DYRK1A, a Novel Determinant of the Methionine-Homocysteine Cycle in Different Mouse Models Overexpressing this Down-Syndrome-Associated Kinase

BACKGROUND:Hyperhomocysteinemia, characterized by increased plasma homocysteine level, is associated with an increased risk of atherosclerosis. On the contrary, patients with Down syndrome appear to be protected from the development of atherosclerosis. We previously found a deleterious effect of hyperhomocysteinemia on expression of DYRK1A, a Down-syndrome-associated kinase. As increased expression of DYRK1A and low plasma homocysteine level have been associated with Down syndrome, we aimed to analyze the effect of its over-expression on homocysteine metabolism in mice. METHODOLOGY/PRINCIPAL FINDINGS:Effects of DYRK1A over-expression were examined by biochemical analysis of methionine metabolites, real-time quantitative reverse-transcription polymerase chain reaction, and enzyme activities. We found that over-expression of Dyrk1a increased the hepatic NAD(P)H:quinone oxidoreductase and S-adenosylhomocysteine hydrolase activities, concomitant with decreased level of plasma homocysteine in three mice models overexpressing Dyrk1a. Moreover, these effects were abolished by treatment with harmine, the most potent and specific inhibitor of Dyrk1a. The increased NAD(P)H:quinone oxidoreductase and S-adenosylhomocysteine hydrolase activities were also found in lymphoblastoid cell lines from patients with Down syndrome. CONCLUSIONS/SIGNIFICANCE:Our results might give clues to understand the protective effect of Down syndrome against vascular defect through a decrease of homocysteine level by DYRK1A over-expression. They reveal a link between the Dyrk1a signaling pathway and the homocysteine cycle

Constitution d'une base de données de patients affectés de polyarthrite rhumatoïde : analyse préliminaire des facteurs pronostiques de la dégradation articulaire et de la gravité ; rôle des anticorps anti-filagrines

LYON1-BU Santé (693882101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Développement et caractérisation d'un modèle d'addiction chez le rat (du comportement aux transcriptomes)

L'addiction est une pathologie chronique qui se caractérise par une recherche compulsive de la drogue, une perte de contrôle sur la prise et une très forte probabilité de rechute. Cette pathologie n'affecte que 15 à 20 % des personnes exposées. Elle résulterait donc de l'interaction entre un phénotype vulnérable et l'exposition à la drogue. La recherche fondamentale et clinique s'est focalisée ces 40 dernières années sur la compréhension des processus psychobiologiques sous-tendant la consommation des drogues. Dans cette démarche, cette recherche a contribué à une très bonne compréhension des bases neurobiologiques des effets inconditionnés et conditionnés de la prise de drogue. Cependant, l'addiction ne correspond pas à une simple consommation de la drogue. Par conséquent, aujourd'hui encore les bases neurobiologiques de l'addiction restent inconnues. C'est certainement l'absence de modèle animal pertinent de la pathologie qui a conduit à cette impasse. En effet, seul un modèle animal de l'addiction permettrait d'en caractériser les mécanismes neurobiologiques associés. Au cours de notre travail de thèse, nous avons : 1, testé le pouvoir addictogène de la cocaine chez le rongeur. Pour ce faire, nous avons opérationnalisé, chez le rat, les 3 principaux critères diagnostiques du DSM IV symptomatiques d'une recherche compulsive et d'une perte de contrôle sur la prise de drogue ; 2, étudié de possibles déterminants psychologiques de l'addiction. Nous avons notamment caractérisé les niveaux d'anxiété et de désinhibition comportementale associés à l'addiction et recherché, avant tout contact avec la drogue, des indices comportementaux prédictifs de l'addiction ; 3, étudié des bases biologiques de l'addiction. Nous avons analysé les modifications transcriptionnelles associées à l'addiction au niveau des structures cérébrales constituant le système de récompense ; système central dans le contrôle des comportements motivés. Comme chez l'homme, seul 17 % de la population exposée développe les critères d'addiction et uniquement après plusieurs mois d'autoadministration intraveineuse de la drogue. De plus, à l'image de l'homme, les animaux dépendants, positifs pour les 3 critères d'addiction, présentent une forte rechute du comportement même après un sevrage de longue durée et une incapacité à limiter la prise (lors d'un accès prolongé à la drogue). De plus, le comportement spécifique de ces animaux ne résulte ni d'une plus grande consommation de la drogue, ni d'une désinhibition comportementale ou d'unniveau d'anxiété particuliers. Enfin, avant exposition à la drogue, ils présentent dans leur majorité un phénotype particulier intégrant des dimensions d'anxiété et de recherche de nouveauté. L'analyse biologique a permis de mettre en évidence l'implication particulière du PFM dans l'addiction. En effet, dans cette structure, l'addiction s'accompagne d'une modification de l'expression de 5 fois plus de gènes que dans les autres structures clés du système de récompense. Ces gènes différentiellement exprimés, correspondant à des protéines impliquées dans la structure des synapses, reflètent une complète réorganisation neuronale et fonctionnelle du réseau. Ces travaux ont permis 1) la caractérisation comportementale du premier modèle animal d'addiction, 2) une meilleure connaissance des indices de vulnérabilité, 3) la détermination de bases cellulaires et moléculaires de la pathologie. A travers ces 3 aspects, ces travaux contribuent à la détermination de nouvelles cibles thérapeutiques pour l'élaboration de traitements efficaces de la pathologie.Although the voluntary intake of drugs of abuse is a behavior largely preserved throughout phylogeny, it is currently unclear whether pathological drug use ("addiction") can be observed in species other than humans. Here, we report that behaviors that resemble three of the essential diagnostic criteria for addiction appear over time in rats trained to self-administer cocaine. As in humans, this addiction-like behavior is present only in a small proportion of subjects using cocaine and is highly predictive of relapse after withdrawal. This addiction-like behaviour seems to be associated with a compulsive seeking of the drug but neither with a differential intake of the drug nor with a disinhibited behaviour or a different anxiety level. This addiction-like behaviour is predicted by behavioural factors relative to anxiety and novelty seeking and is associated with transcriptionnal regulations mainly in the prefrontal cortex.BORDEAUX2-BU Santé (330632101) / SudocSudocFranceF

