Le travail présenté dans ce document consiste à la réalisation d’outils et de méthodes numériques pour modéliser l’influence de la microstructure des shales à la fois sur les propriétés macroscopiques ainsi que sur le processus de fissuration. La première partie du document est dédiée à la description d’un modèle Éléments Finis 3D (E-FEM) développé pour représenter la microstructure ainsi que la fissuration. Ce modèle fait parti des méthodes à discontinuités. Deux critères de fissuration sont décrits, un en mode I (critère de Rankine) et un second en mode II (critère de Mohr-Coulomb). Ces critères seront utilisés pour caractériser l’influence de la microstructure des shales sur les propriétés macroscopiques à l’aide d’essai de compression triaxiale. Plus particulièrement l’impact de la présence de kérogène dans la roche de schiste sera étudié. La seconde partie présente une méthode de décomposition de domaine (la méthode de mortier) utilisée pour réduire les temps de calcul. Cette méthode a pour avantage de permettre l’utilisation de maillage non conforme, ainsi un raffinement local du maillage est possible. Cette méthode a été intégrée à un code de calcul utilisant la programmation orientée composant et plus particulièrement à l’aide du middleware CTL. Le code de calcul permet de résoudre des problèmes linéaires et non linéaires en utilisant le modèle E-FEM. La dernière partie concerne l'étude de l'influence de la minéralogie sur le processus de fissuration à l'aide du code de calcul parallélisé. Un modèle de couplage hydro-mécanique est ensuite développé et appliqué au calcul de fissuration pour mesurer l'impact de la fissuration sur la perméabilité des shales. / This research study aims at developing tools and numerical methods to model the influence of the microstructure of shales on macroscopic properties and cracking process. The first part of the document is dedicated to the description of a 3D Finite Elements model (E-FEM) developed to represent the microstructure and cracking phenomena. This model is part of the methods with discontinuities. Two cracking criteria are described, a mode I criteria (Rankine) and a mode II criteria (Mohr-Coulomb). These criteria will be used to characterize the influence of the microstructure of shales on the macroscopics properties in triaxial compression testing. More particularly, the impact of the presence of kerogen in the shale rock is considered. The second part presents a domain decomposition method (mortar method) used to reduce computation time. This method has the advantage of allowing the use of non-conforming mesh, so a local mesh refinement is possible. This method has been integrated into a computing code using the component-oriented programming and more specifically the CTL middleware. The computing code solves both linear and nonlinear problems using the E-FEM model. The last part concerns the study of the influence of mineralogy on the cracking process using the parallelized calculation code. A hydro-mechanical coupling model is then developed and applied to the calculation of crack to measure the impact of cracking on the shales permeability.

Les sites fragiles communs (SFC) sont des loci instables en cas de stress réplicatif et des lieux préférentiels de réarrangements dans les tumeurs. Les SFC sont associés aux plus grands gènes du génome et il a été proposé que la transcription de ces gènes soit à l'origine de cassures de l'ADN. Cependant, de nombreux grands gènes transcrits ne sont pas fragiles. Un second modèle, celui de notre laboratoire, associe la fragilité des SFC à un programme de réplication particulier, combinant pauvreté en événements d'initiation et réplication tardive. Il serait alors possible que la transcription soit liée à leur programme de réplication, ce qui conduirait à la fragilité. Pour mieux comprendre ces relations, j'ai modifié la transcription de deux grands gènes et analysé les conséquences sur leur réplication et leur fragilité. Ces manipulations génétiques sont réalisées dans le modèle aviaire DT40, qui permet la modification ciblée d'ADN par recombinaison homologue avec une grande efficacité. De façon surprenante, j'ai observé que la fragilité d'un grand gène est diminuée aussi bien en abolissant sa transcription qu'en l'augmentant. J'ai étudié la densité en événements d'initiation par peignage moléculaire au locus et le programme temporel de réplication dans des clones présentant des niveaux différents de transcription. J'ai ainsi pu montrer que la surexpression massive de deux grands gènes avance le programme temporel de la réplication, les préservant de la fragilité. Au cours de ma thèse, j'ai donc montré que la transcription exerce des effets antagonistes sur la stabilité du génome, bénéfiques ou délétères, selon le niveau d'expression des grands gènes associés aux SFC. / Common Fragile Sites (CFSs) are loci displaying instability upon replicative stress, which localization correlates with chromosomal rearrangements in tumours. CFSs are associated with the largest genes of the genome and it has been proposed that their transcription leads to DNA breaks. However, many transcribed large genes are not fragile. Our laboratory proposed an alternative model in which CFS instability results from a specific replication program, combining late replication with paucity in initiation events. To reconcile the two models, we hypothesized that transcription impacts the replication programs. In order to characterize those potential relationships, I manipulated the transcription of two large genes associated with CFSs and determined the consequences of these manipulations on replication and fragility. I used chicken DT40 cells to perform these analyses because this cellular model allows efficient engineering of specific DNA sequences by homologous recombination. Surprisingly, I observed that increasing or suppressing transcription of large gene both lead to a decrease fragility. I then analyzed clones displaying variable transcription levels. I determined the distribution and density of initiation event, using molecular combing at two loci, as well as the profiles of replication timing along the genes. I showed that a massive overexpression of two large genes led to an earlier replication timing. Overall, my results highlight the opposite effects of transcription on genome stability, which range from beneficial to deleterious depending on the expression level of large genes associated with CFSs.

