An adiponectin-like molecule with antidiabetic properties

Adiponectin increases glucose transport, reduces inflammation, and controls vascular functions. Hence, we propose that treatment with a recombinant globular domain of adiponectin (rgAd110-244) has significant therapeutic potential to treat insulin resistance. Mice were fed for 3 months on a high-fat diet (HFD) to induce insulin resistance, diabetes, and moderate weight gain. The mice were first infused iv with different doses of rgAd110-244 (0.12, 0.4, and 1.2 microg/kg x min) for 5 h. Basal and insulin-sensitive glucose use rates were assessed by the use of a submaximal rate of insulin in the awake free-moving mouse. rgAd110-244 reduced, with dose dependence, epinephrine-induced hyperglycemia and HFD-induced insulin resistance by increasing whole-body glucose use (35% at the highest dose) and glycolysis rates. Similarly, the reduction of plasma free fatty acid concentrations by insulin was dramatically improved. Basal hepatic glucose production was unchanged by rgAd110-244 infusion. This acute rgAd110-244 treatment improved glucose homeostasis and was associated with an increased content of muscle phospho-Akt, glycogen synthase kinase-3beta, and AMP-activated kinase. Second, HFD mice were chronically treated with sc rgAd110-244 injections (10, 30, and 100 microg/kg). Fasting glycemia and insulin-sensitive glucose use were improved by rgAd110-244 at the highest dose at completion of the treatment, with concomitant reduction in body weight gain. We here show for the first time that a recombinant adiponectin fragment (110-244 amino acids called rgAd110-244) is able to treat insulin-resistant diabetes. Our results strongly suggest further pharmacological investigation of rgAd110-244 with the objective of developing a new treatment of insulin-resistant diabetes

Epoxyeicosatrienoic acids contribute with altered nitric oxide and endothelin-1 pathways to conduit artery endothelial dysfunction in essential hypertension.: EETs, Vascular Function, and Hypertension

International audienceBACKGROUND: We sought to clarify, using functional and biological approaches, the role of epoxyeicosatrienoic acids, nitric oxide (NO)/reactive oxygen species balance, and endothelin-1 in conduit artery endothelial dysfunction during essential hypertension. METHODS AND RESULTS: Radial artery diameter and mean wall shear stress were determined in 28 untreated patients with essential hypertension and 30 normotensive control subjects during endothelium-dependent flow-mediated dilatation induced by hand skin heating. The role of epoxyeicosatrienoic acids and NO was assessed with the brachial infusion of inhibitors of cytochrome P450 epoxygenases (fluconazole) and NO synthase (N(G)-monomethyl-l-arginine [L-NMMA]). Compared with controls, hypertensive patients exhibited a decreased flow-mediated dilatation in response to postischemic hyperemia as well as to heating, as shown by the lesser slope of their diameter-shear stress relationship. In controls, heating-induced flow-mediated dilatation was reduced by fluconazole, L-NMMA, and, to a larger extent, by L-NMMA+fluconazole. In patients, flow-mediated dilatation was not affected by fluconazole and was reduced by L-NMMA and L-NMMA+fluconazole to a lesser extent than in controls. Furthermore, local plasma epoxyeicosatrienoic acids increased during heating in controls (an effect diminished by fluconazole) but not in patients. Plasma nitrite, an indicator of NO availability, increased during heating in controls (an effect abolished by L-NMMA) and, to a lesser extent, in patients, whereas, inversely, reactive oxygen species increased more in patients (an effect diminished by L-NMMA). Plasma endothelin-1 decreased during heating in controls but not in patients. CONCLUSIONS: These results show that an impaired role of epoxyeicosatrienoic acids contributes, together with an alteration in NO/reactive oxygen species balance and endothelin-1 pathway, to conduit artery endothelial dysfunction in essential hypertension. CLINICAL TRIAL REGISTRATION: https://www.eudract.ema.europa.eu. Unique identifier: RCB2007-A001-10-53

Les risques conchylicoles en Baie de Quiberon. Première partie : le risque de mortalité virale du naissain d’huître creuse Crassostra gigas. Rapport final du projet Risco 2010-2013

