Nous étudions une nouvelles familles d'inhibiteurs de kinase: les benzopyridoindole. Ces molécules ont des effets antiprolifératifs sur des lignées cancéreuses et représentent les têtes de série de possibles agents anti-cancéreux. We study on a new family of kinase inhibitors: benzopyridoindole. These molecules have antiproliferative effects on cancer cell lines and represent the lead of potential anti-cancer products. / Benzo[e]pyridoindoles are novel potent inhibitors of aurora kinases. We performed a SAR study to improve their activity and water solubility. Amino-benzo[e]pyridoindolones were found to be potent hydrosoluble anti-proliferative molecules. They induced a massive arrest in mitosis, prevented histone H3 phosphorylation as well as disorganizing the mitotic spindles. Upon a delay, cells underwent binucleated and finally died. Taking into account their interesting preclinal characteristics, their efficiency towards xenografts in nude mice and their apparent safety in animals, these molecules are promising new anti-cancer drugs. They probably target a metabolic signaling pathway, besides aurora B inhibition. In addition to their possible applications, these inhibitors are tools for cell biology studies. C4, a low ATP affinity inhibitor of aurora B kinase, revealed that the basal activity of the kinase is required for histone H3 phosphorylation in prophase and for chromosome compaction in anaphase. These waves of activation/deactivation of the kinase, during mitosis, corresponded to different conformations of the passenger chromosomal complex.

Afin d’étudier la prise en charge des histones H3 jusqu’à l’ADN et pour comprendre l’influence de leur dynamique dans l’organisation d’ordre supérieur de la chromatine, une analyse des chaperonnes d’histones a été menée. Nous avons identifié et caractérisé les sous-unités du complexe HIR, impliqué dans l’assemblage de la chromatine réplication-indépendante chez Arabidopsis. La perte d’AtHIRA, la sous-unité centrale du complexe, affecte le niveau d’histone soluble, l’occupation nucléosomale des régions euchromatiniennes et héterochromatiniennes ainsi que la mise sous silence transcriptionnel des séquences d’ADN répétées. Alors que le complexe HIR ne participe pas à l’organisation d’ordre supérieur de la chromatine, j’ai montré que CAF-1, impliqué dans l’assemblage de la chromatine au cours de la réplication, joue un rôle central dans la formation des chromocentres. Lors du développement post-germinatif des cotylédons, les séquences d’ADN répétées centromériques et péricentromériques se concentrent dans les chromocentres et s’enrichissent en histone H3.1 de manière CAF-1 dépendante. Cet enrichissement, associé à des modifications post-traductionnelles d’histones associées à un état répressif de la transcription, participe à la formation des chromocentres et met en évidence l’importance de l’assemblage de la chromatine par CAF-1 dans la structure et le maintien du génome. Alors que la perte individuelle de HIR ou de CAF-1 n’affecte pas la viabilité, l’absence des deux complexes altère fortement l’occupation nucléosomale et le développement des plantes. Ceci suggère que la compensation fonctionnelle entre ces complexes de chaperonnes ainsi que la plasticité des voies de dépôt des histones restent limitées. / To understand how histones H3 are handled and how histone dynamics impact higher-order chromatin organization such as chromocenter formation in Arabidopsis, a comprehensive analysis of the different histone chaperone complexes is required. We identified and characterized the different subunits of the Arabidopsis HIR complex. AtHIRA is the central subunit and its loss affects non-nucleosomal histone levels, reduces nucleosomal occupancy not only at euchromatic but also at heterochromatic targets and alleviates transcriptional gene silencing. While the HIR complex-mediated histone deposition is dispensable for higher-order organization of Arabidopsis heterochromatin, I show that CAF-1 plays a central role in chromocenter formation. During postgermination development in cotyledons when centromeric and pericentromeric repeats cluster progressively into chromocenter structures, these repetitive elements but not euchromatic loci become enriched in H3.1 in a CAF-1- dependent manner. This enrichment, together with the appropriate setting of repressive histone post-translational marks, contributes to chromocenter formation, identifying chromatin assembly by CAF-1 as driving force in formation and maintenance of genome structure. Finally, while absence of HIR or CAF-1 complexes sustains viability, only the simultaneous loss of both severely impairs nucleosomal occupancy and plant development, suggesting a limited functional compensation between the different histone chaperone complexes and plasticity in histone variant interaction and deposition in plants.