This research examines the gap between the socio-political and economic reality of Palestine, under Israeli Occupation, and the perceptions, assumptions and limitations of small aid donors like Switzerland in a colonial context. It looks at how global and Swiss aid is formulated and dispensed to fragile ‘non-states’ like Palestine. My thesis found that aid in general is ineffective, with Swiss aid in particular being modest, lacking robustness and failing to respond to the colonial context that prevents Palestine from profiting the most from international aid. In addition, Swiss aid is afflicted by many shortcomings that have been identified by contemporary research: a large part of aid is tied; consultations with local partners are limited, excluding, by and large, civil society; and time constraints are such that current programs are generally designed on a relatively short-term basis.

This dissertation describes separate but related studies that explore visual spatial learning and memory in Fragile X Syndrome. Across all studies, either the performance of individuals affected by FXS and/or fmr1 KO mice was compared to comparison controls on seven H-W mazes of increasing difficulty levels. Study one employed the traditional configuration of the H-W mazes to evaluate performance variables that include latency to complete the maze and number of the errors. The results of study 1 revealed significant differences in performance for both FXS groups as compared to mental age-matched comparison individuals and wild type mice, respectively. In contrast to the FXS group, performance of the comparison group improved as indicated by significantly fewer errors across trials. A similar pattern of results was observed when latency across trials was analyzed. Taken together, the results of study one support the hypothesis that a selective deficit in spatial learning and memory characteristic of the FXS phenotype can be observed in the murine model of FXS, if equivalent tasks are employed in testing humans and mice. Study two expanded on these findings by adding landmarks to the maze environment to evaluate how these may impact spatial learning and memory in fmr1 KO mice. Contrary to our hypotheses, landmarks significantly impaired wild type control performance. In addition, results revealed that the performance of the fmr1 KO mice generally did not differ between landmark and non-landmark tasks, indicating that the presence of landmarks neither enhanced nor hindered mouse performance. Lastly, study three entailed a more in-depth behavior analysis of maze navigation performance for FXS individuals from study 1. Consistent with the hypotheses and findings from study 1, results revealed significant differences in performance variables between individuals, with FXS participants generally performing worse than the comparison group participants. Taken together, the results of study 3 generally supported the hypothesis that there was greater impairment in performance for individuals affected by FXS as compared to controls. This impairment was evident in the pattern of pathways taken to solve H-W mazes, consistent with the notion that affected individuals employed different behavioral strategies.

