BPAG1n4 is essential for retrograde axonal transport in sensory neurons

Disruption of the BPAG1 (bullous pemphigoid antigen 1) gene results in progressive deterioration in motor function and devastating sensory neurodegeneration in the null mice. We have previously demonstrated that BPAG1n1 and BPAG1n3 play important roles in organizing cytoskeletal networks in vivo. Here, we characterize functions of a novel BPAG1 neuronal isoform, BPAG1n4. Results obtained from yeast two-hybrid screening, blot overlay binding assays, and coimmunoprecipitations demonstrate that BPAG1n4 interacts directly with dynactin p150Glued through its unique ezrin/radixin/moesin domain. Studies using double immunofluorescent microscopy and ultrastructural analysis reveal physiological colocalization of BPAG1n4 with dynactin/dynein. Disruption of the interaction between BPAG1n4 and dynactin results in severe defects in retrograde axonal transport. We conclude that BPAG1n4 plays an essential role in retrograde axonal transport in sensory neurons. These findings might advance our understanding of pathogenesis of axonal degeneration and neuronal death

Apprendre des interactions de soin

Ce numéro thématique propose d’étudier les échanges en milieux de soin comme des situations sources d’apprentissage et d’expérience pour ceux qui les vivent et les co-produisent : les patients et les soignants. Il aborde les formes d’activités et d’apprentissages qui se réalisent sur le terrain du soin, notamment à l’occasion de situations mettant en présence au moins deux sujets cherchant à se comprendre, et à agir pour, sur ou avec l’autre. L’étude des interactions permet de questionner les dynamiques expérientielles et formatives qui s’opèrent chez les acteurs. Quatre types d’axes de recherche sont abordés : • La compréhension de la nature des apprentissages qui surviennent durant les interactions de soins (l’apprentissage ouvrant ici sur une diversité d’entrées : négociation des places, rapport de domination, émancipation, coproduction et légitimation des savoirs, etc.) ; • L’étude des conditions et des configurations situationnelles qui rendent possibles ou au contraire inhibent ces processus ; • La présentation des dispositifs méthodologiques permettant d’observer le travail langagier en situation réelle ainsi que les outils de traitement des données qui peuvent être opérationnalisés dans une démarche orientée formation ; • L’analyse des enjeux pédagogiques et didactiques qui se dégagent de l’étude de ces apprentissages, ainsi que la façon dont ils peuvent orienter l’élaboration des dispositifs d’accompagnement, de formation, de recherche-intervention

La Grande Aventure du livre : de la tablette d’argile à la tablette numérique

International audienceCe manuel abondamment illustré, qui donne à voir certains des plus beaux trésors conservés à la Bibliothèque nationale de France, retrace les temps forts de l’histoire du livre. Les enseignants de collège et de lycée y trouveront des repères pédagogiques, des documents commentés et des focus qui leur permettront de faire découvrir aux élèves les nombreux acteurs – imprimeur, libraire, éditeur, relieur, typographe, graphiste, etc. – qui ont contribué à faire du livre un art à part entière.Une structure en 3 parties :• Le livre comme objet• Le texte• Le livre et ses usages : lectures, postures, rituelsDe multiples entrées pour les enseignants de lettres et d’histoire-géographie au collège et au lycée.Des reproductions commentées et des « focus » pour étudier des documents patrimoniaux de l’écrit en lien avec les programmes :• en français, les grands auteurs (Balzac, Hugo, Rousseau, Mallarmé…)• en histoire, les grandes périodes (la naissance de l’écriture, la découverte de l’imprimerie, les Lumières…)Et notamment, plus particulièrement en lycée :• un ouvrage de référence pour les deux premiers thèmes proposés dans l’enseignement « Littérature et société »• un ouvrage précieux pour les élèves dans le cadre de leurs activités de recherche de documentation (TPE, exposés…

Safety and efficacy of the rSh28GST urinary schistosomiasis vaccine: A phase 3 randomized, controlled trial in Senegalese children.

