We sought to evaluate the individual contributions of Notch1 and PKC-ζ to disease progression in a mouse model of immune-mediated bone marrow failure and to define a mechanism for their potential cellular cooperation. We transferred parental bulk splenocytes into F1-hybrid recipients to induce a robust immune-mediated bone marrow failure (BMF) that we could partially rescue by administering a pharmacological inhibitor of Notch activation. Transferring splenocytes from PKC--ζ-/- animals did not induce disease, and treating animals with a pharmacological inhibitor of PKC-ζ also provided full protection from disease. We found that inhibiting Notch1 resulted in PKC-ζ down-regulation, and blocking PKC-ζ reduced Notch1 activation, possibly within a positive feedback loop. Our data suggest that both Notch1 and PKC-ζ contribute to disease progression in our mouse model of immune-mediated bone marrow failure. Furthermore, additional findings from the lab demonstrated physical interactions between Notch1, members of the T cell signalosome and PKC-ζ that are essential to mediating full activation of T cells following signaling through the TCR and CD28. Notch1 and/or PKC-ζ may represent novel therapeutic targets in the treatment of bone marrow failure.

The study was conducted to identify characteristics that are associated with successful transfer to institutions of higher learning from 3 Phi Theta Kappa chapters at a large multi-campus Mississippi community college. The study examined participation rates and transfer rates of Phi Theta Kappa students. The current study also identified student characteristics that predict the successful transfer of Phi Theta Kappa members. A correlational methodological approach was employed. The Phi Theta Kappa chapters in this study have significant differences in membership, yet the factors that predict transfer to a 4-year university or college are few. The factors include age at transfer, cumulative grade point average, type of major, and associate degree completion. The analysis resulted in a model that may be used to predict the probability that a Phi Theta Kappa student will be a successful transfer. The model was able to predict the transfer of these students with significantly higher probabilities than the baseline model.

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Shyness is a personality trait that is stable across time and situations in some individuals. While childhood shyness is a risk factor for later mental health and emotional problems, not all shy children grow up to have these problems. This thesis examined subtypes of shyness identified based on the temporal stability of shyness and based on levels of sociability and their corresponding outcomes, as well as the roles of social and biological contextual factors. Chapters 2-4 comprise the empirical studies. In Chapter 2, I report three shyness trajectories from middle childhood to adulthood (ages 8 to 30-35). Relative to a low-stable non-shy trajectory, children with an increasing, but not a decreasing, shy trajectory were at higher risk for clinically significant social anxiety, depression, and substance use, and were hypervigilant to angry faces in adulthood. Chapters 3 and 4 then report electrocortical correlates and mechanisms during the processing of non-social auditory novelty and social exclusion across children, adolescents, and adults with varying levels of shyness and sociability. Chapter 3 established that shyness, but not sociability, was related to the P300 ERP in processing non-social auditory stimuli in both 10-year-old children and adults, in support of the notion that shyness and sociability are independent personality dimensions. Findings on subtypes of shyness also showed that children characterized by conflicted shyness (with high levels of both shyness and sociability) reported higher neuroticism, but this relation was mediated by increased P300 amplitudes to processing background stimuli. Finally, Chapter 4 reports that individuals characterized by conflicted shyness who exhibited high theta EEG spectral power to social exclusion were most fearful of negative evaluation, irrespective of age. Also, conflicted shy adolescents who showed high theta spectral power to social exclusion were most likely to engage in substance-use. These findings highlight that there is much heterogeneity in shyness, and that shyness is not directly related to adverse mental health outcomes. / Thesis / Doctor of Philosophy (PhD) / Shyness is a personality trait that is stable across time and situations in some individuals. Past research suggests that shy children exhibit more internalizing problems, including anxiety and depression, compared to their non-shy counterparts. However, the development of shyness has not been studied beyond adolescence, and the biological and social factors that contribute to adverse developmental pathways and outcomes related to shyness are not well understood. The goal of this thesis was to understand the mental health outcomes of shy individuals by examining different subtypes of shy individuals. To this end, this thesis first demonstrated how shyness unfolds across the first four decades of life to shape adult mental health outcomes in a cohort of individuals. Second, this thesis examined how neural responses to threatening social and non-social contexts related to the socioemotional outcomes across children, adolescents and adults with varying levels of shyness.

