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The tumor necrosis factor (TNF) receptor-associated factors (TRAFs) were initially discovered as proteins that inducibly interact with the intracellular region of TNF receptors (TNFRs). Because the TNFRs lack intrinsic catalytic activity, the TRAFs are hypothesized to orchestrate signaling activation downstream of the TNFR superfamily, however their mechanism of activation remains unclear (Inoue et al., 2000; Bishop, 2004). Originally, the TRAFs were compared to the signal transducers and activators of transcription (STAT) protein family, due to their sequence homology, and the presence of multiple RING- and zinc-finger domains, suggesting that their function may be to regulate transcriptional activity (Rothe et al., 1994; Hu et al., 1994; Sato et al. 1995; Cheng et al., 1995). However, subsequent research focused predominantly on their cytoplasmic functions, and more recently on their function as E3 ubiquitin ligases (Pineda et al., 2007). In my research, I analyzed the subcellular localizations of the TRAFs following CD40 ligand (CD40L)-stimulation, and found that TRAF2 and 3 rapidly translocate into the nucleus of primary neurons and Neuro2a cells. Interestingly, similar analysis conducted in pre-B lymphocytes (Daudi cells) revealed a different response to CD40L-stimulation, with TRAF2 and 3 being rapidly degraded within 5-minutes of stimulation. These findings are significant because they demonstrate for the first time that the TRAFs translocate into the nucleus and suggest that they may function within the nucleus in a cell-specific manner. I next analyzed the ability of TRAF2 and 3 to bind to DNA, and found that they both bind to chromatin and the NF-kappaB consensus element in Neuro2a cells, following CD40L-stimulation. Similar analyses of the chromatin binding of TRAF2 and 3 in Daudi cells revealed that they were rapidly degraded, similar to the results from my analysis of their subcellular localization. These findings show for the first time that the TRAFs interact with DNA, and therefore support the hypothesis that the TRAFs may function within the nucleus as transcriptional regulators. Finally, I analyzed the ability of the TRAFs to regulate transcriptional activity by luciferase assay. Previous studies showed that overexpression of TRAF2 and 6 could induce NF-kappaB transcriptional activity; however researchers have not been able to determine the mechanism by which they do so. In my studies, I found that every TRAF can directly regulate transcriptional activity either as co-activators or co-repressors of transcription, in a cell- and target protein-specific manner. Additionally, I found that TRAF2 can act as a transcriptional activator, and that its ability to regulate transcription is largely dependent upon the presence of its RING-finger domain. In conclusion, these studies have revealed an entirely novel function for the TRAFs as immediate-early transcriptional regulators. Future research into the genes that are regulated by the specific TRAF complexes will further elucidate how the TRAFs regulate TNFR signaling, as well as whether dysfunctions in TRAF signaling may be associated with known disorders. If specific TRAF complexes are found to regulate specific genes, then pharmacological targeting of the individual TRAF complexes may allow for the highly specific inhibition of signaling events downstream of the TNFRs, without compromising overall receptor signaling, transcription factor pathways, or cellular systems.

Les réseaux optiques sont aujourd’hui l’élément de base des systèmes de communica- tions modernes, en particulier l’Internet. Grâce au multiplexage en longueurs d’onde et au groupage du tra?c, la bande passante disponible sur une ?bre optique est supérieure à plusieurs térabits par seconde. Cependant les équipements opto-électroniques qui permettent d’opérer ces réseaux sont très coûteux car il doivent fonctionner à un débit très important. Le problème de groupage et du routage d’un ensemble de requêtes couplé avec l’affectation des longueurs d’onde (GRWA) est donc un problème stratégique de première importance. L’objectif est de minimiser le coût du réseau, évalué comme le nombre de ports optiques installés aux nœuds. Il peut être modélisé sous la forme d’un problème d’allocation de ressources dans un réseau à capacité multi-niveaux avec multi-?ots non bifurqués. Cette catégorie de problème est connue pour être très dif?cile compte tenu de la faiblesse de la relaxation linéaire des formulations associées. Les travaux réalisés durant cette thèse ont consisté en le développement de méthodes de résolution pour ce problème à partir de multiples techniques de recherche opéra- tionnelle : méta-heuristique de type recherche avec tabous, décomposition de Dantzig- Wolfe, décomposition de Benders, reformulation en variables binaires, méthode de plans coupants, heuristique d’arrondi. Les méthodes résultantes, dont certaines sont hybrides, permettent d’avoir un aperçu des méthodes ef?caces pour ce type de problème. En partic- ulier, les méthodes basées sur la décomposition de Benders, qui donnent lieu à des procédures d’optimisation hiérarchique dans lesquelles l’affectation de longueurs d’onde est placée au dernier niveau, sont les méthodes les plus ef?caces car elles permettent de séparer le routage optique du routage physique. En?n, nous utilisons la meilleure méthode de résolution pour observer l’impact des contraintes de délais sur la qualité des solutions. / Optical networks are the core element of modern communication systems and in particu- lar Internet. With wavelength multiplexing and grooming capability, terabits per second bandwidth can be reached. However, opto-electronic equipment used to operate these networks are very expensive as their bit rate must be very large. The grooming, routing and wavelength assignment (GRWA) problem, which consists in minimizing the net- work cost, evaluated by the number of required optical ports, while guaranteeing that each request is granted, is of great interest. The GRWA problem can be modeled as a multi-layer capacitated network design problem with non-bifurcated multi-?ows. This type of problem is known to be hard to solve as their linear relaxation is weak. The objective of this work was to develop solution methods based on multiple oper- ations research techniques : Tabu search based meta-heuristic, Dantzig-Wolfe decompo- sition, Benders decomposition, 0 1 reformulation, cutting-planes, rounding heuristic. The resulting solution tools, some of them hybrid, give a perspective on the effective solution approaches for this type of problem. From the experiments, it turns out that the methods based on Benders’ decomposition, which lead to hierarchical optimization procedures, are the most ef?cient as they allow to separate the optical routing from the physical routing with the wavelength assignment decisions taken in the lower stage sub- problem. In addition to the approach comparison, we use the most effective method to evaluate the impact of the delay constraints on the solution quality.