BackgroundUrinary schistosomiasis, the result of infection by Schistosoma haematobium (Sh), remains a major global health concern. A schistosome vaccine could represent a breakthrough in schistosomiasis control strategies, which are presently based on treatment with praziquantel (PZQ). We report the safety and efficacy of the vaccine candidate recombinant 28-kDa glutathione S-transferase of Sh (rSh28GST) designated as Bilhvax, in a phase 3 trial conducted in Senegal.Methods and findingsAfter clearance of their ongoing schistosomiasis infection with two doses of PZQ, 250 children aged 6-9 years were randomized to receive three subcutaneous injections of either rSh28GST/Alhydrogel (Bilhvax group) or Alhydrogel alone (control group) at week 0 (W0), W4, and W8 and then a booster at W52 (one year after the first injection). PZQ treatment was given at W44, according to previous phase 2 results. The primary endpoint of the analysis was efficacy, evaluated as a delay of recurrence of urinary schistosomiasis, defined by a microhematuria associated with at least one living Sh egg in urine from baseline to W152. During the 152-week follow-up period, there was no difference between study arms in the incidence of serious adverse events. The median follow-up time for subjects without recurrence was 22.9 months for the Bilhvax group and 18.8 months for the control group (log-rank p = 0.27). At W152, 108 children had experienced at least one recurrence in the Bilhvax group versus 112 in the control group. Specific immunoglobulin (Ig)G1, IgG2, and IgG4, but not IgG3 or IgA titers, were increased in the vaccine group.ConclusionsWhile Bilhvax was immunogenic and well tolerated by infected children, a sufficient efficacy was not reached. The lack of effect may be the result of several factors, including interference by individual PZQ treatments administered each time a child was found infected, or the chosen vaccine-injection regimen favoring blocking IgG4 rather than protective IgG3 antibodies. These observations contrasting with results obtained in experimental models will help in the design of future trials.Trial registrationClinicalTrials.gov NCT 00870649

Extracellular Calpain/Calpastatin Balance Is Involved in the Progression of Pulmonary Hypertension

Excessive growth of pulmonary arterial (PA) smooth muscle cells (SMCs) is a major component of PA hypertension (PAH). The calcium-activated neutral cysteine proteases calpains 1 and 2, expressed by PASMCs, contribute to PH but are tightly controlled by a single specific inhibitor, calpastatin. Our objective was to investigate calpastatin during pulmonary hypertension (PH) progression and its potential role as an intracellular and/or extracellular effector. We assessed calpains and calpastatin in patients with idiopathic PAH and mice with hypoxic or spontaneous (SM22-5HTT(+) strain) PH. To assess intracellular and extracellular roles for calpastatin, we studied effects of the calpain inhibitor PD150606 on hypoxic PH in mice with calpastatin overexpression driven by the cytomegalovirus promoter (CMV-Cast) or C-reactive protein (CRP) promoter (CRP-Cast), inducing increased calpastatin production ubiquitously and in the liver, respectively. Chronically hypoxic and SM22-5HTT(+) mice exhibited increased lung calpastatin and calpain 1 and 2 protein levels and activity, both intracellularly and extracellularly. Prominent calpastatin and calpain immunostaining was found in PASMCs of remodeled vessels in mice and patients with PAH, who also exhibited increased plasma calpastatin levels. CMV-Cast and CRP-Cast mice showed similarly decreased PH severity compared with wild-type mice, with no additional effect of PD150606 treatment. In cultured PASMCs from wild-type and CMV-Cast mice, exogenous calpastatin decreased cell proliferation and migration with similar potency as PD150606 and suppressed fibronectin-induced potentiation. These results indicate that calpastatin limits PH severity via extracellular mechanisms. They suggest a new approach to the development of treatments for PH.status: publishe

Therapeutic efficacy of sonic hedgehog protein in experimental diabetic neuropathy

