Human Neural Cells Transiently Express Reelin during Olfactory Placode Development.

Reelin, an extracellular glycoprotein is essential for migration and correct positioning of neurons during development. Since the olfactory system is known as a source of various migrating neuronal cells, we studied Reelin expression in the two chemosensory olfactory systems, main and accessory, during early developmental stages of human foetuses/embryos from Carnegie Stage (CS) 15 to gestational week (GW) 14. From CS 15 to CS 18, but not at later stages, a transient expression of Reelin was detected first in the presumptive olfactory and then in the presumptive vomeronasal epithelium. During the same period, Reelin-positive cells detach from the olfactory/vomeronasal epithelium and migrate through the mesenchyme beneath the telencephalon. Dab 1, an adaptor protein of the Reelin pathway, was simultaneously expressed in the migratory mass from CS16 to CS17 and, at later stages, in the presumptive olfactory ensheathing cells. Possible involvements of Reelin and Dab 1 in the peripheral migrating stream are discussed.journal articleresearch support, non-u.s. gov't20152015 08 13importe

PloS one

AIMS: Portal hypertension characterized by generalized vasodilatation with endothelial dysfunction affecting nitric oxide (NO) and endothelium-dependent hyperpolarization (EDH) has been suggested to involve bacterial translocation and/or the angiotensin system. The possibility that ingestion of probiotics prevents endothelial dysfunction in rats following common bile duct ligation (CBDL) was evaluated. METHODS: Rats received either control drinking water or the probiotic VSL#3 solution (50 billion bacteria.kg body wt(-)(1).day(-)(1)) for 7 weeks. After 3 weeks, rats underwent surgery with either resection of the common bile duct or sham surgery. The reactivity of mesenteric artery rings was assessed in organ chambers, expression of proteins by immunofluorescence and Western blot analysis, oxidative stress using dihydroethidium, and plasma pro-inflammatory cytokine levels by flow cytometry. RESULTS: Both NO- and EDH-mediated relaxations to acetylcholine were reduced in the CBDL group compared to the sham group, and associated with a reduced expression of Cx37, Cx40, Cx43, IKCa and SKCa and an increased expression of endothelial NO synthase (eNOS). In aortic sections, increased expression of NADPH oxidase subunits, angiotensin converting enzyme, AT1 receptors and angiotensin II, and formation of ROS and peroxynitrite were observed. VSL#3 prevented the deleterious effect of CBDL on EDH-mediated relaxations, vascular expression of connexins, IKCa, SKCa and eNOS, oxidative stress, and the angiotensin system. VSL#3 prevented the CBDL-induced increased plasma TNF-alpha, IL-1alpha and MCP-1 levels. CONCLUSIONS: These findings indicate that VSL#3 ingestion prevents endothelial dysfunction in the mesenteric artery of CBDL rats, and this effect is associated with an improved vascular oxidative stress most likely by reducing bacterial translocation and the local angiotensin system

Loss of STOP Protein Impairs Peripheral Olfactory Neurogenesis

International audienceIn conclusion, STOP protein seems to be involved in the establishment of synapses in the olfactory glomerulus. Our results indicate that the olfactory system of STOP null mice is a well-suited experimental model (1) for the study of the mechanism of action of STOP protein in synaptic function/plasticity and (2) for pathophysiological studies of the mechanisms of altered neuronal connections in schizophrenia

Scalable whole-exome sequencing of cell-free DNA reveals high concordance with metastatic tumors

Whole-exome sequencing of cell-free DNA (cfDNA) could enable comprehensive profiling of tumors from blood but the genome-wide concordance between cfDNA and tumor biopsies is uncertain. Here we report ichorCNA, software that quantifies tumor content in cfDNA from 0.1× coverage whole-genome sequencing data without prior knowledge of tumor mutations. We apply ichorCNA to 1439 blood samples from 520 patients with metastatic prostate or breast cancers. In the earliest tested sample for each patient, 34% of patients have ≥10% tumor-derived cfDNA, sufficient for standard coverage whole-exome sequencing. Using whole-exome sequencing, we validate the concordance of clonal somatic mutations (88%), copy number alterations (80%), mutational signatures, and neoantigens between cfDNA and matched tumor biopsies from 41 patients with ≥10% cfDNA tumor content. In summary, we provide methods to identify patients eligible for comprehensive cfDNA profiling, revealing its applicability to many patients, and demonstrate high concordance of cfDNA and metastatic tumor whole-exome sequencing