This study (“Risco”), implicating both industry, socio-economic experts and biologists, was funded by the Regional Council of Brittany, for 3 years (2010-2013), to investigate upon the origin of oysters (Crassostrea gigas) mortalities in the bay of Quiberon (South Brittany, France). Specific mortalities of adult oysters were recorded in this bay in 2006, whereas mortalities of one year old spat were observed since in 2008 in this bay as at a national scale. The experimental protocol in 2010, including a monthly survey of oyster batches at 15 experimental stations, allowed to assess the risk for one-year oysters, due to viral disease. A clear spatial distribution of this risk was evidenced, with a western area spared from contamination and mortality, and a central and north-east sector strongly affected. The virus analysis clearly demonstrate the responsibility of the OsHV-1 virus in the mortalities. The oysters on the bottom with a lower growth appear less sensitive to the viral disease than the surelevated ones. In order to interpret this spatial distribution, an epidemiological model has been tested : it is based on emission of virus from the stock of spat in surrounding farming areas, dispersion by the hydrodynamic conditions, and inactivation of the virus by solar radiation. The resulting simulations suggest that the contamination would be endogenous to the bay (from contaminated stocks of spat seeded nearby). A decrease of densities for rearing spat, as well as the seeding of non contaminated spat may be recommended.L’étude « Risco », labellisée Pôle Mer et financée par la Région Bretagne, mobilise à la fois des socio-économistes, des biologistes et des professionnels. Elle vise à comprendre et gérer les facteurs de mortalités massives d’huîtres creuses (Crassostrea gigas) enregistrées par les concessionnaires de baie de Quiberon (France, 56), à partir de 2006 sur les huîtres adultes et 2008 sur le naissain. Le protocole engagé en 2010, avec un volet expérimental basé sur le suivi mensuel de lots d’huîtres en 15 stations et des analyses pathologiques, a permis d’éclairer notamment le risque épizootique sur le naissain. Une spatialisation très marquée de ce risque a été mise en évidence, avec une zone à l’ouest relativement épargnée et une zone au centre et à l’est très affectée. Les analyses virales mettent clairement en évidence la responsabilité du virus OsHV-1 dans ces mortalités. Les huîtres élevées au sol, moins poussantes, seraient aussi moins sensibles à la mortalité virale que les huîtres élevées en surélévation. L’existence d’une zone quasi-indemne de contamination et de mortalité à cette échelle est inédite parmi les secteurs ostréicoles français, depuis 2008. Pour interpréter cette distribution spatiale de la contamination et des mortalités, un modèle épidémiologique a été testé : il s’appuie sur une émission de virus à partir des stocks de naissain estimés en 2010 (estran et eau profonde), une dispersion par les courants, et une inactivation du virus en fonction du rayonnement solaire. Avec le taux d’abattement viral retenu, les simulations suggèrent que la contamination serait majoritairement endogène à la baie (à partir de semis de naissain en place, contaminés). Les recommandations qui en découlent sont notamment d’introduire en baie du naissain non contaminé et de diminuer les densités de naissain

Les risques conchylicoles en Baie de Quiberon. Troisième partie : le risque d’hypoxie pour l’huître creuse Crassostrea gigas. Rapport final du projet Risco 2010-2013

