L’enseignement de la biologie du vieillissement en France 1990-2005 : Du DEA au parcours de spécialité de Master Recherche

En 1990, à la suite d’une réflexion entamée dans une intercommission de l’Inserm sur le vieillissement, le Diplôme d’études approfondies (DEA) de Biologie du vieillissement était créé. Depuis, près de 300 étudiants ont suivi ses enseignements, qui couvrent l’ensemble des mécanismes cellulaires du vieillissement et les pathologies associées, des bases fondamentales du vieillissement au vieillissement du système nerveux central et des organes des sens en passant par nutrition, sarcopénie et ostéoporose, vieillissement vasculaire et neuro-endocrinien. Plus de 150 thèses ont été soutenues et plus d’un quart des étudiants a été recruté dans le système de recherche et d’enseignement supérieur (10 %) ou de santé (16 %) français. Dès sa création, une des particularités du DEA a été la forte implication d’industriels du secteur pharmaceutique, puisque les cours ont lieu sur des sites qui leur sont propres.In 1990, following an idea arising from an Inserm study section on aging, the Diplôme d’études approfondies (DEA) de Biologie du vieillissement was created. Since then, more than 300 students have followed these courses which cover the cellular mechanisms of aging and associated diseases, from basic causes of aging to CNS and sensory organs aging, as well as nutritional aspects, sarcopenia and osteoporosis, vascular and neuroendocrine aging. More than 150 thesis have been defended and more than a quarter of students has been recruited on permanent positions in French universities and research institutions (10 %) and hospitals (16 %). Since its creation, one of the particularities of the DEA was the formal links between academia and industry since teaching takes place on private laboratory settings

Cosmological Simulations using Grid Middleware

One way to access the aggregated power of a collection of heterogeneous machines is to use a grid middleware, such as DIET, GridSolve or NINF. It addresses the problem of monitoring the resources, of handling the submissions of jobs and as an example the inherent transfer of input and output data, in place of the user. In this paper we present how to run cosmological simulations using the RAMSES application along with the DIET middleware. We will describe how to write the corresponding DIET client and server. The remainder of the paper is organized as follows: Section 2 presents the DIET middleware. Section 3 describes the RAMSES cosmological software and simulations, and how to interface it with DIET. We show how to write a client and a server in Section 4. Finally, Section 5 presents the experiments realized on Grid'5000, the French Research Grid, and we conclude in Section 6.Comment: submitted Nov 200

Production and oestrogen regulation of FGF1 in normal and cancer breast cells

AbstractTo investigate the relationship between the FGF1 oestrogen regulation and the normal/cancer status of breast cells, we have studied FGF1 17β-oestradiol regulation in normal, transformed and cancerous cells. Normal (NMEC), transformed (HBL-100) and cancerous (MCF-7, MDA-MB-231) human mammary epithelial cells express different levels of FGF1 mRNAs. Western blot analysis allowed us to characterize FGF1 as an 18 kDa form of this polypeptide. Using a neutralizing anti-FGF1 antibody we demonstrated that FGF1 is secreted by all mammary cells studied and stimulates their proliferation in an autocrine manner. We have examined the regulation of FGF1 mRNAs in response to 17β-oestradiol. FGF1 mRNAs were upregulated in hormone-dependent NMEC but was not upregulated either in hormone-sensitive HBL-100 cells or in the hormone-dependent cancerous cell line MCF-7. However, enzyme linked immunosorbent assay indicated an increase of FGF1 protein in NMEC, HBL-100 and MCF-7 cells. We have also examined the 17β-oestradiol regulation of the four alternatively spliced FGF1 mRNAs: 1.A, 1.B, 1.C and 1.D. Only 1.B transcripts were downregulated by 17β-oestradiol in normal cells. These results show that 17β-oestradiol regulates FGF1 mRNAs in a cell-specific manner, and that this regulation may be transcriptional or translational depending on cell phenotype. The specificity of oestradiol effects was checked using its receptor antagonist tamoxifen

