The transcription factor c-Myc plays a central role in cell growth and proliferation owing to the large number of genes it transactivates or transrepresses and to the fact that these genes are in turn implicated in these cellular processes. Also, c-Myc's deregulation and/or overexpression contribute to most aspects of tumoral cellular biology. As a heterodimer with Max, c-Myc activates the transcription of genes leading to cell proliferation and represses the transcription of cytostatic genes such as p15[superscript ink4b] and p21[superscript CiP1]. In contrast to the transactivation mechanism, our current understanding of the transrépression by c-Myc is still incomplete, aside from the fact that an interaction with Miz-1 is essential. Coupling preliminary results from a collaboration with Martin Eilers' group to data obtained following a bioinformatics' approach to predict Miz-1 DNA binding, we were able to elaborate a now transrepression mechanism for c-Myc/Miz-1. In this mechanism, the c-Myc/Max heterodimer directly binds the noncanonical E-box sequences present in the promoters and provoke the supercoiling of DNA assisted by the interaction between c-Myc and Miz-1. This supercoiling impairs accessibility to the initiation site to the transcriptional machinery. This thesis aims at the study on a structural and biophysics viewpoint of the determinants for the specific heterodimerization and DNA binding by c-Myc and Max and the interaction between c-Myc and Miz-1 in order to validate our mechanistic model for the transrépression by c-Myc. In chapter 1, we present an overview of the actual knowledge on Myc and the repression model along with some of the results that led to its elaboration. Chapters 2 and 3 report the study of the structural determinants for the heterodimerization and E-box binding by the b-HLH-LZ domains of c-Myc and Max. Our model allows to predict that b-HLH-LZ peptides able to bind the E-box present in the repressed promoters without interaction with Miz-1 could reverse the inaccessibility and reactivate p15[superscript ink4b] and p21[superscript Cip1] expression in cancer cells where c-Myc is overexpressed.The results presented in this thesis will find application in the development of new inhibitors of c-Myc eventually leading to novel therapies to fight cancer.

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

A STUDY ON THE ESTABLISHMENT AND OPERATION OF THE CONGRESSIONAL LIAISON SYSTEM IN THE MINISTRY OF NATIONAL DEFENSE R.O.C. Abstract With the implementation of the Defense Act and the Organization Law of the Ministry of National Defense in 2002, all defense-related matters became formally regulated by law. The relationship between the military and other civilian agencies in the government are therefore of vital importance to national security and defense development. Especially the relationship with Congress, it could influence not only the approval of defense budgets and legislative proposals regarding armed forces, but also the development of military organizations. Based on the author¡¦s previous experience serving as an MND congressional liaison officer, there are some issues need to be worked out, and they become the research motives of this study: Due to confrontations between the Administration and Congress, defense related matters are constantly questioned by lawmakers and encounter considerable difficulties, the author wanted to identify whether the source of this problem is the legal system itself, the personnel involved, or the effectiveness of current congressional liaison system. Since the operation of current military congressional liaison teams depend only on personal experiences and lack professional expertise from related fields such as political science, media propaganda, public relations, administrative management, policy marketing, etc., liaison officers are forced to explore the delicate interactions between the Administration and Legislation all by themselves. Furthermore, liaison personnel from different levels fail to integrate effectively and can not cooperate functionally with the Office of Military Spokesmen. With the above shortcomings, current military liaison teams can only be regarded as congressional contacts, the author would like to provide helpful recommendations through this practical research. Since the MND was among the first few government agencies that established corresponding congressional liaison teams, there are a lot of references available. This research took a qualitative approach, related studies, then interviews with legislators, MND officials, congressional staff, media reporters, and officers serving as (or used to be) military congressional liaisons were conducted and analyzed to investigate the function and effectiveness of current MND congressional liaison system. The first objective of this research is to clearly define the role and functions of the MND congressional liaison system and to enhance its effectiveness in the interactions between the military and Congress. The second objective is to help MND congressional liaison personnel establish enough professional expertise and knowledge to facilitate appropriate approvals of defense budgets and legislative proposals while maintaining a politically neutral stand under the omnipresent political pressures from opposing parties. The third objective of this research is to provide findings and recommendations for the establishment of MND congressional liaison system by examining current liaison procedures from different aspects such as military relations, public policies, issue management, policy marketing, propaganda, and public relations, as well as by investigating the effectiveness of the operations of current liaison system from in-depth interviews with professionals. The Congress plays as a role of Constitutional politics due to the process of making defence policies. Congressional liaison system is main organization of MND for communicating, assisting law makers to conduct the responsibilities of supervising the Constitution. Also, it is the bridge and interface for obtaining ¡§support defence policies ¡¨ from public, political parties and excellent politicians. This article provides recommendations of academics and policies, and as a reference of creating congressional liaison system, focus on organizations, law and regulations, personnel and operations.