Les DIPG représentent les tumeurs cérébrales pédiatriques les plus sévères. Aucun progrès dans leur prise en charge n’a été accompli au cours des 50 dernières années et la radiothérapie ne demeure que transitoirement efficace. Récemment, une mutation somatique de l’histone H3 (K27M) spécifique des DIPG a été trouvée chez environ 95% des patients. Elle est aujourd’hui considérée comme l'événement oncogénique initiateur de ces tumeurs. Deux sous-groupes majeurs de patients présentant des programmes oncogéniques et une réponse à la radiothérapie distincts peuvent être définis en fonction du gène dans lequel l’altération survient, codant les variantes protéiques H3.1 ou H3.3. Nous avons réalisé deux cribles de létalité synthétique par ARN interférence ciblant le kinome humain afin d'identifier d’une part les gènes nécessaires à la survie des DIPG et d’autre part les gènes dont l’inhibition sensibilise ces tumeurs à la radiothérapie. Le double objectif de ce projet était de mieux comprendre la biologie sous-jacente à l’oncogenèse des DIPG et de découvrir de nouvelles cibles thérapeutiques.Nous avons mis en évidence 41 gènes requis pour la survie des DIPG sans effet délétère majeur sur des cellules contrôles normales. Parmi eux, nous avons identifié VRK3 codant une serine thréonine kinase dont les fonctions restent peu décrites à ce jour et qui n'avait jamais été associée préalablement à l'oncogenèse de DIPG. Nous avons pu confirmer par la suite que son inhibition conduit à un arrêt total de la prolifération des cellules de DIPG associé à d’importants changements morphologiques, plus particulièrement dans les tumeurs mutées pour H3.3-K27M. VRK3 constitue par conséquent une nouvelle cible thérapeutique prometteuse dans cette pathologie à l’issue fatale pour la totalité des patients.En parallèle, un crible de survie similaire a été réalisé en conjonction avec l’irradiation des cellules. Très peu d’ARN interférents ont permis de sensibiliser les cellules H3.3-K27M à la radiothérapie contrairement aux cellules H3.1-K27M. Ce travail nous a permis de mettre en évidence une différence significative de radiosensibilité des modèles vitro de DMG en fonction du sous-groupe de tumeurs considéré, H3.1- ou H3.3-K27M muté, conformément à la survie des patients observée suite à la radiothérapie. Ces résultats inédits laissent entrevoir des perspectives d’amélioration du traitement de référence des patients atteints de DIPG actuellement identique quelle que soit leur génotype. / DIPG is one of the most severe paediatric brain tumours. No progress has been made in their management over the past 50 years and radiotherapy remains only transiently effective. Recently, a specific somatic mutation in the histone H3 (K27M) has been found in approximately 95% of DIPG patients and can be considered as the oncogenic driver of these tumours. Two major subgroup of patients with distinct oncogenic program and response to radiotherapy can be defined according to the gene in which the alteration occurs, encoding the H3.1 or H3.3 protein variants. We performed two synthetic lethality screens by RNA interference targeting the human kinome in order to identify the genes responsible for DIPG cell survival, as well as those sensitizing tumour cells to radiotherapy after inhibition. The dual purpose of this project was to better understand the biology underlying oncogenesis of DIPGs and to discover new therapeutic targets.We identified 41 genes required for DIPG cell survival with no major deleterious effect on normal control cells. Among them, we identified VRK3, a serine threonine kinase never involved in DIPG oncogenesis with functions remaining poorly described to date. We have shown that its inhibition leads to a complete arrest of DIPG cell proliferation and is additionally associated with important morphological changes, more particularly in H3.3-K27M mutated tumours. VRK3 is therefore a promising new therapeutic target for all patients in this fatal pathology.In parallel, a similar survival screen was performed in conjunction to cell radiation and very few interfering RNAs enhance H3.3-K27M cell radiosensitivity, in contrast to H3.1-K27M cells. These data highlighted a significant difference in radiosensitivity of the DMG in vitro models in H3.1- versus H3.3-K27M mutated tumours, in a concordant way with patient survival following radiotherapy. These unprecedented results suggest new opportunities for improving the current treatment of DIPG patients regardless of their genotype.

No description available.

This paper provides a comprehensive empirical assessment of the relation between the cyclicality of fiscal expenditure policy, output volatility, and economic growth, using a large cross-section of 88 countries over the period 1960 to 2004. Identification of the effects of (endogenous) cyclical expenditure policy is achieved by exploiting the exogeneity of countries political and institutional characteristics, which we find to be relevant determinants of the cyclicality of expenditures. There are three main results: First, both pro- and countercyclical expenditure policy amplify output volatility, much in a way like pure fiscal shocks that are unrelated to the cycle. Second, output volatility, due to variations in cyclical and discretionary fiscal policy, is negatively associated with economic growth. Third, there is no direct effect of cyclicality on economic growth other than through output volatility. These findings advocate the introduction of fiscal rules that limit the use of (discretionary and) cyclical fiscal (expenditure) policy to improve growth performance by reducing volatility. (author's abstract)

No description available.

