In vivo importance of homologous recombination DNA repair for mouse neural stem and progenitor cells

We characterized the in vivo importance of the homologous recombination factor RAD54 for the developing mouse brain cortex in normal conditions or after ionizing radiation exposure. Contrary to numerous homologous recombination genes, Rad54 disruption did not impact the cortical development without exogenous stress, but it dramatically

Maintenance of differentiation capacity of HT-29 cells after radiation exposure

Purpose: Following ionizing radiation exposure, intestinal crypt regeneration is possible but it is still not known if regenerating crypts give rise to differentiated functional epithelial cells on villi. The aim of this study was to demonstrate that irradiated progeny of enterocytic precursor cells are capable of proliferation and subsequent differentiation using the HT-29 cell line. Materials and methods: Cells were cultured, irradiated (5 Gy or 10 Gy) and incubated in the presence or absence of butyrate (5 mM). Cell numbers, cell cycle parameters, alkaline phosphatase (ALP) activity, occludin labelling and gene expression were determined at different times post-exposure. Results: Butyrate-induced inhibition of cell growth and arrest in G0 phase was comparable in both sham and irradiated cells in addition to similar development of ALP activity and expression. Cells also formed a monolayer with tight junctions post-irradiation. Butyrate-stimulated modulation of integrin expression during differentiation was unchanged after radiation exposure. Genes known to be implicated in differentiation mechanisms, i.e., growth and transcription factors (vascular Epidermal Growth Factor, v-EGF; Activating Transcription Factor 4, ATF4), cell cycle genes (Cyclin-Dependent Kinase Inhibitor 1A, CDKN1A/p21Cip1/waf1), were studied. Most responded similarly to the differentiation stimulus whether irradiated or not. Conclusion: These results demonstrate that irradiated HT-29 cells still respond to butyrate to form a differentiated, functional epithelium. © 2005 Taylor & Francis Group Ltd

Imbalance of the antioxidant network of mouse small intestinal mucosa after radiation exposure

The aim of this study was to investigate acute variations in antioxidant defense systems in the intestinal mucosa after abdominal radiation exposure and the role played by radiation-induced inflammation in these variations. Antioxidant defense systems of mouse small intestinal mucosa were studied at 6 h and 4 days after abdominal radiation exposure. Superoxide dismutases, glutathione peroxidases, catalase, metallothioneins and thioredoxins were followed in terms of mRNA expression, protein expression and enzyme activities. Dexamethasone was administered to investigate the relationship between variations in mucosal antioxidant capacity and radiation-induced inflammation. Six hours after exposure, only mitochondrial-associated antioxidant systems were induced (the superoxide dismutase and thioredoxin 2). Four days after exposure, during the inflammatory phase, superoxide dismutases were decreased and modulations of the second line of the antioxidant network were also observed: Catalase was decreased and glutathione peroxidases and metallothioneins were induced. Dexamethasone treatment modulated only glutathione peroxidase expression and did not influence either metallothionein or superoxide dismutase expression. Our findings provide direct in vivo evidence that antioxidant mechanisms of the small intestinal mucosa were not markedly mobilized during the very acute tissue radiation response. During the radiation-induced acute inflammatory response, the antioxidant capacity appeared to be dependent on inflammatory status to a certain extent. © 2007 by Radiation Research Society

Plasma levels of beta-endorphin, prolactin and gonadotropins in male athletes after an international nordic ski race.

Plasma beta-endorphin, prolactin (PRL), FSH and LH were measured in 17 volunteer male subjects at rest and under the stress caused by a long-distance nordic ski race. The race induced increased levels of beta-endorphin and PRL in all skiers. The changes in PRL with exercise were significantly related to the changes in beta-endorphin (r = 0.69, p less than 0.001). Furthermore, the highly trained skiers training over 150 km.week-1 of nordic ski showed consistently higher post-exercise beta-endorphin and PRL levels than the moderately trained skiers who trained for 20 km.week-1. In addition the race induced slight falls in FSH and LH; however plasma gonadotropin levels did not show any correlation with plasma beta-endorphin concentrations and did not differ between the two groups of skiers. These results suggest that endogenous opioid peptides may modulate PRL secretion in heavy exercise, since they are of minor importance in the release of FSH and LH in such a situation. The observations also suggest that the degree of previous training and the exercise intensity do seem to be responsible for the hormonal changes

Wolcott-Rallison syndrome: Clinical, genetic, and functional study of EIF2AK3 mutations and suggestion of genetic heterogeneity

PubMedID: 15220213Wolcott-RaRison syndrome (WRS) is a rare autosomal-recessive disorder characterized by the association of permanent neonatal or early-infancy insulin-dependent diabetes, multiple epiphyseal dysplasia and growth retardation, and other variable multisystemic clinical manifestations. Based on genetic studies of two inbred families, we previously identified the gene responsible for this disorder as EIF2AK3, the pancreatic eukaryotic initiation factor 2? (eIF2?) kinase. Here, we have studied 12 families with WRS, totalling 18 cases. With the exception of one case, all patients carried EIF2AK3 mutations resulting in truncated or missense versions of the protein. Exclusion of EIF2AK3 mutations in the one patient case was confirmed by both linkage and sequence data. The activities of missense versions of EIF2AK3 were characterized in vivo and in vitro and found to have a complete lack of activity in four mutant proteins and residual kinase activity in one. Remarkably, the onset of diabetes was relatively late (30 months) in the patient expressing the partially defective EIF2AK3 mutant and in the patient with no EIF2AK3 involvement (18 months) compared with other patients (<6 months). The patient with no EIF2AK3 involvement did not have any of the other variable clinical manifestations associated with WRS, which supports the idea that the genetic heterogeneity between this variant form of WRS and EIF2AK3 WRS correlates with some clinical heterogeneity