The purpose of this thesis was to investigate a proposed neurophysiological model for Necker cube reversals by using electroencephalography. It is suggested that Necker cube reversals are mediated by sustained focused attention to the overall drawing with visual selective attention to vertices of the cube. The main hypotheses were that deliberate attention would increase Necker cube reversals over passive attention, there would be greater high theta power during the deliberate focusing of attention than during passive attentional processing, and there would be greater theta power in the right hemisphere. Thirty undergraduate psychology students had monopolar EEG recorded bilaterally from frontal and parietal electrode sites. The subjects viewed computer presentations of the Necker cube under two different experimental conditions: a passive condition in which they were not instructed to influence reversals, and an active condition in which subjects deliberately shifted their focus of attention. / Master of Science

Alors qu'initialement utilisés pour résoudre le Problème du Logarithme Discret (DLP) dans le groupe de points d'une courbe elliptique, les couplages sont très à la mode en cryptographie ces années car ils permettent de construire de nouveaux protocoles cryptographiques. Cependant, le calcul efficace du couplage dépend de l'arithmétique du modèle de courbe elliptique choisi et du corps sur lequel cette courbe est définie. Dans cette thèse, nous calculons le couplage sur deux modèles de Jacobi de courbes elliptiques puis nous introduisons et étudions l'arithmétique d'un nouveau modèle d'Ewards de courbe elliptique défini en toutes caractéristiques. Plus précisément, Nous utilisons l'interprétation géométrique de la loi de groupe sur l'intersection des quadriques de Jacobi pour obtenir pour la première fois dans la littérature, les formules explicites de la fonction de Miller pour le calcul du couplage de Tate sur cette courbe. Pour un calcul de couplage avec un degré de plongement pair, nous définissons la tordue quadratique pour obtenir des étapes de doublement et d'addition efficaces dans l'algorithme de Miller. Ensuite nous utilisons un isomorphisme entre la quartique spéciale de Jacobi Ed: Y²=dX⁴+Z⁴ et le modèle de Weierstrass pour obtenir la fonction de Miller nécessaire au calcul du couplage de Tate. Pour un degré de plongement divisible par 4, nous définissons la tordue d'ordre 4 de cette courbe pour obtenir un résultat meilleur du calcul du couplage de Tate par rapport aux courbes elliptiques sous forme de Weierstrass. Notre résultat améliore en même temps les derniers résultats obtenus sur cette courbe. Ce résultat est donc le meilleur connu à ce jour, à notre connaissance, pour le calcul du couplage de Tate sur les courbes possédant des tordues d'ordre 4. En 2006, Hess et al. introduisent le couplage Ate, qui est une version améliorée du couplage de Tate. Nous calculons ce couplage et ses variantes sur la même quartique. Nous y obtenons encore des résultats meilleurs. Notre troisième contribution est l'introduction d'un nouveau modèle d'Edwards de courbe elliptique d'équation 1+x²+y²+x²y²=Xxy. Ce modèle est ordinaire sur les corps de caractéristique 2 et nous montrons qu'il est birationnellement équivalent au modèle original d'Edwards x²+y²=c²(1+x²y²) en caractéristique différente de 2. Pour ce faire, nous utilisons la théorie des fonctions thêta et un modèle intermédiaire que nous appelons modèle thêta de niveau 4. Nous utilisons les relations de Riemann des fonctions thêta pour étudier l'arithmétique de ces deux courbes. Nous obtenons d'une part une loi de groupe complète, unifiée et en particulier compétitive en caractéristique 2 et d'autre part nous présentons les meilleures formules d'addition différentielle sur le modèle thêta de niveau 4. / While first used to solve the Discrete Logarithm Problem (DLP) in the group of points of elliptic curves, bilinear pairings are now useful to construct many public key protocols. The efficiency of pairings computation depends on the arithmetic of the model chosen for the elliptic curve and of the base field where the curve is defined. In this thesis, we compute and implement pairings on elliptic curves of Jacobi forms and we study the arithmetic of a new Edwards model for elliptic curves defined over any finite field. More precisely, We