La longue séquence pliocène de Marchésieux - Résultats analytiques et premiers résultats

National audienceLe sondage intégralement carotté de Marchésieux a permis d'atteindre l'objectif fixé dans le projet AR42 du BRGM : l'analyse paléoclimatique du premier épisode glaciaire de l'hémisphère nord (Prétiglien, -2,4 Ma) et probablement le premier rafraîchissement de -3,1 Ma. Les 159,3 m de sédiments datés du Reuvérien et du Prétiglien ont déjà livré une quantité importante d'informations aussi bien climatiques que paléoenvironnementales. De par sa position géographique privilégiée et de par son environnement côtier, la "Longue sequence" de Marchésieux a précisé les modalités de la séquence de dégradation climatique en milieu continental et marin à nos latitudes moyennes. La méthodologie fortement pluridisciplinaire, le plus souvent il très haute résolution, permet d'affiner notablement les modalités de la réponse de chaque environnement au changement climatique, et apparaît, en ce sens, beaucoup plus riche que les études monodisciplinaires classiques. Ainsi, les réponses zoologiques, phytosociologiques, sedimentologiques et géochimiques au stimulus climatique externe peuvent être comparées et calibrées

Epigenetic loss of RNA-methyltransferase NSUN5 in glioma targets ribosomes to drive a stress adaptive translational program

Altres ajuts: This work was supported by the Obra Social "La Caixa" (to M. Esteller).Tumors have aberrant proteomes that often do not match their corresponding transcriptome profiles. One possible cause of this discrepancy is the existence of aberrant RNA modification landscapes in the so-called epitranscriptome. Here, we report that human glioma cells undergo DNA methylation-associated epigenetic silencing of NSUN5, a candidate RNA methyltransferase for 5-methylcytosine. In this setting, NSUN5 exhibits tumor-suppressor characteristics in vivo glioma models. We also found that NSUN5 loss generates an unmethylated status at the C3782 position of 28S rRNA that drives an overall depletion of protein synthesis, and leads to the emergence of an adaptive translational program for survival under conditions of cellular stress. Interestingly, NSUN5 epigenetic inactivation also renders these gliomas sensitive to bioactivatable substrates of the stress-related enzyme NQO1. Most importantly, NSUN5 epigenetic inactivation is a hallmark of glioma patients with long-term survival for this otherwise devastating disease

Xenogeneic cellular interaction in an ex vivo model of pig kidney perfused with human lymphocytes

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La longue séquence de Marchésieux: étude pluridisciplinaire du premier cycle glaciaire de l'hémisphère nord

International audienceA l'échelle des cinq derniers millions d'années, les enregistrements paléoclimatiques restitués par les sédiments océaniques illustrent le contrôle des paramètres orbitaux (précession, obliquité et excentricité) sur le climat global. La tendance au refroidissement qui accompagne la fin du Néogène est ainsi marquée, vers -2,4 Ma, par le développement rapide des calottes de glace de l'hémisphère nord (Shackleton et al., 1984), dont les faibles changements de volume entre -2,4 et -0,7 Ma apparaissent dominés par l'obliquité (période de 41 Ka) (Raymo et al., 1989). Après -0,7 Ma, l'amplitude des variations de volume des calottes augmente considérablement et la période dominante de ces variations passe de 41 à 100 ka (Ruddiman et al., 1989). Alors que l'histoire du climat global restituée par les enregistrements océaniques est sans cesse précisée, les données concernant l'évolution des environnements continentaux et côtiers au cours de ces changements restent essentiellement fragmentaires. Le forage effectué à Marchésieux (Manche; Normandie) à permis de réaliser une étude pluridisciplinaire de la signature continentale de ce premier cycle glaciaire de l'hémisphère nord