Involvement of LEI/L-DNase II pathway in light-induced retinal degeneration

Retinal degenerations, a major cause of visual loss in people over 50 years old in industrialized countries, are characterized by the death of photoreceptors. Although they have various origins (genetic, oxidative), these diseases share a common physiopathological mechanism, i.e. death by apoptosis of the photoreceptors. Apoptosis is a programmed cell death mechanism, which results in the destruction of nuclear DNA. Two molecular pathways of apoptosis are known to date: the caspase-dependent pathway, involved in numerous apoptosis models, and caspase-independent pathways, which activate proteases other than caspases. Caspases are intracellular cysteine proteases. Our study focuses on a caspase-independent pathway: the LEI (Leukocyte Elastase Inhibitor)/LDNase II pathway in a light-induced retinal degeneration model, a model of apoptosis which does not involve the activation of caspases. When subjected to certain apoptosis-inducing factors, LEI, a cytoplasmic protein with anti-protease activity, undergoes post-translational modification and nuclear translocation, producing L-DNase II, a nuclear protein with endonuclease activity. Evidence of the involvement of the LEI/L-DNase II pathway in this model of retinal degeneration was provided by immunohistochemistry studies and immunoblot analyses, correlated to the endonuclease activity of rat retinal extracts exposed to continuous illumination. Further studies are currently under way, to determine the importance of this pathway in photoreceptor death, and to identify partner proteins able to activate LEI into L-DNase II in this model of apoptosis.Les dégénérescences rétiniennes, cause majeure de cécité chez les personnes âgées de plus de 50 ans dans les pays industrialisés, se traduisent par une perte des photorécepteurs. Malgré des origines diverses (génétiques, oxydatives), ces affections présentent un mécanisme physiopathologique commun : la mort par apoptose des photorécepteurs. L'apoptose est un mécanisme de mort cellulaire programmée qui aboutit à la dégradation de l'ADN nucléaire. Deux types de voies moléculaires de l'apoptose sont actuellement reconnus : la voie des caspases, protéases à cystéine, qui est impliquée dans de nombreux modèles d'apoptose et les voies indépendantes des caspases qui mettent en jeu différentes protéines impliquées dans l'apoptose. Notre travail consiste à étudier une voie indépendante des caspases, la voie de la LEI (Leucocyte Elastase Inhibitor)/L-DNase II dans un modèle de dégénérescence rétinienne induite par la lumière, modèle d'apoptose pour lequel les caspases ne sont pas activées. Sous l'effet de certains inducteurs de l'apoptose, la LEI, protéine cytoplasmique à activité anti-protéase, subit une modification post-traductionnelle et une nucléarisation: elle se transforme en L-DNase II, protéine nucléaire à activité endonucléase. Les résultats d'études immunohistochimiques et d'immunoblot, corrélés à la mesure de l'activité endonucléase dans les extraits de rétine des rats soumis à une illumination continue montrent l'implication de la voie de la LEI/L- DNase II dans ce modèle de dégénérescence rétinienne. Des travaux sont en cours pour déterminer l'importance de cette voie dans la mort des photorécepteurs et pour définir des protéines partenaires capables d'activer la LEI en L-DNase II dans ce modèle d'apoptose

The protective role of transferrin in Müller glial cells after iron-induced toxicity

PURPOSE: Transferrin (Tf) expression is enhanced by aging and inflammation in humans. We investigated the role of transferrin in glial protection. METHODS: We generated transgenic mice (Tg) carrying the complete human transferrin gene on a C57Bl/6J genetic background. We studied human (hTf) and mouse (mTf) transferrin localization in Tg and wild-type (WT) C57Bl/6J mice using immunochemistry with specific antibodies. Müller glial (MG) cells were cultured from explants and characterized using cellular retinaldehyde binding protein (CRALBP) and vimentin antibodies. They were further subcultured for study. We incubated cells with FeCl(3)-nitrilotriacetate to test for the iron-induced stress response; viability was determined by direct counting and measurement of lactate dehydrogenase (LDH) activity. Tf expression was determined by reverse transcriptase-quantitative PCR with human- or mouse-specific probes. hTf and mTf in the medium were assayed by ELISA or radioimmunoassay (RIA), respectively. RESULTS: mTf was mainly localized in retinal pigment epithelium and ganglion cell layers in retina sections of both mouse lines. hTf was abundant in MG cells. The distribution of mTf and hTf mRNA was consistent with these findings. mTf and hTf were secreted into the medium of MG cell primary cultures. Cells from Tg mice secreted hTf at a particularly high level. However, both WT and Tg cell cultures lose their ability to secrete Tf after a few passages. Tg MG cells secreting hTf were more resistant to iron-induced stress toxicity than those no longer secreted hTf. Similarly, exogenous human apo-Tf, but not human holo-Tf, conferred resistance to iron-induced stress on MG cells from WT mice. CONCLUSIONS: hTf localization in MG cells from Tg mice was reminiscent of that reported for aged human retina and age-related macular degeneration, both conditions associated with iron deposition. The role of hTf in protection against toxicity in Tg MG cells probably involves an adaptive mechanism developed in neural retina to control iron-induced stress

