predicate can access a single stream and the model where each predicate can access multiple streams.