Correlating Global Gene Regulation to Angiogenesis in the Developing Chick Extra-Embryonic Vascular System

International audienceBACKGROUND: Formation of blood vessels requires the concerted regulation of an unknown number of genes in a spatial-, time- and dosage-dependent manner. Determining genes, which drive vascular maturation is crucial for the identification of new therapeutic targets against pathological angiogenesis. METHOLOGY/PRINCIPAL FINDINGS: We accessed global gene regulation throughout maturation of the chick chorio-allantoic membrane (CAM), a highly vascularized tissue, using pan genomic microarrays. Seven percent of analyzed genes showed a significant change in expression (>2-fold, FDR<5%) with a peak occurring from E7 to E10, when key morphogenetic and angiogenic genes such as BMP4, SMO, HOXA3, EPAS1 and FGFR2 were upregulated, reflecting the state of an activated endothelium. At later stages, a general decrease in gene expression occurs, including genes encoding mitotic factors or angiogenic mediators such as CYR61, EPAS1, MDK and MYC. We identified putative human orthologs for 77% of significantly regulated genes and determined endothelial cell enrichment for 20% of the orthologs in silico. Vascular expression of several genes including ENC1, FSTL1, JAM2, LDB2, LIMS1, PARVB, PDE3A, PRCP, PTRF and ST6GAL1 was demonstrated by in situ hybridization. Up to 9% of the CAM genes were also overexpressed in human organs with related functions, such as placenta and lung or the thyroid. 21-66% of CAM genes enriched in endothelial cells were deregulated in several human cancer types (P<.0001). Interfering with PARVB (encoding parvin, beta) function profoundly changed human endothelial cell shape, motility and tubulogenesis, suggesting an important role of this gene in the angiogenic process. CONCLUSIONS/SIGNIFICANCE: Our study underlines the complexity of gene regulation in a highly vascularized organ during development. We identified a restricted number of novel genes enriched in the endothelium of different species and tissues, which may play crucial roles in normal and pathological angiogenesis

<i>GRIN2A</i>-related disorders:genotype and functional consequence predict phenotype

Alterations of the N-methyl-d-aspartate receptor (NMDAR) subunit GluN2A, encoded by GRIN2A, have been associated with a spectrum of neurodevelopmental disorders with prominent speech-related features, and epilepsy. We performed a comprehensive assessment of phenotypes with a standardized questionnaire in 92 previously unreported individuals with GRIN2A-related disorders. Applying the criteria of the American College of Medical Genetics and Genomics to all published variants yielded 156 additional cases with pathogenic or likely pathogenic variants in GRIN2A, resulting in a total of 248 individuals. The phenotypic spectrum ranged from normal or near-normal development with mild epilepsy and speech delay/apraxia to severe developmental and epileptic encephalopathy, often within the epilepsy-aphasia spectrum. We found that pathogenic missense variants in transmembrane and linker domains (misTMD+Linker) were associated with severe developmental phenotypes, whereas missense variants within amino terminal or ligand-binding domains (misATD+LBD) and null variants led to less severe developmental phenotypes, which we confirmed in a discovery (P = 10-6) as well as validation cohort (P = 0.0003). Other phenotypes such as MRI abnormalities and epilepsy types were also significantly different between the two groups. Notably, this was paralleled by electrophysiology data, where misTMD+Linker predominantly led to NMDAR gain-of-function, while misATD+LBD exclusively caused NMDAR loss-of-function. With respect to null variants, we show that Grin2a+/- cortical rat neurons also had reduced NMDAR function and there was no evidence of previously postulated compensatory overexpression of GluN2B. We demonstrate that null variants and misATD+LBD of GRIN2A do not only share the same clinical spectrum (i.e. milder phenotypes), but also result in similar electrophysiological consequences (loss-of-function) opposing those of misTMD+Linker (severe phenotypes; predominantly gain-of-function). This new pathomechanistic model may ultimately help in predicting phenotype severity as well as eligibility for potential precision medicine approaches in GRIN2A-related disorders

Électrodéposition de matériaux thermoélectriques de basse dimensionnalité : le cas de SnSe

Since recent works highlighting its high figure of merit (2.6 at 923 K), SnSe is fingered as promising candidate for thermoelectric applications. Mainly synthesized by physical way and in bulk shape, few works present the elaboration of SnSe at a decreased dimensionality. However, it was shown that the thermal conductivity of thermoelectric materials is considerably reduced at low dimensionality. A synthesis method which is particularly suitable to the elaboration of low dimensionality deposits is the electrodeposition, poorly used for SnSe. In this thesis, the electrodeposition of SnSe was thus thoroughly discussed. In continuous mode, the influence of the potential on the films composition and morphology was studied from an innovative electrochemical bath, regarding the literature. The conditions providing the best films were preserved in order to study the pulse mode syntheses. The pulse conditions have also proved to be decisive on the composition and morphology of the films. As first prospect of this work, doping with copper was investigated from the best pulse conditions. As second promising prospect, this thesis work was extended to the electrodeposition of SnSe nanowires and nanotubes. These 1D nanostructures, synthesized in continuous mode, show an evolution of the crystallinity, of the composition and even of the morphology with the potential.Depuis des travaux récents mettant en avant son facteur de mérite élevé (2,6 à 923 K), SnSe est pointé du doigt en tant que candidat prometteur pour des applications thermoélectriques. Principalement synthétisé par voie physique et sous forme massive, peu de travaux présentent l’élaboration de SnSe à une dimensionnalité diminuée. Pourtant, il a été montré que la conductivité thermique des matériaux thermoélectriques est considérablement réduite à basse dimensionnalité. Une méthode de synthèse qui se prête particulièrement à l’élaboration de dépôts à basse dimensionnalité est l’électrodéposition, faiblement utilisée pour SnSe. Dans cette thèse, l’électrodéposition de SnSe a donc été abordée de manière approfondie. En mode continu, l’influence du potentiel sur la composition et la morphologie des films a été étudiée à partir d’un bain électrochimique innovant au regard de la littérature. Les conditions procurant les meilleurs films ont été conservées afin d’étudier les synthèses en mode impulsionnel. Les conditions d’impulsion se sont également révélées déterminantes sur la composition et la morphologie des films. Comme première perspective de ce travail, le dopage par le cuivre a été étudié, à partir des meilleures conditions impulsionnelles. Comme seconde perspective prometteuse, ce travail de thèse a été étendu à l’électrodéposition de nanofils et de nanotubes de SnSe. Ces nanostructures 1D, synthétisées en mode continu, montrent une évolution de la cristallinité, la composition et voire la morphologie avec le potentiel

