The role of transcription factories-mediated interchromosomal contacts in the organization of nuclear architecture.

Using numerical simulations, we investigate the underlying physical effects responsible for the overall organization of chromosomal territories in interphase nuclei. In particular, we address the following three questions: (i) why are chromosomal territories with relatively high transcriptional activity on average, closer to the centre of cell's nucleus than those with the lower activity? (ii) Why are actively transcribed genes usually located at the periphery of their chromosomal territories? (iii) Why are pair-wise contacts between active and inactive genes less frequent than those involving only active or only inactive genes? We show that transcription factories-mediated contacts between active genes belonging to different chromosomal territories are instrumental for all these features of nuclear organization to emerge spontaneously due to entropic effects arising when chromatin fibres are highly crowded.

Functional architecture of olfactory ionotropic glutamate receptors.

Ionotropic glutamate receptors (iGluRs) are ligand-gated ion channels that mediate chemical communication between neurons at synapses. A variant iGluR subfamily, the Ionotropic Receptors (IRs), was recently proposed to detect environmental volatile chemicals in olfactory cilia. Here, we elucidate how these peripheral chemosensors have evolved mechanistically from their iGluR ancestors. Using a Drosophila model, we demonstrate that IRs act in combinations of up to three subunits, comprising individual odor-specific receptors and one or two broadly expressed coreceptors. Heteromeric IR complex formation is necessary and sufficient for trafficking to cilia and mediating odor-evoked electrophysiological responses in vivo and in vitro. IRs display heterogeneous ion conduction specificities related to their variable pore sequences, and divergent ligand-binding domains function in odor recognition and cilia localization. Our results provide insights into the conserved and distinct architecture of these olfactory and synaptic ion channels and offer perspectives into the use of IRs as genetically encoded chemical sensors. VIDEO ABSTRACT:

Essays on the principles and adoption of entreprise-wide architecture

Enterprise-wide architecture has become a necessity for organizations to (re)align information technology (IT) to changing business requirements. Since a city planning metaphor inspired enterprise-wide architecture, this dissertation's research axes can be outlined by similarities between cities and enterprises. Both are characterized as dynamic super-systems that need to address the evolving interest of various architecture stakeholders. Further, both should simultaneously adhere to a set of principles to guide the evolution of architecture towards the expected benefits. The extant literature on enterprise-wide architecture not only disregards architecture adoption's complexities but also remains vague about how principles guide architecture evolution. To bridge this gap, this dissertation contains three interrelated research streams examining the principles and adoption of enterprise-wide architecture. The first research stream investigates organizational intricacies inherent in architecture adoption. It characterizes architecture adoption as an ongoing organizational adaptation process. By analyzing organizational response behaviors in this adaptation process, it also identifies four archetypes that represent very diverse architecture approaches. The second research stream ontologically clarifies the nature of architecture principles along with outlining new avenues for theoretical contributions. This research stream also provides an empirically validated set of principles and proposes a research model illustrating how principles can be applied to generate expected architecture benefits. The third research stream examines architecture adoption in multinational corporations (MNCs). MNCs are Specified by unique organizational characteristics that constantly strive for balancing global integration and local responsiveness. This research stream characterizes MNCs' architecture adoption as a continuous endeavor. This endeavor tries to constantly synchron ize architecture with stakeholders' beliefs about how to balance global integration and local responsiveness. To conclude, this dissertation provides a thorough explanation of a long-term journey in Which organizations learn over time to adopt an effective architecture approach. It also clarifies the role of principles to purposefully guide the aforementioned learning process. - L'Architecture d'Entreprise (AE) est devenue une nécessité pour permettre aux organisations de (ré)aligner les technologies de l'information (TI) avec les changements en termes de besoins métiers. En se basant sur la métaphore de la planification urbaine dont l'AE s'est inspirée, cette dissertation peut être présentée comme une comparaison entre les villes et les entreprises; les deux sont des super-systèmes dynamiques ayant besoin de répondre aux intérêts d'acteurs divers et variés en constants évolution. De plus, les deux devraient souscrire simultanément à un ensemble de principes afin de faire converger l'évolution de l'architecture vers les bénéfices attendus. La littérature sur l'AE, non seulement ne prend pas en considération les complexités de l'adoption d'architecture, mais aussi reste vague sur la manière dont les principes guident l'évolution de l'architecture. Pour pallier ce manque, cette dissertation est composée de trois volets de recherche étroitement liés examinant les principes et l'adoption de l'AE. Le premier volet examine la complexité organisationnelle inhérente à l'adoption de l'architecture. Il caractérise l'adoption de l'architecture en tant que processus d'adaptation continu. En analysant le comportement organisationnel en réponse à ce processus d'adaptation, ce volet distingue quatre archétypes représentant la diversité des approches de l'architecture. Le deuxième volet de recherche clarifie de manière ontologique la nature des principes d'architecture et envisage les contributions théoriques futures possibles. Cet axe de recherche fournit aussi un ensemble de principes, validés de manière empirique, et propose un modèle de recherche illustrant la manière dont ces principes peuvent être appliqués afin de générer les bénéfices attendus de l'architecture. Le troisième volet examine l'adoption de l'architecture dans les entreprises multinationales. Ces dernières possèdent des caractéristiques organisationnelles uniques et sont constamment à la recherche d'un équilibre entre une intégration globale et une flexibilité locale tout en prenant en compte les convictions des divers acteurs sur la manière d'atteindre cet équilibre. Pour conclure, cette dissertation fournit une explication sur le long voyage au cours duquel les entreprises apprennent à adopter une approche d'architecture efficace. Elle clarifie aussi le rôle des principes dans l'accompagnement de ce processus d'apprentissage.