The project “Risco”, supported by the “Pôle Mer” and funded by the Regional Council of Brittany, deals with specific risks of mortality of oysters, Crassostrea gigas, cultivated on the bottom, in a subtidal bay of South Brittany : the bay of Quiberon (56, France). Massive mortalities of oysters were reported in summer 2006 in this bay, exclusively located in the deep muddy area with a positive gradient eastward. A validated biogeochemical model was applied in order to simulate the dissolved oxygen over 2000-2006 : it revealed several episodes of hypoxia, more or less intense according to years, but with the same spatial distribution. This approach proved 2006 to be the most hypoxic year since 2000. The hypoxia was due to a rare conjunction of 3 factors : (a) a local upwelling generated by north-west winds, during a neap tide; (b) an abnormal high temperature of coastal waters; (c) probably an intense phytoplankton bloom in summertime. Due to the stratification induced, oxygen consumption near the bottom exceeded its renewal. The hydrodynamism of Mor Bras, at a larger scale, excludes any import of hypoxic water from the nearby “Baie de Vilaine”, whatever the wind or tide regime. The simulated hypoxia area fitted fairly well to the 2006 mortalities. In 2010, experimental oysters deployed at 15 stations and monitored monthly, exhibited also a lower growth rate in the same area, in spite of higher chlorophyll concentration. The application of a Dynamic Energy Budget (DEB) model to growth data confirmed the responsibility of hypoxia in abnormally slow growth rates. So hypoxia may be considered as a stressful factor limiting growth prior to mortalities. It may be concluded from our study that hydro-climatic and trophic conditions have the capacity to deplete oxygen in bottom coastal zones with possible consequences on biotopes and cultivated species: farm yields may be severely affected. This study will allow to manage more closely the commercial risk of shellfish farming at spatial and temporal scale.L’étude « Risco », labellisée par le Pôle Mer et financée par la région Bretagne, a révélé un facteur insoupçonné d’altération des résultats d’élevage ostréicole en baie de Quiberon (France, 56): l’hypoxie. Elle a ainsi fourni une explication convaincante des mortalités anormales observées sur les huîtres adultes l’été 2006. Le modèle biogéochimique appliqué sur la période 2000-2006 a mis en évidence plusieurs épisodes d’hypoxie d’intensité variable selon les années, mais très géolocalisés. Parmi eux, celui de 2006 s’est avéré exceptionnel, tant par son emprise spatiale que par son intensité. L’hypoxie de 2006 résulte de la conjonction rare de plusieurs phénomènes : (a) un upwelling local généré par des vents de nord-ouest en période de morte-eau ; (b) des eaux côtières anormalement chaudes ; (c) probablement un fort bloom estival de phytoplancton. Du fait de la stratification induite, la consommation d’oxygène au niveau du fond excède alors son renouvellement. Le secteur profond et envasé, à l’est de la zone concédée, est particulièrement affecté en raison de la géomorphologie de la baie de Quiberon. L’analyse du fonctionnement hydrodynamique à l’échelle du Mor Bras montre par ailleurs qu’il n’y a pas d’importation d’eau hypoxique depuis la baie de Vilaine, ceci quel que soit le régime de vent et de marée. La diminution de la teneur en oxygène dissous apparaît responsable de ralentissements de croissance des huîtres même en année peu hypoxique (comme 2010). C’est probablement le facteur explicatif des déficits de croissance marqués chez les huîtres au sol (par rapport aux huîtres en surélévation). En situation d’hypoxie extrême (année 2006), les huîtres des deux classes d’âge subissent des mortalités. Les huîtres d’un an paraissent plus affectées par le déficit d’oxygène, tant en croissance qu’en mortalité (étude 2010). Cette étude permet d’évaluer le risque d’hypoxie (sa probabilité d’occurrence, sa répartition géographique) et d’orienter les mesures préventives applicables en conchyliculture telles que la répartition des stocks en élevage ou l’entretien des parcs. L’incidence sur les peuplements naturels et les ressources exploitées, peut également être mieux prise en compte, à l’échelle du Mor Bras. Plus généralement, une meilleure connaissance des effets de l’hypoxie fournit des arguments en faveur du contrôle de l’eutrophisation (limitation des apports en nutriments par les bassins versants…)

Les risques conchylicoles en Baie de Quiberon: Deuxième partie : le risque de prédation sur l’huître creuse Crassostrea gigas. Rapport final du projet Risco 2010-2013