use the geometric interpretation of the group law of Jacobi intersection curves to obtain the first explicit formulas for the Miller function in Tate pairing computation in this case. For pairing computation with even embedding degree, we define and use the quadratic twist of this curve to obtain efficient formulas in the doubling and addition stages in Miller's algorithm. Moreover, for pairing computation with embedding degree divisible by 4 on the special Jacobi quartic elliptic curve Ed :Y²=dX⁴+Z⁴, we define and use its quartic twist to obtain a best result with respect to Weierstrass curves. Our result is at the same time an improvement of a result recently obtained on this curve, and is therefore, to our knowledge, the best result to date on Tate pairing computation among all curves with quartic twists. In 2006, Hess et al. introduced the concept of Ate pairing which is an improving version of the Tate pairing. We extend the computation of this pairing and its variations to the curve E_d. Again our theoretical results show that this curve offers the best performances comparatively to other curves with quartic twists, especially Weiertrass curves. As a third contribution, we introduce a new Edwards model for elliptic curves with equation 1+x²+y²+x²y²=\lambda xy. This model is ordinary over binary fields and we show that it is birationally equivalent to the well known Edwards model x²+y²=c²(1+x²y²) over non-binary fields. For this, we use the theory of theta functions to obtain an intermediate model that we call the level 4 theta model. We study the arithmetic of these curves, using Riemann relations of theta functions. The group laws are complete, unified, efficient and are particularly competitive in characteristic 2. Our formulas for differential addition on the level four theta model over binary fields are the best to date among well known models of elliptic curves.

Le Stress Réplicatif est caractérisé par une accumulation de fourches bloquées et est connu pour être une source majeure d'instabilité génétique dans les cellules humaines. Le Stress Réplicatif et l'instabilité génétique sont des marqueurs précoces de la tumorigenèse. Il est connu que les fourches de réplication bloquées peuvent dégénérer en cassures double brin. En effet, après un stress réplicatif prolongé (24h) induit par l'hydroxyurée (HU), l'endonucléase MUS81-EME1 peut promouvoir l'effondrement des fourches de réplication. Cette endonucléase prévient l'accumulation de régions sous-répliquées en G2 et des défauts de ségrégation chromosomique en mitose. Dans cette étude, en suivant l'apparition de cassures double brin (CDB) par les techniques sensibles d'essai comète neutre et de QIBC (Quantitative Image-Based Cytometry), nous avons pu mettre en évidence que l'effondrement des fourches est un événement qui peut être visualisé rapidement suite au stress réplicatif (dès 2h après HU). Nous avons pu caractériser cet effondrement rapide comme étant un mécanisme indépendant de MUS81, sous unité catalytique du complexe MUS81-EME1. De plus, en réalisant des extinctions de l'expression de gènes par siARN, nous avons identifié deux nucléases, Artémis et XPF, comme étant impliquées dans ce mécanisme d'effondrement rapide des fourches de réplication. Nos résultats suggèrent un rôle de ce mécanisme d'effondrement rapide dans la prévention d'intermédiaires mitotiques et de la transmission de lésions aux cellules filles. Nous avons également identifié l'ADN polymérase alternative, Pol theta comme étant un facteur impliqué dans la prévention de la mort cellulaire induite par ce mécanisme. L'exploration de données de qPCR sur des prélèvements de tissus cancéreux nous a permis d'identifier la surexpression de Pol theta comme étant corrélée à des gènes de la HR. Ceci suggère un potentiel mécanisme d'adaptation pour prévenir de l'accumulation de fourches effondrées dans les cellules cancéreuses. L'ensemble de ces données révèle que les cellules humaines ont acquis au cours de l'évolution la capacité de cliver rapidement des fourches bloquées qui pourrait s'avérer importante pour la stabilité du génome, notamment en contexte de stress réplicatif. / Replicative stress is characterized by an accumulation of stalled replication forks and is known to be a major source of genetic instability in human cells. Replicative stress and genetic instability