AgNO3 spray tests : Advantages, weaknesses, and various applications to quantify chloride ingress into concrete : Part 1, Non-steady-state diffusion tests and exposure to natural conditions

Within the framework of the evaluation and the prediction of chloride-induced corrosion risks, simple and rapid AgNO3 spray tests can be proposed for various issues. This paper forms the first part of a series. In this first part, the Maultzsch procedure (spraying of 0.1-N AgNO3 solution + K2CrO4) as well as the procedure based on the use of a sole AgNO3 solution have been investigated on a broad range of concretes. These procedures have also been compared to the Collepardi procedure (spraying of 0.1-N AgNO3 + fluoresceine). The feasibility of these colorimetric Techniques on saturated specimens cast in laboratory, after non-steady-state diffusion tests carried out in various conditions, is discussed. In addition, the results obtained from applying such spray tests in field conditions on cores drilled out from various RC test specimens exposed to a marine environment (tidal zone) and to a road and cold environment (freezing-thawing cycles and spraying of deicing salts) are presented. Colorimetric methods have in particular been applied here to the assessment of the average chloride penetration depth and of its evolution versus time (kinetics). Moreover, the detection threshold of these techniques has been investigated in various environments. The possible sources of discrepancy on the results have been analysed

Modelling of isothermal drying process in cementitious materials : Analysis of the moisture transfer and proposal of simplified approaches

A model is proposed that accounts for the isothermal drying process of hardened cement-based materials. It constitutes a further development of previous works. The equations of isothermal drying are derived (i) from mass balance equations written for the liquid water phase, water vapour and dry air, (ii) from the Fick's law governing the relative diffusion process of water vapour and dry air to the gaseous mixture, and (iii) from the Darcy's law describing the transport of wet air and liquid water. Intrinsic liquid water (Kl) and gas (Kg) permeabilities are distinguished, since the concept of intrinsic permeability, which is independent of the fluid nature, is not relevant for a cementitious material. New laws for gas transfers are introduced according to measurements on concrete specimens. Thus, a semi-empirical law gives the effective diffusion coefficient of water vapour vs. porosity and degree of liquid water saturation. In the same way, a new function, expressing the relative permeability to gas with respect to this degree of saturation, is proposed on the basis of experimental results. In order to describe the global movement of gas, viscous and slip flows are taken into account according to the Klinkenberg's concept. A numerical study shows, on the one hand, that a gas depression (below the atmospheric gas pressure) can be observed and, on the other hand, that transfers of water in the gas phase may significantly contribute to the drying of cementitious materials in addition to liquid water transport by capillarity movements. Simplified approaches and their range of application are presented

Processing and nuclear localization of CRMP2 during brain development induce neurite outgrowth inhibition.