Thèse (M.Sc.)--Université Laval, 2007. / Bibliogr.: f. 68-75. Publié aussi en version électronique dans la Collection Mémoires et thèses électroniques.

Les périodiques tels que Liaison, L’Étoile de l’A.E.F. ou La Semaine de l’A.E.F. ont joué un rôle primordial dans ce que H.J. Lüsebrink appelle « la conquête de l’espace public » par les élites colonisées, en l’occurrence celles de l’Afrique équatoriale française (Gabon, Moyen-Congo, Oubangui-Chari et Tchad), et notamment dans la constitution d’un champ littéraire local. À partir de 1950, on assiste à un foisonnement des revues grâce à la presse coloniale qui gérait les rares imprimeries et maisons d’édition du continent. La présente étude concerne l’impact de la presse coloniale dans la naissance des premières œuvres africaines, et spécialement aéfiennes. Elle concerne une époque pionnière de l’histoire littéraire africaine, encore trop peu étudiée en détail aujourd’hui. Elle n’est pas cependant centrée sur les livres, mais bien sur les revues, documents irremplaçables pour toute approche historique de la vie littéraire / Periodicals such as Liaison, L’Etoile de l’AEF or La Semaine de l’A.E.F. played a fundamental role in what H.J. Lüsebrink called “the conquest of the public space” by the colonised elites, in this case those of French Equatorial Africa (Gabon, Middle Congo, Ubangui Shari and Chad), and in particular, in the constitution of a local literary field. Since 1950, there was a profusion of journals, thanks to the colonial press which managed the rare printing presses and publishing houses of the continent. This study examines the influence of the press on the birth of the first African works, especially for the Frech Equatorial Africa of this time. It refers to a founding era of the African literary history, still too little really studied to day. Although, it is not centered as often on books, but on periodicals which are essential keys for any historical approach of literary life

Abstract General hospital psychiatry operates between the somatic and psychiatric approaches concerning the treatment of patients, combining knowledge from both somatic and psychiatric medicine. To establish its position, the general hospital psychiatry has to specify its role and means when rendering services. This study revealed how consultation had been arranged in six Finnish polyclinics of general hospitals. The goal was to find out which types of patients were referred to the consultation of the general hospital psychiatry and the extent of collaboration of the consulting psychiatrist with colleagues from other medical disciplines. Moreover, the focus of attention was on whether there were operational differences between the polyclinics of the University Hospital of Oulu and other hospitals. The work was also addressed to probing operational differences, if any, pertaining to people under or over 65. Additionally, one aspect to be clarified was how requests for psychogeriatric consultations and the responses of the consulting psychiatrists had developed during the five years period of the study. This study was part of a broad European Consultation Liaison Working Group effort aimed at clarifying the organization of general hospital psychiatry in 56 units in 11 European countries. The Finnish material consisted of 1255 patients, of whom 202 were over 65. The research methods applied here were psychiatric interviewing of clinical patients, and filling in of data collection forms following the instructions of the ECLW Group. The current work revealed that the number of psychiatric consultations was less than expected considering the incidence of psychiatric symptoms among somatically ill patients. Of the general hospital patients, elderly people were especially underrepresented. More than 90% of the patients who had a psychiatric consultation were diagnosed with a psychiatric problem. Thus the general hospital made available psychiatric treatment via psychiatric consultation, with a recommendation for future psychiatric care for more than half of the patients. However, one third of the patients under 65 and quarter of those above that age had already had on going psychiatric treatment. In view of this type of situation the position of the general hospital appears problematic. The object of consultation was in 90% of the cases the patients themselves, but in Oulu, almost half of the consultations were due to the personnel of the somatic disciplines in charge of the of the patients. The action mode in separate general hospitals was connected to established traditions, although the history of general hospital psychiatry is short and faces constraints put forward by the somatic hospitals. Collaboration between psychiatric and somatic disciplines was facing increasing difficulties during the five years observation period, probably due to economic recession.