Orientadora : Drª Lucélia DonattiTese (doutorado) - Universidade Federal do Paraná, Setor de Ciências Biológicas, Programa de Pós-Graduação em Biologia Celular e Molecular. Defesa: Curitiba, 31/07/2014Inclui referências : f. 71-83Resumo: Os peixes que habitam o Oceano Antártico são extremamente adaptados ao frio, sendo seu metabolismo, bioquímico e fisiológico, eficiente em baixas temperaturas. Oscilações sazonais de luminosidade e do suprimento alimentar são também apontados como fatores determinantes da biodiversidade e limitantes da biomassa e da produtividade primária do Oceano Antártico. A tolerância a temperaturas mais altas dos organismos marinhos antárticos tem sido estudada devido à preocupação dos pesquisadores frente ao aquecimento global e da Península Antártica. Os poucos resultados existentes têm demonstrado que esses organismos são extremamente estenotérmicos e que alterações de temperatura podem ser letais. O sistema antioxidante representa um importante marcador de resposta dos organismos submetidos a situações de estresse e alterações de temperatura podem promover a geração de espécies reativas de oxigênio ocasionando danos celulares. Atualmente, a extrema estenotermia dos organismos marinhos antárticos também tem sido estudada através da expressão das proteínas do choque térmico (HSPs). Dentre a família das HSPs, a HSP70 apresenta síntese rápida e significativa diante de diferentes estressores, por isso é uma ferramenta útil para quantificar e prever níveis de estresse em organismos. As coletas e os bioensaios deste trabalho, foram realizados na Baía do Almirantado, Ilha Rei George, no Arquipélago das Shetlands do Sul, Península Antártica, onde se localiza a Estação Antártica Comandante Ferraz (EACF). O presente trabalho tem como objetivo investigar variações nos níveis de HSP70, nos níveis de atividade de várias enzimas antioxidantes (SOD, CAT, GPx, GR e GST) e nos níveis dos marcadores não enzimáticos (GSH, PC e LPO) do estresse oxidativo nos peixes antárticos, Notothenia rossii e Nottohenia coriiceps em condições naturais e de estresse térmico. Para tanto, três capítulos compõem este trabalho, onde o primeiro analisa o efeito da temperatura no metabolismo oxidativo de N. rossii e N. coriiceps; o segundo avalia os níveis de expressão de HSP70 no fígado de N. rossii e N. coriiceps submetidos a estresse térmico e o terceiro analisa ao longo do ano os níveis de atividades dos marcadores de estresse oxidativo em diferentes órgãos de N. rossii e N. coriiceps da Baia do Almirantado, Ilha Rei George, Península Antártica. Palavras-chaves: temperatura, sazonalidade, estresse oxidativo, peixes antárticos, proteína do choque térmico.Abstract: The fish that inhabit the Southern Ocean are highly adapted to the cold, and its metabolism, biochemical and physiological, efficient at low temperatures. Seasonal fluctuations of light and food supply are determinants of biodiversity and limiting biomass and primary productivity of the Southern Ocean. The tolerance to higher temperatures of Antarctic marine organisms have studied due to the concern of researchers against global warming and the Antarctic Peninsula. The few results have demonstrated that these organisms are extremely stenothermal and rapid temperature change can be lethal. The antioxidant system is an important response marker of organisms subjected to stress and temperature changes situations can promote the generation of reactive oxygen species causing cell damage. Currently, the extreme stenothermal of Antarctic marine organisms has studied through the expression of heat shock proteins (HSPs). Among the family of HSPs, the HSP70 has significant and rapid synthesis on different stressors, so it is a useful tool to quantify and predict stress levels in organisms. The experiments of were performed in Admiralty Bay, King George Island, in the Archipelago of the South Shetlands, Antarctic Peninsula, where is the Comandante Ferraz Antarctic Station (EACF). This study aims to investigate variations in the levels of HSP70 in the activity levels of several antioxidant enzymes (SOD, CAT, GPx, GR and GST) and the levels of non-enzymatic markers (GSH, PC and LPO) oxidative stress in Antarctic fish, Notothenia rossii and Nottohenia coriiceps in natural and heat stress conditions. Therefore, three chapters make this work, where the first examines the effect of temperature on the oxidative metabolism of N. rossii and N. coriiceps; the second evaluates the HSP70 expression levels in liver N. rossii and N. coriiceps submited to thermal stress and the third analyzes throughout the year, the activity levels of oxidative stress markers in different tissues of N. rossii and N. coriiceps of Admiralty Bay, King George Island, Antarctic Peninsula. Keywords: temperature, seasonality, oxidative stress, Antarctic fish, heat shock proteins