Healthy brain development requires coordinated synapse growth and synapse elimination, with disruptions to these processes often resulting in neurodevelopmental disorder. While glia, the non-neuronal cells of the brain, are increasingly recognized as important regulators of both of these processes, the extent of this regulation and, in the case of disorder, dysregulation is still unknown. In this dissertation, I made classic use of the mouse visual system to outline the contours of glial regulation of synapse development in both synapse growth and synapse elimination. First, I examined astrocytes and microglia in the context of normal brain development, characterizing their spatiotemporal expression patterns in and around the mouse optic tract throughout late embryonic and early postnatal development, as RGC axons are growing into their synaptic target, the dLGN (Chapter 2). Next, I examined astrocyte and microglia in the context of disorder. Here, I found that synapses are reduced in size and eye-specific RGC synapse segregation is enhanced in a mouse model of Fragile X Syndrome, the most common single-gene cause of autism and intellectual disability, (Fmr1 KO mouse) during brain development. I identified glial phagocytic genes as disrupted within the developing Fmr1 KO dLGN and demonstrated that both microglial and astrocytic engulfment of synapses were aberrantly increased during this period of enhanced segregation, providing evidence that over-active glial engulfment may drive aberrant synapse refinement during development in a model of Fragile X Syndrome (Chapter 3).

A history of fragility and conflicts in Somalia has had severe impact on the security of citizens, most notably children. Different non-state actors and armed militias have appeared in Somalia’s timeline impacting the region’s, neighboring and global security. The prevalence of child soldiers in Somalia is alarming and so is the presence of armed groups that regularly recruit them. This paper focuses on studying the causes of child recruitment from a human security lens, examining the impact of fragility in Somalia and the ways by which one particular group; al- Shabaab exploits the fragile environment to recruit children. Qualitative data from different online sources is analyzed indicating that the instability in Somalia and the recruitment of children remain closely interlinked, and human security and development in the region are compromised by corruption, poor governance, societal division, ongoing conflicts and displacement.

Mutations in TSC2 cause the disorder tuberous sclerosis (TSC), which has a high incidence of autism and intellectual disability. TSC2 regulates mRNA translation required for group 1 metabotropic glutamate receptor-dependent synaptic long-term depression (mGluR-LTD), but the identity of mRNAs responsive to mGluR-LTD signaling in the normal and TSC brain is largely unknown. We generated Tsc2+/- mice to model TSC autism and performed ribosome profiling to identify differentially expressed genes following mGluR-LTD in the normal and Tsc2+/- hippocampus. Ribosome profiling reveals that in Tsc2+/-mice, RNA-binding targets of Fragile X Mental Retardation Protein (FMRP) are increased. In wild-type hippocampus, induction of mGluR-LTD caused rapid changes in the steady state levels of hundreds of mRNAs, many of which are FMRP targets. Moreover, mGluR-LTD signaling failed to promote phosphorylation of eukaryotic elongation factor 2 (eEF2) in Tsc2+/- mice, and chemically mimicking phospho-eEF2 with low cycloheximide enhances mGluR-LTD in the Tsc2+/- brain. These results suggest a molecular basis for bidirectional regulation of synaptic plasticity by TSC2 and FMRP. Furthermore, deficient mGluR-regulated translation elongation contributes to impaired synaptic plasticity in Tsc2+/- mice.