La Polyarthrite Rhumatoïde, une des maladies auto-immunes les plus répandues, est caractérisée par une destruction progressive des articulations, conduisant à des déformations et handicaps. La nature multifactorielle de la PR fournit une hétérogénéité élevée avec des combinaisons spécifiques entre un profil génétique et des facteurs environnementaux qui influencent la susceptibilité, la gravité et le développement de la maladie. L’objectif de cette thèse est l’identification et la caractérisation de gènes candidats dans la PR. Nous avons confirmé l’association ainsi que la liaison des régions TRAF1-C5 et 6q23, et démontré une tendance pour une association et liaison entre la région génique 4q27 et la PR dans la population européenne. De plus, nous avons fourni des résultats concluants qui s’opposent à une implication des gènes PRKCH, CASP7, RANK, RANKL et PTPN22-1123G dans la susceptibilité génétique à la PR dans la population européenne. Nous avons effectué une étude d’expression génique utilisant 48.701 ADNc des PBMC de patients et contrôles sains. Une expression différentielle de 339 gènes entre les deux groupes a été observée. Nous avons identifié une expression élevée d’un spectre de nouveaux gènes impliqués dans différents mécanismes immunitaires de la PR. Nous avons aussi identifié une association entre les allèles HLA EP et le tabac au sein des patients ACPA positifs avec une PR familiale ou sporadique. Ces différentes approches complémentaires ont permis l’identification de nouveaux gènes et la mise en évidence d’interactions gène-autoanticorps-environnement, contribuant ainsi à une meilleure compréhension des mécanismes pathologiques de la PR. / Rheumatoid Arthritis, one of the most common autoimmune diseases, is characterized by progressive articular damage leading to joint deformities and disability. The multifactorial nature of RA provides high disease heterogeneity with specific combinations of a genetic background and environmental factors that influence the susceptibility, severity and outcome of the disease. The aim of this thesis was the identification and characterization of candidate genes in RA. We have confirmed the association and linkage of TRAF1-C5 and 6q23 gene regions, and demonstrated a trend for the association and linkage of the 4q27 gene region with RA in European descent populations. Furthermore, we provided evidence against the involvement of the PRKCH, CASP7, RANK and RANKL genes and the PTPN22–1123G allele in RA genetic susceptibility in the European population. We performed a large-scale gene expression profiling study using 48.701 cDNAs in PBMCs of RA patients and healthy controls. A differentially expression of 339 genes (238 down-regulated and 101 up-regulated) between the two groups was observed. We identified a remarkably elevated expression of a spectrum of new genes involved in immunity and defense mechanisms. Finally, we identified an association between HLA SE alleles and tobacco smoking for anti-CCP positivity in French population with familial and sporadic RA. All these complementary approaches that allowed the identification of new genes and gene-autoantibodies-environment interactions contribute to a better understanding of RA disease mechanisms and could lead to the identification of innovative clinical biomarkers for diagnostic procedures and therapeutic interventions.

This thesis addresses two important aspects of automatic assembly viz., assembly sequence planning and assembly path planning. These issues are addressed separately starting with sequence planning followed by assembly path planning. For efficient assembly without feedback systems (or, passive assembly), an assembler should know the ideal orientation of each component and the order in which to put the parts together (or, assembly sequence). A heuristic is presented to find the optimal assembly sequence and prescribe the orientation of the components for a minimum set of grippers = ideally one. The heuristic utilizes an index of difficulty (ID) that quantifies assembly. The ID for each task in the assembly process is computed on the basis of a number of geometrical and operational properties. The objective of the optimization problem here is to minimize the assembly ID and categorize parts/subassemblies based on their preferred direction of assembly while allowing re-orientation of the base part. It is assumed that the preferred direction of assembly is vertically downward, consistent with manual as well as most automatic assembly protocols. Our attempt is to minimize the number of degrees of freedom required in a re-orienting fixture and derive the requirements for such a fixture. The assembly of a small engine is used as an example in this study due to the variety of ideally rigid parts involved. In high precision assembly tasks, contact motion is common and often desirable. This entails a careful study of contact states of the parts being assembled. Recognition of contact states is crucial in planning and executing contact motion plans due to inevitable uncertainties. Dr. Jing Xiao of UNCC introduced the concept of principal contacts (PC) and contact formation (CF) for contact state recognition. The concept of using CFs (as sets of PCs) has the inherent advantage that a change of CF is often coincident with a discontinuity of the general contact force (force and torque). Previous work in contact motion planning has shown that contact information at the level of PCs along with the sensed location and force information is often sufficient for planning high precision assembly operations. In this thesis, we present results from experiments involving planned contact motions to validate the notion of PCs and CFs -- an abrupt change in general contact force often accompanies a change between CFs. We are only concerned with solving the 2D peg-in-corner problem. / Master of Science

No description available.