Orna Kupferman Fair Equivalence Relations

Abstract. Equivalence between designs is a fundamental notion in verification. The linear and branching approaches to verification induce different notions of equivalence. When the designs are modeled by fair state-transition systems, equivalence in the linear paradigm corresponds to fair trace equivalence, and in the branching paradigm corresponds to fair bisimulation. In this work we study the expressive power of various types of fairness conditions. For the linear paradigm, it is known that the Büchi condition is sufficiently strong (that is, a fair system that uses Rabin or Streett fairness can be translated to an equivalent Büchi system). We show that in the branching paradigm the expressiveness hierarchy depends on the types of fair bisimulation one chooses to use. We consider three types of fair bisimulation studied in the literature: ©-bisimulation, game-bisimulation, and �-bisimulation. We show that while gamebisimulation and �-bisimulation have the same expressiveness hierarchy as tree automata, ©-bisimulation induces a different hierarchy. This hierarchy lies between the hierarchies of word and tree automata, and it collapses at Rabin conditions of index one, and Streett conditions of index two.

Parametrized variational inequality approaches to generalized Nash equilibrium problems with shared constraints

Generalized Nash equilibrium, Variational inequality, Karush-Kuhn-Tucker condition, Lagrange multiplier, Price-directed parametrizations, Resource-directed parametrizations,

Identification of a new VHL exon and complex splicing alterations in familial erythrocytosis or von Hippel-Lindau disease

Chuvash polycythemia is an autosomal recessive form of erythrocytosis associated with a homozygous p.Arg200Trp mutation in the von Hippel-Lindau (VHL) gene. Since this discovery, additional VHL mutations have been identified in patients with congenital erythrocytosis, in a homozygous or compound-heterozygous state. VHL is a major tumor suppressor gene, mutations in which were first described in patients presenting with VHL disease, which is characterized by the development of highly vascularized tumors. Here, we identify a new VHL cryptic exon (termed E19) deep in intron 1 that is naturally expressed in many tissues. More importantly, we identify mutations in E19 in 7 families with erythrocytosis (1 homozygous case and 6 compound-heterozygous cases with a mutation in E19 in addition to a mutation in VHL coding sequences) and in 1 large family with typical VHL disease but without any alteration in the other VHL exons. In this study, we show that the mutations induced a dysregulation of VHL splicing with excessive retention of E19 and were associated with a downregulation of VHL protein expression. In addition, we demonstrate a pathogenic role for synonymous mutations in VHL exon 2 that altered splicing through E2-skipping in 5 families with erythrocytosis or VHL disease. In all the studied cases, the mutations differentially affected splicing, correlating with phenotype severity. This study demonstrates that cryptic exon retention and exon skipping are new VHL alterations and reveals a novel complex splicing regulation of the VHL gene. These findings open new avenues for diagnosis and research regarding the VHL-related hypoxia-signaling pathway. © 2018 by The American Society of Hematology

Identification of a new VHL exon and complex splicing alterations in familial erythrocytosis or von Hippel-Lindau disease

Chuvash polycythemia is an autosomal recessive form of erythrocytosis associated with a homozygous p.Arg200Trp mutation in the von Hippel-Lindau (VHL) gene. Since this discovery, additional VHL mutations have been identified in patients with congenital erythrocytosis, in a homozygous or compound-heterozygous state. VHL is a major tumor suppressor gene, mutations in which were first described in patients presenting with VHL disease, which is characterized by the development of highly vascularized tumors. Here, we identify a new VHL cryptic exon (termed E19) deep in intron 1 that is naturally expressed in many tissues. More importantly, we identify mutations in E19 in 7 families with erythrocytosis (1 homozygous case and 6 compound-heterozygous cases with a mutation in E19 in addition to a mutation in VHL coding sequences) and in 1 large family with typical VHL disease but without any alteration in the other VHL exons. In this study, we show that the mutations induced a dysregulation of VHL splicing with excessive retention of E19 and were associated with a downregulation of VHL protein expression. In addition, we demonstrate a pathogenic role for synonymous mutations in VHL exon 2 that altered splicing through E2-skipping in 5 families with erythrocytosis or VHL disease. In all the studied cases, the mutations differentially affected splicing, correlating with phenotype severity. This study demonstrates that cryptic exon retention and exon skipping are new VHL alterations and reveals a novel complex splicing regulation of the VHL gene. These findings open new avenues for diagnosis and research regarding the VHL-related hypoxia-signaling pathway. © 2018 by The American Society of Hematology