Development of microdevices for the in-plane thermoelectric characterization of deposited films

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Generation of the induced pluripotent stem cell line UHOMi002-A from peripheral blood mononuclear cells of a healthy male donor

International audienc

Electrodeposition of Tin Selenide from Oxalate-Based Aqueous Solution

In this work, we report a study of the electrodeposition of SnSe. Considering the difficulty to stabilize the baths containing Sn(II) and Se(IV) precursors, we investigated the benefits of using sodium oxalate as a complexing agent. Preliminary cyclic voltammetric (CVs) experiments were performed to study the electrochemical behavior of tin and selenium redox systems within this specific electrolyte solution. The study revealed that the oxalate reagent stabilizes the bath chelating Sn(II) and then preventing the precipitation of SnO2. From the CVs, a growth mechanism is proposed and a synthesis potential window is defined, in which the electrodeposition of SnSe films was investigated. Between -0.5 and -0.6 V vs sat. AgCl/Ag, the deposits exhibit typical polycrystalline SnSe needle-like grains. SnSe was shown by Raman spectroscopy and the XRD patterns display an orthorhombic single-phase for this compound. Additional Mössbauer analyses confirm the presence of Sn(II), which is in good agreement with the chemical composition of SnSe films. Moreover, a cross-analysis between the methods shows also the presence of SnSe2 in minor proportion. The depth profile analyses of the samples reveal an in-depth homogeneity as well as the presence of oxygen at the layer surface

Bone marrow processing for hematopoietic stem cell transplantation: recommendations of the SFGM-TC

peer reviewedLe prélèvement de moelle osseuse fait l’objet d’un ou de plusieurs traitements préalablement à son injection au receveur. Ces transformations sont basées sur l’évaluation de la compatibilité érythrocytaire entre le donneur et le receveur, et sur le volume maximal acceptable du greffon. Elles doivent préserver la quantité de cellules mononucléées et de cellules CD34+ injectées ainsi que leur qualité. Une enquête au sein de centres de thérapie cellulaire francophones a révélé une hétérogénéité, d’une part, des pratiques d’ingénierie cellulaire, en partie liée au marché des automates et, d’autre part, des techniques de titrage des anticorps anti-érythrocytaires et de leur absence de normalisation. Dans une démarche qui vise à uniformiser les pratiques d’allogreffe de cellules souches hématopoïétiques (CSH), la Société franc¸aise de greffe de moelle et de thérapie cellulaire (SFGM-TC) a organisé les cinquièmes ateliers d’harmonisation des pratiques en septembre 2014 à Lille. Nous proposons des recommandations concernant la transformation des greffons de moelle osseuse et les critères de libératio

Poor timing and failure of source control are risk factors for mortality in critically ill patients with secondary peritonitis

Purpose: To describe data on epidemiology, microbiology, clinical characteristics and outcome of adult patients admitted in the intensive care unit (ICU) with secondary peritonitis, with special emphasis on antimicrobial therapy and source control. Methods: Post hoc analysis of a multicenter observational study (Abdominal Sepsis Study, AbSeS) including 2621 adult ICU patients with intra-abdominal infection in 306 ICUs from 42 countries. Time-till-source control intervention was calculated as from time of diagnosis and classified into 'emergency' (&lt; 2 h), 'urgent' (2-6 h), and 'delayed' (&gt; 6 h). Relationships were assessed by logistic regression analysis and reported as odds ratios (OR) and 95% confidence interval (CI). Results: The cohort included 1077 cases of microbiologically confirmed secondary peritonitis. Mortality was 29.7%. The rate of appropriate empiric therapy showed no difference between survivors and non-survivors (66.4% vs. 61.3%, p = 0.1). A stepwise increase in mortality was observed with increasing Sequential Organ Failure Assessment (SOFA) scores (19.6% for a value ≤ 4-55.4% for a value &gt; 12, p &lt; 0.001). The highest odds of death were associated with septic shock (OR 3.08 [1.42-7.00]), late-onset hospital-acquired peritonitis (OR 1.71 [1.16-2.52]) and failed source control evidenced by persistent inflammation at day 7 (OR 5.71 [3.99-8.18]). Compared with 'emergency' source control intervention (&lt; 2 h of diagnosis), 'urgent' source control was the only modifiable covariate associated with lower odds of mortality (OR 0.50 [0.34-0.73]). Conclusion: 'Urgent' and successful source control was associated with improved odds of survival. Appropriateness of empirical antimicrobial treatment did not significantly affect survival suggesting that source control is more determinative for outcome