Tableau d'honneur de la Faculté des études supérieures et postdoctorales, 2011-2012 / La sclérose latérale amyotrophique (SLA) est une maladie mortelle caractérisée par une dégénérescence des neurones moteurs supérieurs et inférieurs. La présence d’inclusions ubiquitinylées de la protéine TDP-43 (Transactive response DNA-binding protein 43) est une caractéristique de la SLA. Afin de comprendre le mécanisme pathogène impliquant cette protéine, nous avons généré et étudié des souris transgéniques en utilisant des fragments génomiques codant pour la TDP-43 humain, de type sauvage ou mutant, associés aux cas familiaux de la SLA. Ces souris développent de nombreux changements liés au processus pathologique et biochimique de la SLA chez l’homme : présence d’inclusions de la protéine TDP-43 ubiquitinylées, anomalies au niveau des filaments intermédiaires, axonopathie et neuroinflammation. Pour mieux comprendre le rôle de la protéine TDP-43 dans la régénération des axones, nous avons utilisé des souris pré-symptomatiques et effectué une lésion du nerf sciatique sur celles-ci. Suite à cette intervention, les souris transgéniques ont eu une paralysie marquée du membre lésé, ont démontré une redistribution altéré de TDP-43 et une regénération plus lente des axones distaux par rapport aux souris non transgéniques. De plus, nous avons constaté que la protéine TDP-43 interagit et colocalise avec la sous-unité p65 du facteur nucléaire κΒ (NF-κΒ). Cette interaction se produit dans les cellules gliales et les neurones des souris transgéniques TDP-43 et aussi chez les patients atteints de la SLA. Nous avons démontré que les niveaux d’ARNm des protéines TDP-43 et NF-κΒ p65, sont plus élevés dans la moelle épinière des patients atteints de SLA que chez les individus sains et que la protéine TDP-43 agit comme un coactivateur de p65. Finalement, le traitement des souris transgéniques TDP-43 avec la Withaférine A, un inhibiteur de l’activité NF-κΒ, réduit le niveau de dénervation des jonctions neuromusculaires et des symptômes liés à la SLA. Nous suggérons donc que le dérèglement de la protéine TDP-43 contribue à la pathogenèse de la SLA en partie par l'augmentation de l'activation de NF-κΒ, et que NF-κΒ pourrait constituer une cible thérapeutique pour la maladie. / Amyotrophic lateral sclerosis (ALS) is a lethal disease characterized by degeneration of lower and upper motor neurons. Transactive response DNA-binding protein 43 (TDP-43) ubiquitinated inclusions are a hallmark of ALS. In order to understand the pathogenic mechanism caused by TDP-43, we generated transgenic mice with genomic fragments encoding human TDP-43 wild-type or FALS-linked mutants TDP-43G348C and TDP-43A315T. These novel TDP-43 transgenic mice develop many age-related pathological and biochemical changes reminiscent of human ALS including ubiquitinated TDP-43 positive inclusions, intermediate filament abnormalities, axonopathy and neuroinflammation. In order to understand the role of TDP-43 in axon regeneration, we used pre-symptomatic 3-months old mice and performed sciatic nerve crush on them. After axonal crush, TDP-43 transgenic mice were noticeably paralyzed at the injured limb, have altered TDP-43 redistribution and the distal axons regenerated slowly as compared to non-transgenic mice. Moreover, we found that TDP-43 interacts with and colocalizes with p65, a NF-κΒ subunit, in glial and neuronal cells from TDP-43 transgenic mice and also from ALS patients. We report that TDP-43 and NF-κΒ p65 mRNA and protein expression is higher in spinal cords of ALS patients than healthy individuals. TDP-43 acted as a co-activator of p65, and glial cells expressing higher amounts of TDP-43 produced more proinflammatory cytokines and neurotoxic mediators after stimulation with lipopolysaccharide or reactive oxygen species. TDP-43 overexpression in neurons also increased their vulnerability to toxic mediators. Treatment of TDP-43 mice with Withaferin A, an inhibitor of NF-κΒ activity, reduced denervation in the neuromuscular junction and ALS disease symptoms. We propose that TDP-43 deregulation contributes to ALS pathogenesis in part by enhancing NF-κΒ activation, and that NF-κΒ may constitute a therapeutic target for the disease.