Wolcott-Rallison syndrome - Clinical, genetic, and functional study of EIF2AK3 mutations and suggestion of genetic heterogeneity

WOS: 000222397000030PubMed ID: 15220213Wolcott-Rallison syndrome (WRS) is a rare autosomal-recessive disorder characterized by the association of permanent neonatal or early-infancy insulin-dependent diabetes, multiple epiphyseal dysplasia and growth retardation, and other variable multisystemic clinical manifestations. Based on genetic studies of two inbred families, we previously identified the gene responsible for this disorder as EIF2AK3, the pancreatic eukaryotic initiation factor 2alpha (eIF2alpha) kinase. Here, we have studied 12 families with WRS, totalling 18 cases. With the exception of one case, all patients carried EIF2AK3 mutations resulting in truncated or missense versions of the protein. Exclusion of EIF2AK3 mutations in the one patient case was confirmed by both linkage and sequence data. The activities of missense versions of EIF2AK3 were characterized in vivo and in vitro and found to have a complete lack of activity in four mutant proteins and residual kinase activity in one. Remarkably, the onset of diabetes was relatively late (30 months) in the patient expressing the partially defective EIF2AK3 mutant and in the patient with no EIF2AK3 involvement (18 months) compared with other patients (<6 months). The patient with no EIF2AK3 involvement did not have any of the other variable clinical manifestations associated with WRS, which supports the idea that the genetic heterogeneity between this variant form of WRS and EIF2AK3 WRS correlates with some clinical heterogeneity.NIGMS NIH HHSUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of General Medical Sciences (NIGMS) [GM643540

Cooperative effect of roscovitine and irradiation targets angiogenesis and induces vascular destabilization in human breast carcinoma

International audienceAngiogenesis is considered as an essential process for tumour development and invasion. Previously, we demonstrated that cyclin-dependent kinase inhibition by roscovitine induces a radiosensitization and a synergistic antitumoral effect in human carcinoma but its effect on the microenvironment and tumour angiogenesis remains unknown. Here, we investigated the effect of the combination roscovitine and ionizing radiation (IR) on normal cells in vitro and on tumour angiogenesis in MDA-MB 231 tumour xenografts. We observed that the combination roscovitine and IR induced a marked reduction of angiogenic hot spot and microvascular density in comparison with IR or roscovitine treatments alone. The Ang-2/Tie-2 ratio was increased in presence of reduced vascular endothelial growth factor level suggesting vessel destabilization. In vitro, no radiosensitization effect of roscovitine was found in endothelial, fibroblast, and keratinocyte cells. IR potentiated the antiproliferative effect of roscovitine without inducing apoptosis in endothelial cells. Roscovitine decreased IR-stimulated vascular endothelial growth factor secretion of MDA-MB 231 and endothelial cells. A reduction in the endothelial cells invasion and the capillary-like tube formation in Matrigel were observed following the combination roscovitine and IR. This combined treatment targets angiogenesis resulting in microvessel destabilization without inducing normal cell toxicity. © 2008 Blackwell Publishing Ltd

Assessment of plasma opioid peptides, beta-endorphin and met-enkephalin, at the end of an international nordic ski race.

Plasma met-enkephalin, beta-endorphin, cortisol and lactic acid concentrations were measured in seventeen volunteer male subjects at rest and after a long-distance nordic ski race. Immediately after the race, mean plasma met-enkephalin did not show any significant change, but significant rises in beta-endorphin, cortisol and lactic acid were noted in all skiers. The change in beta-endorphin with exercise was significantly related to the change in cortisol (r = 0.68; p less than 0.001) and to the change in plasma lactic acid (r = 0.60; p less than 0.001). Furthermore, the experienced skiers training over 150 km X week-1 of nordic ski had significantly faster skiing times in this event and showed greater beta-endorphin, cortisol and lactic acid levels than the recreational skiers who trained for 20 km X week-1. Our results imply that the changes in plasma beta-endorphin depend on the intensity of exercise. However the significance of higher levels of skiing training or previous nordic ski experience in the release of beta-endorphin is expected and cannot be excluded

Simulating Automated Cars in a Virtual Urban Environment

. Real world simulation by creating virtual environments is indispensable when you need to design complex entities which have to evolve in the real urban world. For example, testing control algorithms of autonomous vehicles needs an environment composed of a variety of active, moving entities and different kinds of vehicles. Virtual simulation environments have to provide this capability during the design step. To perform a realistic simulation of a real environment composed of a large set of vehicles (where some of them are autonomous, the others are controled by the user or by some specific control law), we need to implement different models : geometric modeling of the environment, mechanical simulation of the vehicles, motion control models, driver models for autonomous vehicle, captor models to manage the interactions between objects, and visualisation algorithms. We present a simulation platform which complies with our needs. Keywords: Virtual Environment, Simulation..