Les interactions protéine–protéine jouent un rôle essentiel dans le fonctionnement cellulaire et sont impliquées dans diverses pathologies. L'étude de ces interactions est donc primordiale. Nous avons entrepris de développer une méthode de « footprinting » basée sur la différence d'accessibilité à l'eau des acides aminés d'une protéine selon qu'elle est seule ou en interaction. Le principe de cette méthode de caractérisation des zones d'interactions protéine–ligand, est basé sur une étape de génération de radicaux carbo-centrés sur les chaînes latérales des acides aminés de la protéine, et sur une étape de réparation de ces radicaux par un atome de tritium.<br /> <br />La première étape a été de déterminer la réactivité des 20 acides aminés communs vis-à-vis de notre méthode : <br />Lys>Leu>Arg>Ile>Trp>Phe>Val>Cys>Met>His>Tyr>Glu>Thr>Asp><br />Gln>Pro>Ala>Asn> Ser>Gly. Notre méthode ensuite appliquée à l'étude du complexe entre la protéine hAsf11-156 et un fragment de l'histone H3 a permis de caractériser sans ambiguïté les trois résidus principaux de H3 (L126, R129 et I130) impliqués dans cette interaction. De plus, nous avons mis en évidence que notre méthode de caractérisation des interactions protéique est à la fois sensible aux phénomènes d'interaction et de repliement.

Aún a pesar de la importancia de los movimientos poblacionales en nuestro país, la revisión de la literatura existente sugiere una falta de esfuerzo en estudiar de manera integrada la magnitud y la dirección de los flujos migratorios, especialmente de los movimientos internos. Este trabajo además de describir el proceso migratorio en Argentina y caracterizar a la población migrante, estudia los determinantes de las decisiones de migración, con especial énfasis en las características individuales y regionales, así como la influencia de las políticas públicas provinciales. Utilizando datos de la Encuesta Permanente de Hogares, se estiman modelos para la probabilidad de ser migrante, tendiendo en cuenta estas características sociodemográficas y de las regiones de origen y destino de la población. Las estimaciones indican que las características individuales y los gastos en educación, vivienda pública y en programas de empleo que realizan las provincias son factores que determinan significativamente las decisiones de migración. El grado de urbanización y los recursos naturales de las provincias son las características regionales que más influencia tienen sobre los movimientos entre provincias.

Data on primary productivity, chlorophyll a, nitrate, and phosphate in surface waters were collected on a 14-month (March, 1970 to April, 1971) series of approximately biweekly cruises in Kaneohe Bay, Oahu, Hawaii. During the latter part of the survey data ammonium ion concentrations and light penetration through the water column were also collected. The year is divided into two seasons on the basis of rainfall, and the effects on the dynamics of the phytoplankton community of terrestrial runoff and sewage effluents entering the bay are separated on the basis of differences between wet season and dry season productivity indices (productivity/Chl. a). The bay is divided into three sectors; South, Transition, and North. The most important nutrient sources are; the Kaneohe Municipal Sewage Treatment Plant effluent to the South Sector, terrestrial runoff to the Transition Sector, and a persistent, but unidentified nitrate input to the North Sector. The Municipal Treatment Plant effluent is shown to be toxic to phytoplankton in the immediate area. Phosphate concentration is not correlated with rainfall, and is present in non-limiting concentrations in all sectors. Nitrate concentration is strongly correlated with rainfall in the Transition Sector, and low dry season (summer) concentrations may limit phytoplankton growth. Wet season (winter) nitrate concentrations in the other two sectors are also higher than summer values, but the differences are not significant. Fluctuations in phytoplankton population size seem to be primarily a function of variable grazing pressure by herbivorous zooplankton. Phytoplankton growth rates peak in summer and winter, and may be related to the availability of light. Light penetration itself is directly related to phytoplankton density in the water column, and the winter growth rate peak may result from increasing light penetration due to extensive grazing on the phytoplankton population. The present data are compared with similar data collected 10 years earlier. Based on a hyperbolic relationship between substrate concentration and growth rate, the South Sector is shown to have been eutrophic for at least the past decade, while in the Transition and North Sectors symptoms of eutrophication have appeared during this decade. / Typescript. Theses for the degree of Master of Science (University of Hawaii at Manoa)--University of Hawaii, 1973. Bibliography: leaves 87-90.

The growth of popular protestantism and the increased demands of Irish Catholicism were two nineteenth century developments which would not take place without conflict. The high Churchmanship and Toryism of Wesley coupled with Methodist experiences in Ireland ensured that Wesleyans would not support concessions to the Irish Catholics. The remarkable numerical growth of Methodism in England only highlighted its apparent failure in Ireland when confronted by a surprisingly resilient Catholicism. Most religious and social conflicts have political ramifications and this one was no exception. Battle lines were dram over three important questions. Were Roman Catholics entitled to the same political, rights as everyone else? What were the relative responsibilities of Church and State in the provision of education? What was to be the fate of protestantism in Ireland when it was in such a hopeless minority? In all of these questions Methodism and Roman Catholicism found themselves on completely opposite sides. As with later non-conformists the Wesleyans could not accept that what was theologically and morally wrong could ever be politically right. In response the Irish Catholics could appeal to the government for change in a country where the religion of the majority was politically and socially in subjection to the religion of the minority. Methodism's allies were the Established Church and the Tory party, and both let them down. In the disappointment of political failure over the Maynooth Bill the Wesleyans reaffirmed their belief in religious methods by participating in the Evangelical Alliance. In spite of short term successes Methodism's political objectives were not achieved and participation in public affairs often produced connexional disharmony.