DMTs and Covid-19 severity in MS: a pooled analysis from Italy and France

We evaluated the effect of DMTs on Covid-19 severity in patients with MS, with a pooled-analysis of two large cohorts from Italy and France. The association of baseline characteristics and DMTs with Covid-19 severity was assessed by multivariate ordinal-logistic models and pooled by a fixed-effect meta-analysis. 1066 patients with MS from Italy and 721 from France were included. In the multivariate model, anti-CD20 therapies were significantly associated (OR = 2.05, 95%CI = 1.39–3.02, p < 0.001) with Covid-19 severity, whereas interferon indicated a decreased risk (OR = 0.42, 95%CI = 0.18–0.99, p = 0.047). This pooled-analysis confirms an increased risk of severe Covid-19 in patients on anti-CD20 therapies and supports the protective role of interferon

Évaluation de polymères amphiphiles pour l’extraction, la purification et la caractérisation de protéines membranaires d’intérêt thérapeutique

Within the last two decades, alternative approaches to detergent have been developed for the study of membrane proteins in solution, with the goal to better mimic the natural lipidic environment of the membrane and to improve the stability of the protein. Recently, new amphipathic polymers have been described for their effective capacity to isolate membrane proteins of interest within nanolipidic particles. Although this approach seems particularly promising, few data are available regarding the generation and the study of such particles containing eukaryotic membrane proteins produced with eukaryotic expression systems, and in particular with the yeast Pichia pastoris.The aim of this study is thus to evaluate the performance of such polymers for the extraction and purification of two model membrane proteins produced in the P. pastoris system, namely the adenosine A2A receptor and the calcium permeant channel Transient Receptor Potential Vanilloid 4 (TRPV4). In comparison with detergent-based approaches, we investigate the suitability of such molecules for the isolation and functional and structural characterization of these two membrane proteins.Au cours de deux dernières décennies, des approches alternatives à l’utilisation de détergents ont été développées pour l’étude de protéines membranaires en solution, dans le but de reproduire un environnement lipidique plus stable et plus proche des membranes biologiques. Récemment, de nouveaux polymères amphiphiles ont ainsi été décrits avec la capacité de déstabiliser les membranes biologiques et de générer des nanoparticules lipidiques contenant les protéines d’intérêt. Si cette approche semble particulièrement prometteuse, peu de données sont disponibles quant à l’obtention et à l’étude de telles particules contenant des protéines membranaires eucaryotes produites dans des systèmes d’expression eucaryotes, et en particulier dans la levure Pichia pastoris. L’objet de cette étude est d’évaluer l’efficacité de ce type de polymères pour l’extraction et la purification de deux protéines modèles produites dans le système P. pastoris, à savoir le récepteur à l’adénosine A2A et le canal perméable au calcium Transient Receptor Vanilloid 4 (TRPV4). En comparaison avec des approches basées sur les détergents, notre but est d’évaluer la performance de ces molécules dans le cadre d’études fonctionnelles et structurales de ces protéines membranaires en solution

Evaluation of amphiphilic polymers for the extraction, purification and characterization of membrane proteins of therapeutic interest

Au cours de deux dernières décennies, des approches alternatives à l’utilisation de détergents ont été développées pour l’étude de protéines membranaires en solution, dans le but de reproduire un environnement lipidique plus stable et plus proche des membranes biologiques. Récemment, de nouveaux polymères amphiphiles ont ainsi été décrits avec la capacité de déstabiliser les membranes biologiques et de générer des nanoparticules lipidiques contenant les protéines d’intérêt. Si cette approche semble particulièrement prometteuse, peu de données sont disponibles quant à l’obtention et à l’étude de telles particules contenant des protéines membranaires eucaryotes produites dans des systèmes d’expression eucaryotes, et en particulier dans la levure Pichia pastoris. L’objet de cette étude est d’évaluer l’efficacité de ce type de polymères pour l’extraction et la purification de deux protéines modèles produites dans le système P. pastoris, à savoir le récepteur à l’adénosine A2A et le canal perméable au calcium Transient Receptor Vanilloid 4 (TRPV4). En comparaison avec des approches basées sur les détergents, notre but est d’évaluer la performance de ces molécules dans le cadre d’études fonctionnelles et structurales de ces protéines membranaires en solution.Within the last two decades, alternative approaches to detergent have been developed for the study of membrane proteins in solution, with the goal to better mimic the natural lipidic environment of the membrane and to improve the stability of the protein. Recently, new amphipathic polymers have been described for their effective capacity to isolate membrane proteins of interest within nanolipidic particles. Although this approach seems particularly promising, few data are available regarding the generation and the study of such particles containing eukaryotic membrane proteins produced with eukaryotic expression systems, and in particular with the yeast Pichia pastoris.The aim of this study is thus to evaluate the performance of such polymers for the extraction and purification of two model membrane proteins produced in the P. pastoris system, namely the adenosine A2A receptor and the calcium permeant channel Transient Receptor Potential Vanilloid 4 (TRPV4). In comparison with detergent-based approaches, we investigate the suitability of such molecules for the isolation and functional and structural characterization of these two membrane proteins