No inherent left and right side in human ‘mental number line': evidence from right brain damage

Spatial reasoning has a relevant role in mathematics and helps daily computational activities. It is widely assumed that in cultures with left-to-right reading, numbers are organized along the mental equivalent of a ruler, the mental number line, with small magnitudes located to the left of larger ones. Patients with right brain damage can disregard smaller numbers while mentally setting the midpoint of number intervals. This has been interpreted as a sign of spatial neglect for numbers on the left side of the mental number line and taken as a strong argument for the intrinsic left-to-right organization of the mental number line. Here, we put forward the understanding of this cognitive disability by discovering that patients with right brain damage disregard smaller numbers both when these are mapped on the left side of the mental number line and on the right side of an imagined clock face. This shows that the right hemisphere supports the representation of small numerical magnitudes independently from their mapping on the left or the right side of a spatial-mental layout. In addition, the study of the anatomical correlates through voxel-based lesion-symptom mapping and the mapping of lesion peaks on the diffusion tensor imaging-based reconstruction of white matter pathways showed that the rightward bias in the imagined clock-face was correlated with lesions of high-level middle temporal visual areas that code stimuli in object-centred spatial coordinates, i.e. stimuli that, like a clock face, have an inherent left and right side. In contrast, bias towards higher numbers on the mental number line was linked to white matter damage in the frontal component of the parietal-frontal number network. These anatomical findings show that the human brain does not represent the mental number line as an object with an inherent left and right side. We conclude that the bias towards higher numbers in the mental bisection of number intervals does not depend on left side spatial, imagery or object-centred neglect and that it rather depends on disruption of an abstract non-spatial representation of small numerical magnitude

Overexpressed or intraperitoneally injected human transferrin prevents photoreceptor degeneration in rd10 mice

PURPOSE: Retinal degeneration has been associated with iron accumulation in age-related macular degeneration (AMD), and in several rodent models that had one or several iron regulating protein impairments. We investigated the iron concentration and the protective role of human transferrin (hTf) in rd10 mice, a model of retinal degeneration. METHODS: The proton-induced X-ray emission (PIXE) method was used to quantify iron in rd10 mice 2, 3, and 4 weeks after birth. We generated mice with the β-phosphodiesterase mutation and hTf expression by crossbreeding rd10 mice with TghTf mice (rd10/hTf mice). The photoreceptor loss and apoptosis were evaluated by terminal deoxynucleotidyl transferase dUTP nick end labeling in 3-week-old rd10/hTf mice and compared with 3-week-old rd10 mice. The neuroprotective effect of hTf was analyzed in 5-day-old rd10 mice treated by intraperitoneal administration with hTf for up to 25 days. The retinal hTf concentrations and the thickness of the outer nuclear layer were quantified in all treated mice at 25 days postnatally. RESULTS: PIXE analysis demonstrated an age-dependent iron accumulation in the photoreceptors of rd10 mice. The rd10/hTf mice had the rd10 mutation, expressed high levels of hTf, and showed a significant decrease in photoreceptor death. In addition, rd10 mice intraperitoneally treated with hTf resulted in the retinal presence of hTf and a dose-dependent reduction in photoreceptor degeneration. CONCLUSIONS: Our results suggest that iron accumulation in the retinas of rd10 mutant mice is associated with photoreceptor degeneration. For the first time, the enhanced survival of cones and rods in the retina of this model has been demonstrated through overexpression or systemic administration of hTf. This study highlights the therapeutic potential of Tf to inhibit iron-induced photoreceptor cell death observed in degenerative diseases such as retinitis pigmentosa and age-related macular degeneration

Atom cooling and trapping by disorder

We demonstrate the possibility of three-dimensional cooling of neutral atoms by illuminating them with two counterpropagating laser beams of mutually orthogonal linear polarization, where one of the lasers is a speckle field, i.e. a highly disordered but stationary coherent light field. This configuration gives rise to atom cooling in the transverse plane via a Sisyphus cooling mechanism similar to the one known in standard two-dimensional optical lattices formed by several plane laser waves. However, striking differences occur in the spatial diffusion coefficients as well as in local properties of the trapped atoms.Comment: 11 figures (postscript