Second primary cancers in the Vaud and Neuchâtel Cancer Registries

An increasing proportion of new cancers is registered in patients who have received a previous cancer diagnosis. As data are inconsistent across studies, we provided information for populations long covered by valid cancer registration. Data were derived from the Swiss cancer Registries of Vaud and Neuchâtel (885 000 inhabitants). Patients diagnosed with a new malignancy (except skin basal and squamous cell carcinomas) during the period 2005-2010 were included. Over the period 2005-2010, 24 859 patients were registered with incident cancer. Of these, 3127 (13%) had multiple primary cancers and 578 (2.3%) were synchronous. Breast, prostate, colorectum, skin, melanomas, and squamous cell carcinomas of the head and neck (SHN) and bladder/ureter were the most common sites of first neoplasms, whereas breast, lung, colorectum, prostate, melanoma, and SHN were the most common sites of second neoplasms. The most common pairing was breast with breast (31% synchronous), followed by the bladder/ureter with the prostate (72% synchronous), prostate with the colorectum, SHN with SHN, and SHN with lung. Five-year crude survival of patients with synchronous cancers (34%) was not significantly lower than that of patients with single neoplasms (39%).

Structural variation-associated expression changes are paralleled by chromatin architecture modifications.

Copy number variants (CNVs) influence the expression of genes that map not only within the rearrangement, but also to its flanks. To assess the possible mechanism(s) underlying this "neighboring effect", we compared intrachromosomal interactions and histone modifications in cell lines of patients affected by genomic disorders and control individuals. Using chromosome conformation capture (4C-seq), we observed that a set of genes flanking the Williams-Beuren Syndrome critical region (WBSCR) were often looping together. The newly identified interacting genes include AUTS2, mutations of which are associated with autism and intellectual disabilities. Deletion of the WBSCR disrupts the expression of this group of flanking genes, as well as long-range interactions between them and the rearranged interval. We also pinpointed concomitant changes in histone modifications between samples. We conclude that large genomic rearrangements can lead to chromatin conformation changes that extend far away from the structural variant, thereby possibly modulating expression globally and modifying the phenotype. GEO SERIES ACCESSION NUMBER: GSE33784, GSE33867.

Réforme de la péréquation financière et de la répartition des tâches : incidences du transfert du domaine des institutions pour personnes handicapées aux cantons : [analyse comparative entre les cantons de Neuchâtel, Vaud, du Valais, de Bâle-Ville et de Bâle-Campagne]

La réforme de la péréquation financière et de la répartition des tâches entre la Confédération et les cantons (RPT) entrera en vigueur le 1er janvier 2008. Elle prévoit notamment le transfert de la responsabilité des institutions pour personnes handicapées de la Confédération aux cantons. Ce mémoire se concentre sur ce domaine particulier en décrivant de quelle manière les cantons se préparent pour assumer leurs nouvelles responsabilités et comment ils envisagent de redéfinir leurs relations avec les institutions spécialisées et les personnes handicapées. Par une analyse comparative menée dans les cantons de Neuchâtel, Vaud, Valais, Bâle-Ville et Bâle-Campagne des différences intercantonales importantes sont mise en évidence et permettent d'aborder la problématique générale de la mise en oeuvre d'une politique sociale dans un Etat fédéral.