L’étude « Risco » s’attache aux causes possibles de mortalités massives d’huîtres creuses, de toutesclasses d’âge, enregistrées par les concessionnaires de baie de Quiberon (France, 56), à partir de2006. Le protocole engagé en 2010, avec son volet expérimental fondé sur le suivi mensuel de 15lots d’huîtres et son volet d’imagerie in situ par sonar et vidéo, permet d’éclairer en particulier lerisque lié aux prédateurs. Une spatialisation très marquée de ce risque est mise en évidence, avec unezone à l’ouest relativement épargnée, une zone à l’est très affectée par les étoiles de mer (A. rubens,M. glacialis) et une zone intermédiaire à forte prédation de bigorneaux perceurs (O. erinacea, P.inornata). Entre ces deux groupes, la prédation est réalisée pour les ¾ par les étoiles de mer et pour¼ par les bigorneaux. Les pertes maximales ont lieu au printemps (recrudescence d’étoiles de mer) eten été (efficacité maximale de prédation). La prédation par dorades, devenue très préoccupante cesdernières années, n’a pas pu être estimée. L’analyse met aussi en évidence l’importance des mesuresd’entretien des parcs pour limiter l’incidence des prédateurs. Pour autant, la prédation n’est sansdoute pas le facteur principal des mortalités de 2006, une piste environnementale basée sur le risqued’hypoxie étant explorée par ailleurs

From First Base: The Sequence of the Tip of the X Chromosome of Drosophila melanogaster, a Comparison of Two Sequencing Strategies

We present the sequence of a contiguous 2.63 Mb of DNA extending from the tip of the X chromosome of Drosophila melanogaster. Within this sequence, we predict 277 protein coding genes, of which 94 had been sequenced already in the course of studying the biology of their gene products, and examples of 12 different transposable elements. We show that an interval between bands 3A2 and 3C2, believed in the 1970s to show a correlation between the number of bands on the polytene chromosomes and the 20 genes identified by conventional genetics, is predicted to contain 45 genes from its DNA sequence. We have determined the insertion sites of P-elements from 111 mutant lines, about half of which are in a position likely to affect the expression of novel predicted genes, thus representing a resource for subsequent functional genomic analysis. We compare the European Drosophila Genome Project sequence with the corresponding part of the independently assembled and annotated Joint Sequence determined through “shotgun” sequencing. Discounting differences in the distribution of known transposable elements between the strains sequenced in the two projects, we detected three major sequence differences, two of which are probably explained by errors in assembly; the origin of the third major difference is unclear. In addition there are eight sequence gaps within the Joint Sequence. At least six of these eight gaps are likely to be sites of transposable elements; the other two are complex. Of the 275 genes in common to both projects, 60% are identical within 1% of their predicted amino-acid sequence and 31% show minor differences such as in choice of translation initiation or termination codons; the remaining 9% show major differences in interpretation. [All of the sequences analyzed in this paper have been deposited in the EMBL-Bank database under the following accession nos.: AL009146, AL009147, AL009171, AL009188–AL009196, AL021067, AL021086, AL021106–AL021108, AL021726, AL021728, AL022017, AL022018, AL022139, AL023873, AL023874, AL023893, AL024453, AL024455–AL024457, AL024485, AL030993, AL030994, AL031024–AL031028, AL031128, AL031173, AL031366, AL031367, AL031581–AL031583, AL031640, AL031765, AL031883, AL031884, AL034388, AL034544, AL035104, AL035105, AL035207, AL035245, AL035331, AL035632, AL049535, AL050231, AL050232, AL109630, AL121804, AL121806, AL132651, AL132792, AL132797, AL133503–AL133506, AL138678, AL138971, AL138972, and Z98269. A single file (FASTA format) of the 2.6-Mb contig is available from ftp://ftp.ebi.ac.uk/pub/databases/edgp/contigs/contig_1.fa.

Mapping and identification of essential gene functions on the X chromosome of Drosophila

The Drosophila melanogaster genome consists of four chromosomes that contain 165 Mb of DNA, 120 Mb of which are euchromatic. The two Drosophila Genome Projects, in collaboration with Celera Genomics Systems, have sequenced the genome, complementing the previously established physical and genetic maps. In addition, the Berkeley Drosophila Genome Project has undertaken large-scale functional analysis based on mutagenesis by transposable P element insertions into autosomes. Here, we present a large-scale P element insertion screen for vital gene functions and a BAC tiling map for the X chromosome. A collection of 501 X-chromosomal P element insertion lines was used to map essential genes cytogenetically and to establish short sequence tags (STSs) linking the insertion sites to the genome. The distribution of the P element integration sites, the identified genes and transcription units as well as the expression patterns of the P-element-tagged enhancers is described and discussed