Les modèles murins de schizophrénie

STRASBOURG-Medecine (674822101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Étude morphologique et fonctionnelle d'un modèle de dysconnexion synaptique

La schizophrénie est une maladie psychiatrique qui touche 1% de la population et qui se déclenche tardivement à l adolescence. On considère qu elle résulte d une vulnérabilité d origine génétique associée à des facteurs déclencheurs environnementaux. L hypothèse physiopathologique actuelle suppose des dysconnexions cortico-corticales, où la synapse serait l élément principalement perturbé. Nous avons recherché quelles modifications morpho-fonctionnelles auraient pu être engendrées par de telles perturbations. Pour cela, nous avons choisi comme modèle une souris transgénique, la souris KO-STOP, qui présente des anomalies synaptiques (au moins dans l hippocampe) et des troubles comportementaux lui conférant un phénotype adapté à l étude de la schizophrénie. Nous avons établi la cartographie d expression spatiale et temporelle de la protéine mutée afin de connaître la localisation et l évolution des perturbations synaptiques chez cette souris. Nos résultats montrent des expressions localisées dans des régions cérébrales qui, pour la plupart, pourraient avoir un lien avec la schizophrénie. Du fait d une expression robuste et précoce dans le système olfactif, nous nous sommes focalisés sur le glomérule, zone synaptique par excellence et de grande plasticité. Nous avons montré que des anomalies synaptiques y sont également présentes : l expression en GAP43 est réduite et des accumulations de membranes sont trouvées au niveau de l élément pré-synaptique. Ce travail a donc permis de caractériser de manière globale les conséquences des perturbations synaptiques d un microcircuit neuronal, la synapse olfactive principale, sur son microenvironnement. Ces résultats ouvrent des perspectives d études des circuits neuronaux corticaux plus complexes afin de permettre l élaboration de thérapies innovantes.Schizophrenia is a severe psychiatric illness with a lifetime prevalence of 1% and a late adolescence onset. Schizophrenia probably results from the combination of genetic vulnerability and environmental factors. The main hypothesis supposes cortico-cortical dysconnections where the synapse is the main disturbed element. We looked for the consequences of these modifications both from morphologic and functional aspects. We chose to study the transgenic KO-STOP mouse. Synaptic defects (at least in the hippocampus) and behavioral troubles confer to this mouse a good phenotype for the study of schizophrenia. We established the spatial and temporal STOP protein expression map in order to find the localization and the evolution of the synaptic perturbations. We found expressions in well delimitated cerebral regions with, for most of them, a potential link with schizophrenia. A robust and precocious expression of STOP in the olfactory system leads us to study the olfactory glomerulus. The glomerulus is a synaptic zone with a large plasticity. We also found synaptic defects in this region: GAP43 expression was reduced and membranes were abnormally accumulated in the pre-synaptic part of the synapse. Thus, in this work, we characterized the consequences of the synaptic defects on the micro-environment of the main olfactory synapse, which could be considered as a neuronal micro-circuit. These results offer research perspectives on more complex cortical neuronal circuits in order to find out new therapeutic strategies.STRASBOURG-Sc. et Techniques (674822102) / SudocSudocFranceF

Les modèles murins de schizophrénie

STRASBOURG-Medecine (674822101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Expression pattern of STOP lacZ reporter gene in adult and developing mouse brain.

International audienceStable tubulin-only polypeptide (STOP) proteins are microtubule-associated proteins responsible for microtubule stabilization in neurons. STOP null mice show apparently normal cerebral anatomy but display synaptic defects associated with neuroleptic-sensitive behavioral disorders. STOP null mice have therefore been proposed as an animal model for the study of schizophrenia. In the present study, the expression pattern of STOP gene in developing and adult brain has been examined by using lacZ gene inserted in the STOP locus, as a reporter gene. beta-Galactosidase (beta-gal) immunostaining was confined to neuronal cells and projections. Strong labeling was observed in the whole olfactory system, cortical layer VII, hippocampus, hypothalamus, cerebellum, habenula, fasciculus retroflexus, and interpeduncular nucleus in adults. Additionally, ventral thalamic nucleus, clusters of positive cells in striatum, and Cajal-Retzius cells of cortical layer I were labeled in young mice. The strong expression of STOP lacZ reporter gene observed in brain is confined to areas that may be involved in the schizophrenia-related symptoms observed in STOP-deficient mice