Les sites fragiles communs (SFCs) sont des régions génomiques particulièrement sensibles au stress réplicatif et sont impliqués dans l’initiation et la progression du cancer. L’Anémie de Fanconi (AF) est une maladie génétique rare qui se caractérise principalement par une aplasie médullaire, des malformations congénitales ainsi qu’une forte prédisposition au cancer chez les patients (leucémies myéloïdes et tumeurs solides de la tête et du coup). L’instabilité génomique a été identifiée comme étant une source majeure de prédisposition des patients AF au cancer et les SFCs sont particulièrement sensibles dans cette maladie. L’AF est causée par la mutation de gènes codant des protéines participant à une voie moléculaire appelée voie FANC qui a été décrite dans la réparation des ponts inter-brins. Malgré l’importance de la voie FANC dans le maintien de la stabilité des SFCs, les mécanismes sous-jacents restent à élucider. Au cours de ma thèse, nous avons identifié un nouveau rôle de FANCD2 dans le maintien des SFCs. En effet, nous montrons que FANCD2 atténue l’expression des gènes présents au sein des SFCs maintenant leur stabilité. De plus, nous montrons que la transcription de ces gènes est nécessaire au recrutement et au rôle de FANCD2 au sein de ces régions. Enfin, nous avons identifié le stress métabolique comme étant un signal induisant l’expression des gènes des SFCs et que FANCD2 module cette réponse. La réduction de ce stress pourrait être une piste thérapeutique intéressante afin de prévenir l’instabilité des SFCs dans l’AF. / Common fragile sites (CFSs) are genomic regions prone to form breaks and gaps on metaphase chromosomes after replicative stress and promote genomic instability in the earliest steps of tumor development. Proteins involved in replication/repair of CFSs are necessary to prevent their instability. Among them is FANCD2, a key protein of the FANC pathway necessary to resolve inter-strand crosslinks and defective in Fanconi Anemia (FA). FA is a rare genomic instability disorder characterized by bone marrow failure, congenital abnormalities and predisposition to acute myeloid leukemia and epithelial cancer. Genomic instability in FA is supposed to predispose patients to cancers. Importantly, CFSs are more unstable in FA and chromosome breaks observed in FA cells occur preferentially at CFSs. During my PhD, we identified a new role of FANCD2 in CFS stability maintenance. We show that FANCD2 attenuates transcription of the large genes present at CFSs, preventing their instability. Moreover, we demonstrate that transcription is necessary for FANCD2 recruitment and function at CFSs. Importantly, we identified the metabolic stress as a signal triggering CFS gene expression and FANCD2 is necessary to modulate this response. Reducing this stress is a promising therapeutic issue to prevent CFS and genomic instability in FA.

Parental incarceration is connected to many negative outcomes for children including negative externalizing behaviors. Most studies are not conclusive in determining whether maternal incarceration or paternal incarceration has a more detrimental impact on children. This study looks at a sample of 2,458 youth from the Fragile Families and Child Well-Being Study (FFCWS) and their parents and compares the gender of the incarcerated parent and that of the child to determine if there are differences in the risk of delinquent behavior among adolescent children. Results found that parental incarceration overall increased the risk of juvenile delinquency and that female children are at greater risk of delinquency if their mothers were incarcerated. Overall, the empirical results suggest that the gender of the parent and child matter in influencing delinquent behavior. Because maternal incarceration appears to be more consequential for female daughters' participation in delinquent acts, there may be a need to have more gendered research when studying juvenile delinquency and parental incarceration.

Background: Prevalence of metabolic disturbances is higher among individuals with neurodevelopmental disorders (NDDs), yet this association has been poorly studied. Investigation into human disease remains challenging, as a complete pathophysiological understanding relies on accurate modeling and highly controlled variables. As such, genetically engineered mouse models are increasingly used to gain insight into the biology of human NDDs, but preclinical research focus has been mainly on behavioral and neurophysiological abnormalities. Mouse models engineered to embody human-equivalent genetic variations can display discrepancies to human phenotypes, therefore a thorough characterization of mouse phenotypes must be conducted in order to evaluate how accurately a mouse model embodies a human phenotype. Also, mouse models can help discover unsuspected abnormalities that can be further validated in humans. Objective: In this study, we sought to investigate the metabolic alterations derived from NDD-associated genetic polymorphisms in previously-validated genetic mouse models. Due to the similarities in NDD-associated phenotypic expression, we hypothesized that our NDDs of interest would express similar metabolic signatures. Further, we anticipated that we might uncover unknown metabolic anomalies, and that sex may alter these differences. Methods: We used the Comprehensive Lab Animal Monitoring System coupled to EchoMRI, as well as quantification of key plasma metabolites by liquid chromatography-mass spectrometry to characterize and compare basal metabolism in three mouse models of NDDs, namely Down syndrome (Dp(16)Yey/+ mice), 16p11.2 deletion syndrome (16p11.2df/+ mice) and Fragile X syndrome (Fmr1-/- KO mice) and their wild-type (WT) counterparts. Results: Our study reveals that each mouse model expresses a unique metabolic signature that is sex-specific, independent of the amount of food consumed and minimally influenced by physical activity. We found striking differences in body composition, respiratory exchange ratio, caloric expenditure and concentrations of circulating plasma metabolites related to mitochondrial function. Conclusion: Providing novel insight into NDD-associated metabolic alterations provides a basis for future studies aimed at understanding physiological mechanisms and provides a point of reference for research aimed at detecting changes in response to intervention.