Production and Preparation of Isotopically Labeled Human Membrane Proteins in Pichia pastoris for Fast-MAS-NMR Analyses

International audienceMembrane proteins (MPs) comprise about one third of the human proteome, playing critical roles in many physiological processes and associated disorders. Consistently, they represent one of the largest classes of targets for the pharmaceutical industry. Their study at the molecular level is however particularly challenging, resulting in a severe lack of structural and dynamic information that is hindering their detailed functional characterization and the identification of novel potent drug candidates

T Lymphocyte Serotonin 5-HT7 Receptor Is Dysregulated in Natalizumab-Treated Multiple Sclerosis Patients

International audienceSerotonin (5-HT) is known as a potent immune cell modulator in autoimmune diseases and should be protective in the pathogenesis of multiple sclerosis (MS). Nevertheless, there is limited knowledge about receptors involved in 5-HT effects as well as induced mechanisms. Among 5-HT receptors, the 5-HT7 receptor is able to activate naïve T cells and influence the inflammatory response; however, its involvement in the disease has never been studied so far. In this study, we collected blood sample from three groups: acute relapsing MS patients (ARMS), natalizumab-treated MS patients (NTZ), and control subjects. We investigated the 5-HT7 expression on circulating lymphocytes and evaluated the effects of its activation on cytokine production with peripheral blood mononuclear cell (PBMC) cultures. We found a significant increase in the 5-HT7 surface expression on T lymphocytes and on the different CD4+ T cell subsets exclusively in NTZ-treated patients. We also showed that the selective agonist 5-carboxamidotryptamine (5-CT)-induced 5-HT7R activation significantly promotes the production of IL-10, a potent immunosuppressive cytokine in PBMCs. This study provides for the first time a dysregulation of 5-HT7 expression in NTZ-MS patients and its ability to promote IL-10 release, suggesting its protective role. These findings strengthen the evidence that 5-HT7 may play a role in the immuno-protective mechanisms of NTZ in MS disease and could be considered as an interesting therapeutic target in MS.</jats:p

Voyages illustrés aux pays froids (xvie-xixe siècle)

Pourquoi, à la lecture des récits de voyage illustrés dans les Alpes, dans le « Grand Nord » (Arctique, Nord de l'Amérique, Scandinavie) ou encore en Sibérie et dans l'Antarctique, a-t-on le sentiment d’une parenté aussi diffuse et mystérieuse qu’évidente ? D’où provient l’impression, que nous procurent les textes et les images, d’un univers à la fois proche et lointain, familier et déroutant, celui des pays froids ? Jusqu’à l’apparition de la photographie, le livre imprimé et ses illustrations offrent aux lecteurs un moyen de connaissance en même temps qu’une véritable machine à fantasme sur cet ailleurs étrange qui se révèle à la fois d’accès difficile et à portée de main, fascinant et terrifiant. En croisant la variété des paysages et celle des approches disciplinaires, les auteurs du présent ouvrage entendent contribuer à l’exploration de ce continent encore méconnu de la littérature viatique

Impact of targeted hypothermia in expanded-criteria organ donors on recipient kidney-graft function: study protocol for a multicentre randomised controlled trial (HYPOREME)

International audienceIntroduction: Expanded-criteria donors (ECDs) are used to reduce the shortage of kidneys for transplantation. However, kidneys from ECDs are associated with an increased risk of delayed graft function (DGF), a risk factor for allograft loss and mortality. HYPOREME will be a multicentre randomised controlled trial (RCT) comparing targeted hypothermia to normothermia in ECDs, in a country where the use of machine perfusion for organ storage is the standard of care. We hypothesise that hypothermia will decrease the incidence of DGF.Methods and analysis: HYPOREME is a multicentre RCT comparing the effect on kidney function in recipients of targeted hypothermia (34°C-35°C) and normothermia (36.5°C-37.5°C) in the ECDs. The temperature intervention starts from randomisation and is maintained until aortic clamping in the operating room. We aim to enrol 289 ECDs in order to analyse the kidney function of 516 recipients in the 53 participating centres. The primary outcome is the occurrence of DGF in kidney recipients, defined as a requirement for renal replacement therapy within 7 days after transplantation (not counting a single session for hyperkalemia during the first 24 hours). Secondary outcomes include the proportion of patients with individual organs transplanted in each group; the number of organs transplanted from each ECD and the vital status and kidney function of the recipients 7 days, 28 days, 3 months and 1 year after transplantation. An interim analysis is planned after the enrolment of 258 kidney recipients.Ethics and dissemination: The trial was approved by the ethics committee of the French Intensive Care Society (CE-SRLF-16-07) on 26 April 2016 and by the competent French authorities on 20 April 2016 (Comité de Protection des Personnes-TOURS-Région Centre-Ouest 1, registration #2016-S3). Findings will be published in peer-reviewed journals and presented during national and international scientific meetings