The prevalence of badnaviruses in West African yams (Dioscorea cayenensis-rotundata) and evidence of endogenous pararetrovirus sequences in their genomes

Yam (Dioscorea spp.) is an important vegetatively-propagated staple crop in West Africa. Viruses are pervasive in yam worldwide, decreasing growth and yield, as well as hindering the international movement of germplasm. Badnaviruses have been reported to be the most prevalent in yam, and genomes of some other badnaviruses are known to be integrated in their host plant species. However, it was not clear if a similar scenario occurs in Dioscorea yam. This study was conducted to verify the prevalence of badnaviruses, and determine if badnavirus genomes are integrated in the yam genome

Foucault avec Lacan (ponctuations et problématiques autour de la sexualité)

Il est question, dans cette thèse, de la vie et de la mort ; il est question du regard, de l écrit, de la jouissance enfin ! Foucault avec Lacan fait écho au titre du texte de Lacan, Kant avec Sade. Foucault avec Lacan ne veut pas dire que la pensée de l un est conforme à la pensée de l autre. Il ne s agit pas non plus d une lutte entre la philosophie et la psychanalyse. Le point de départ de notre thèse a été la question de la sexualité chez Foucault, et notamment celle de son changement de style dans ses dernières années, qui fait énigme. La coupure majeure dans l histoire de la pensée et des pratiques qui est en lien avec la psychanalyse est d après Foucault, la disparition de la parrhésia et l instauration de l aveu chrétien, puis la Naissance de la clinique qui met en cause la technique de la confession. Autrement dit le point de non rencontre entre Foucault et Lacan est que pour Foucault, la psychanalyse ne présente aucune nouveauté historique, mais bien plutôt la simple continuation d une tradition ancienne, tandis que pour Lacan, Freud a créé une pratique inédite produisant un type de lien social qui n avait jamais existé auparavant.ST DENIS-BU PARIS8 (930662101) / SudocSudocFranceF

A combined approach to early detect in vitro drug-induced hemostatic changes in preclinical safety

Early detection of drug-induced alterations of hemostasis is challenging. Drugs can affect different components of the Virchow's triad and measurement of plasmatic coagulation times lacks sensitivity. New techniques for a more global assessment of the hemostasis are now available: the impedance platelet aggregometry, the thromboelastography and the thrombin generation measurement. The aim of this study was to evaluate three techniques (i.e.: Multiplate®, TEG® and CAT) for the in vitro detection of the effect of a drug known to induce hemostatic alterations in a preclinical safety environment. Cyclosporine A was chosen and tested at 4 concentrations after solubilization in DMSO in Wistar rats and Beagle dogs. The results obtained were comparable between both species except for the thrombin generation in platelet rich plasma. Enhanced platelet aggregability was observed after ADP stimulation and alterations of the thromboelastograms consisted in decreased maximum amplitude and increased LY30. A dual effect on thrombin generation was observed and suggested that CsA may interact with platelets in rat platelet rich plasma and speed up thrombin generation. The results of this study indicate that using a combined approach on hemostasis testing in preclinical safety it is possible to detect in vitro drug-induced alterations of hemostasis

Optimization of Multiplate® whole blood platelet aggregometry in the Beagle dog and Wistar rat for ex vivo drug toxicity testing

This study was performed to optimize and standardize the use of the Multiplate® whole blood impedance aggregometer in the Beagle dog and Wistar rat for use in a research laboratory environment. The anticoagulants citrate, heparin and hirudin were compared and platelet aggregation responses to ADP, collagen, arachidonic acid and Par-4 agonist were evaluated to determine their half maximal effective concentrations (EC50) in blood containing low concentrations of a drug solvent (0.1% DMSO). The results indicate that citrate anticoagulation is not suitable for Multiplate® whole blood aggregometry because of the presence of spontaneous aggregation. ADP and collagen were found to be appropriate agonists for both species, whereas in the Beagle dog Par-4 agonist failed to induce aggregation and arachidonic acid induced platelet aggregation showed a high interindividual variability. The agonists EC50 calculated in hirudin blood were 2.70μM ADP, 0.85μg/ml collagen, 0.03mM arachidonic acid and 165.7μM Par-4 agonist in the Wistar rat, and 0.95μM ADP and 0.23μg/ml collagen in the Beagle dog

Toward a better control of the viral constraints hampering the multiplication and exchange of Musa germplasm

International audienc

Large Scale Prediction and Testing of Drug Activity on Side-Effect Targets

Discovering the unintended “off-targets” that predict adverse drug reactions (ADRs) is daunting by empirical methods alone. Drugs can act on multiple protein targets, some of which can be unrelated by traditional molecular metrics, and hundreds of proteins have been implicated in side effects. We therefore explored a computational strategy to predict the activity of 656 marketed drugs on 73 unintended “side effect” targets. Approximately half of the predictions were confirmed, either from proprietary databases unknown to the method or by new experimental assays. Affinities for these new off-targets ranged from 1 nM to 30 µM. To explore relevance, we developed an association metric that prioritized those new off-targets that explained side effects better than any known target of a given drug, creating a Drug-Target-ADR network. Among these new associations was the prediction that the abdominal pain side effect of the synthetic estrogen chlorotrianisene was mediated through its newly discovered inhibition of the enzyme COX-1. The clinical relevance of this inhibition was borne-out in whole human blood platelet aggregation assays. This approach may have wide application to de-risking toxicological liabilities in drug discovery

Reduced activity of sphingosine-1-phosphate lyase Induces podocyte-related glomerular proteinuria, skin Irritation, and platelet activation

Sphingosine-1-phosphate (S1P) lyase is considered as a drug target in autoimmune diseases based on the protective effect of reducing activity of the enzyme in animal models of inflammation. Since S1P lyase deficiency in mice causes a severe, lethal phenotype, it was of interest to investigate any pathological alterations associated with only partially reduced activity of S1P lyase as may be encountered upon pharmacological inhibition. Both genetic reduction of S1P lyase activity in mice and inhibition of S1P lyase with a low-molecular-weight compound in rats consistently resulted in podocyte-based kidney toxicity, which is the most severe finding. In addition, skin irritation and platelet activation were observed in both instances. The similarity of the findings in both the genetic model and the pharmacological study supports the value of analyzing inducible partially target-deficient mice for safety assessment. If the findings described in rodents translate to humans, target-related toxicity, particularly podocyte dysfunction, may limit chronic systemic treatment of autoimmune diseases with S1P lyase inhibitors. Furthermore, partial deficiency or inhibition of S1P lyase appears to provide an in vivo rodent model to enable studies on the mechanism of podocyte dysfunction