International audienceCollapsin response mediator proteins (CRMPs) are believed to play a crucial role in neuronal differentiation and axonal outgrowth. Among them, CRMP2 mediates axonal guidance by collapsing growth cones during development. This activity is correlated with the reorganization of cytoskeletal proteins. CRMP2 is implicated in the regulation of several intracellular signaling pathways. Two subtypes, A and B, and multiple cytosolic isoforms of CRMP2B with apparent masses between 62 and 66 kDa have previously been reported. Here, we show a new short isoform of 58 kDa, expressed during brain development, derived from C-terminal processing of the CRMP2B subtype. Although full-length CRMP2 is restricted to the cytoplasm, using transfection experiments, we demonstrate that a part of the short isoform is found in the nucleus. Interestingly, at the tissue level, this short CRMP2 is also found in a nuclear fraction of brain extract. By mutational analysis, we demonstrate, for the first time, that nuclear translocation occurs via nuclear localization signal (NLS) within residues Arg(471)-Lys(472) in CRMP2 sequence. The NLS may be unmasked after C-terminal processing; thereby, this motif may be surface-exposed. This short CRMP2 induces neurite outgrowth inhibition in neuroblastoma cells and suppressed axonal growth in cultured cortical neurons, whereas full-length CRMP2 promotes neurite elongation. The NLS-mutated short isoform, restricted to the cytoplasm, abrogates both neurite outgrowth and axon growth inhibition, indicating that short nuclear CRMP2 acts as a dominant signal. Therefore, post-transcriptional processing of CRMP2 together with its nuclear localization may be an important key in the regulation of neurite outgrowth in brain development

Immunochemotherapy versus rituximab in anti-MAG neuropathy: a report of 64 patients

International audienceMonoclonal immunoglobulin M (IgM) anti-myelin-associated glycoprotein (MAG) neuropathy is a rare disabling condition, most commonly treated with rituximab monotherapy (R), which leads to neurological improvement in only 30%-50% of patients. The combination of rituximab plus chemotherapy has been proven to improve the level of responses. We studied the outcomes of anti-MAG neuropathy patients treated either by R, or by immunochemotherapy (ICT) in our centre, focusing on the incidence of the first neurological response evaluated by the modified Rankin Scale (mRS). From 2011 to 2018, 64 patients were studied: 34 were treated with R and 30 with ICT. According to our treatment decisionmaking process, the median mRS was higher in the ICT group (mRS 2) compared to the R group (mRS 1). At 1 year, mRS improvement rates were 46% and 18% of the ICT and R groups of patients respectively, with a median time to response of 8 and 13 months (p=0.023). Adverse effects were higher in the ICT group: 62% vs 15% (p˂0.01) all grades included. One secondary acute leukaemia occurred 5 years after treatment by ICT. In conclusion, ICT may be used as a valid option for patients with rapidly progressive and/or severe anti-MAG neuropathy symptoms

Conseiller

Depuis la crise des banlieues et la création des ZEP le métier de conseiller est au centre de l'éducation des élèves, au moment où la surveillance et le contrôle pourraient remplacer la tâche éducative. Des professionnels expliquent ici leurs pratiques quotidiennes et proposent des solutions concrètes pour améliorer la vie lycénne et la gestion humaine des élèves

Defining biomarkers in oral cancer according to smoking and drinking status

International audienceIntroduction Oral Squamous Cell Carcinomas (OSCC) are mostly related to tobacco consumption eventually associated to alcohol (Smoker/Drinker patients: SD), but 25-30% of the patients have no identified risk factors (Non-Smoker/Non-Drinker patients: NSND). We hypothesized that these patients have distinguishable immune profiles that could be useful for prognosis. Materials and Methods Cells present in immune tumor microenvironment (TME) and blood from 87 OSCC HPV-negative patients were analyzed using a multiparameter flow cytometry assay, in a prospective case-control study. Cytokine levels in tumor supernatants and blood were determined by a cytometric bead array (CBA) assay. Results Normal gingiva and blood from healthy donors (HD) were used as controls. A significant increase of granulocytes (p<0.05 for blood), of monocytes-macrophages (p<0.01 for blood) and of CD4 + T cells expressing CD45RO and CCR6 (p<0.001 for blood; p<0.0001 for TME) as well as higher levels of IL-6 (p<0.01 for sera, p<0.05 for tumor supernatant) were observed in SD patients as compared to NSND OSCC patients and HD. High percentages of CD4 + T cells expressing CD45RO and CCR6 cells in tumor tissue (p=0.05) and blood (p=0.05) of SD OSCC patients were also associated with a poorer prognosis while a high percentage of regulatory T cells (Treg) in tumor tissue was associated with a more favorable prognostic factor (p=0.05). Also, a higher percentage of blood CD8 + T lymphocytes among CD45 + cells in NSND patients was associated with a better disease-free survival (p=0.004). Conclusion Granulocytes, monocytes-macrophages, and CD4 + T cells expressing CD45RO and CCR6 in blood and TME as well as serum IL-6 can therefore distinguish OSCC SD and NSND patients. Quantifying the proportion of CD4 + T cells expressing CD45RO and CCR6 and of Treg in SD patients and CD8 + T cells in NSND patients could help defining the prognostic of OSCC patients