are early markers of tumorigenesis. It is known that stalled replication forks can degenerate into double strand breaks (DSB), a process called replication fork collapse. Indeed, after an extended replicative stress (24h) induced by hydroxyurea (HU), the endonuclease MUS81-EME1 can promote the collapse of replication forks. This endonuclease prevents accumulation of under replicated regions in G2 and mitotic segregation defects. Here, by monitoring DSB with sensitive neutral comet assay and QIBC (Quantitative Image-Based Cytometry) approaches, we found that replication forks can also collapse rapidly after replicative stress (as early as 2 hours after HU). We characterised this rapid replication fork collapse as a MUS81-independent mechanism. Moreover, by performing siRNA based knock down, we identified two nucleases, Artemis and XPF, involved in rapid replication fork collapse mechanism. Our results point toward a role of this rapid collapse mechanism in preventing mitotic intermediates and lesion transmission to daughter cells. Also, we identified the role of an alternative DNA polymerase Pol theta as a molecular factor involved in preventing this mechanism to induce cell death. Data mining of expression data from tumour samples allowed us to identify Pol theta verexpression as correlated with HR genes, underpinning a potential adaptation mechanism to prevent collapsed fork accumulation in cancer cells. Collectively, these data reveal that human cells have evolved a quick cleavage response to stalled forks that might be important for genome stability notably in cells undergoing replicative stress.

Fra-1 appartient à la famille des facteurs de transcription AP-1. Son expression est particulièrement élevée dans les cellules de cancer du sein qui n'expriment pas le récepteur aux œstrogènes (RE-), c'est-à-dire les cellules les plus agressives. L'inhibition de Fra-1 dans ces cellules entraîne une diminution de la motilité, de l'invasion et de la prolifération, mais elle entraîne aussi de profonds changements de morphologie. Les cellules RE-, qui présentent un phénotype mésenchymateux s'arrondissent et établissent un plus grand nombre de contacts cellule-cellule après l'inhibition de Fra-1. Dans les cellules RE-, la β-caténine est localisée au noyau ou dans le cytoplasme, ce qui est un marqueur de mauvais pronostic. Au cours de cette thèse, j'ai montré que Fra-1 régule la localisation nucléaire de la β-caténine et ainsi régule son activité transcriptionelle en agissant très tardivement sur la voie Wnt. J'ai également mis en évidence une interaction physique directe entre Fra-1 et la β-caténine qui pourrait être responsable de cet effet. De plus, l'analyse de microarrays par RT-QPCR a révélé la régulation d'autres gènes comme la mœsine, la fibronectine et l'extracellular matrix protein 1, qui pourraient également jouer un rôle dans la régulation de l'agressivité tumorale par Fra-1. Par ailleurs, Fra-1 est une protéine instable et nous avons montré qu'elle est phosphorylée et stabilisée par PKCθ. Fra-1 est d'ailleurs nécessaire à l'effet de la kinase sur la motilité cellulaire. / Fra-1 is a member of the AP-1 transcription factor family. It is aberrantly expressed in breast cancer cells lacking Estrogen Receptor (ER-) expression, which are the most aggressive ones. Fra-1 inhibition in these cells leads to a decreased in motility, invasion and proliferation, but also to deep morphologic changes. ER- cells, which present a mesenchymal phenotype, become rounder and establish a greater number of cell-cell contacts after Fra-1 inhibition. In ER- cells, β-catenin is nuclear or cytoplasmic, which is considering as a poor prognosis marker. During this PhD, I demonstrate that Fra-1, which acts very downstream in the Wnt/β-catenin signaling pathway, regulates the nuclear localization of β-catenin leading to up-regulation transcriptional activity of β-catenin. I also found that Fra-1 directly interacts with β-catenin. In addition, RT-QPCR microarrays analysis has revealed the regulation of other genes such as mœsin, fibronectin and extracellular matrix protein 1, which might also take part in the tumoral aggressiveness regulated by Fra-1. Moreover, we show that Fra-1, which is an unstable protein, is phosphorylated and stabilized by PKCθ. Furthermore, Fra-1 is necessary to mediate the kinase effect on cell motility.