Rab27a and Rab27b control different steps of the exosome secretion pathway

Exosomes are secreted membrane vesicles that share structural and biochemical characteristics with intraluminal vesicles of multivesicular endosomes (MVEs). Exosomes could be involved in intercellular communication and in the pathogenesis of infectious and degenerative diseases. The molecular mechanisms of exosome biogenesis and secretion are, however, poorly understood. Using an RNA interference (RNAi) screen, we identified five Rab GTPases that promote exosome secretion in HeLa cells. Among these, Rab27a and Rab27b were found to function in MVE docking at the plasma membrane. The size of MVEs was strongly increased by Rab27a silencing, whereas MVEs were redistributed towards the perinuclear region upon Rab27b silencing. Thus, the two Rab27 isoforms have different roles in the exosomal pathway. In addition, silencing two known Rab27 effectors, Slp4 (also known as SYTL4, synaptotagmin-like 4) and Slac2b (also known as EXPH5, exophilin 5), inhibited exosome secretion and phenocopied silencing of Rab27a and Rab27b, respectively. Our results therefore strengthen the link between MVEs and exosomes, and introduce ways of manipulating exosome secretion in vivo

Lack of Evidence for Neonatal Misoprostol Neurodevelopmental Toxicity in C57BL6/J Mice

Misoprostol is a synthetic analogue of prostaglandin E1 that is administered to women at high doses to induce uterine contractions for early pregnancy termination and at low doses to aid in cervical priming during labor. Because of the known teratogenic effects of misoprostol when given during gestation and its effects on axonal growth in vitro, we examined misoprostol for its potential as a neurodevelopmental toxicant when administered to neonatal C57BL6/J mice. Mice were injected subcutaneously (s.c.) with 0.4, 4 or 40 µg/kg misoprostol on postnatal day 7, the approximate developmental stage in mice of human birth, after which neonatal somatic growth, and sensory and motor system development were assessed. These doses were selected to span the range of human exposure used to induce labor. In addition, adult mice underwent a battery of behavioral tests relevant to neurodevelopmental disorders such as autism including tests for anxiety, stereotyped behaviors, social communication and interactions, and learning and memory. No significant effects of exposure were found for any measure of development or behavioral endpoints. In conclusion, the results of the present study in C57BL/6J mice do not provide support for neurodevelopmental toxicity after misoprostol administration approximating human doses and timed to coincide with the developmental stage of human birth

Adding 6 months of androgen deprivation therapy to postoperative radiotherapy for prostate cancer: a comparison of short-course versus no androgen deprivation therapy in the RADICALS-HD randomised controlled trial

Background Previous evidence indicates that adjuvant, short-course androgen deprivation therapy (ADT) improves metastasis-free survival when given with primary radiotherapy for intermediate-risk and high-risk localised prostate cancer. However, the value of ADT with postoperative radiotherapy after radical prostatectomy is unclear. Methods RADICALS-HD was an international randomised controlled trial to test the efficacy of ADT used in combination with postoperative radiotherapy for prostate cancer. Key eligibility criteria were indication for radiotherapy after radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to radiotherapy alone (no ADT) or radiotherapy with 6 months of ADT (short-course ADT), using monthly subcutaneous gonadotropin-releasing hormone analogue injections, daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as distant metastasis arising from prostate cancer or death from any cause. Standard survival analysis methods were used, accounting for randomisation stratification factors. The trial had 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 80% to 86% (hazard ratio [HR] 0·67). Analyses followed the intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. Findings Between Nov 22, 2007, and June 29, 2015, 1480 patients (median age 66 years [IQR 61–69]) were randomly assigned to receive no ADT (n=737) or short-course ADT (n=743) in addition to postoperative radiotherapy at 121 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 9·0 years (IQR 7·1–10·1), metastasis-free survival events were reported for 268 participants (142 in the no ADT group and 126 in the short-course ADT group; HR 0·886 [95% CI 0·688–1·140], p=0·35). 10-year metastasis-free survival was 79·2% (95% CI 75·4–82·5) in the no ADT group and 80·4% (76·6–83·6) in the short-course ADT group. Toxicity of grade 3 or higher was reported for 121 (17%) of 737 participants in the no ADT group and 100 (14%) of 743 in the short-course ADT group (p=0·15), with no treatment-related deaths. Interpretation Metastatic disease is uncommon following postoperative bed radiotherapy after radical prostatectomy. Adding 6 months of ADT to this radiotherapy did not improve metastasis-free survival compared with no ADT. These findings do not support the use of short-course ADT with postoperative radiotherapy in this patient population

Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial

Background Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. Methods RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov , NCT00541047 . Findings Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60–69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0–10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612–0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6–75·7) in the short-course ADT group and 78·1% (74·2–81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths. Interpretation Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy. Funding Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society

The effect of recent competition between the native Anolis oculatus and the invasive A. cristatellus on display behavior

Invasive species are a global threat to biodiversity. Cases where the invasion has been tracked since its beginning are rare, however, such that the first interactions between invasive and native species remain poorly understood. Communication behavior is an integral part of species identity and is subject to selection. Consequently, resource use and direct interference competition between native and invasive species may drive its evolution. Here, we tested the role of interactions between the recently introduced invasive lizard Anolis cristatellus and the native Anolis oculatus on variation in behavior and communication in Calibishie (Dominica). From May to June 2016, we filmed 122 adult males of both species displaying in banana farms under two contexts (allopatry and sympatry). We then recorded (i) the proportion of time spent displaying and (ii) the relative frequency of dewlap vs. push-up displays. To control for habitat variation, we measured and compared the habitat characteristics (canopy openness and habitat openness) of 228 males in allopatry and sympatry. While the habitat characteristics and total display-time did not differ between the contexts for the two species, the proportion of display-time spent dewlapping by A. cristatellus decreased in sympatry. The display of A. oculatus did not differ between the contexts, however. Shifts in microhabitat use, predation pressure, or interspecific interference are potential factors which might explain the behavioral changes in display observed in A. cristatellus. This study highlights the role of behavioral traits as a first response of an invasive species to recent competition with a closely related native species

When parasitoid males make decisions: information used when foraging for females.

Optimal foraging models predict how an organism allocates its time and energy while foraging for aggregated resources. These models have been successfully applied to organisms such as predators looking for prey, female parasitoids looking for hosts, or herbivorous searching for food. In this study, information use and patch time allocation were investigated using male parasitoids looking for mates. The influence of the former presence of females in absence of mates and the occurrence of mating and other reproductive behaviours on the patch leaving tendency was investigated for the larval parasitoid Asobara tabida. Although males do not modify their patch residence time based on the number of females that visited the patch, they do show an increase in the patch residence time after mating a virgin female and performing courtship behaviour such as opening their wings. These results are in concordance with an incremental mechanism, as it has been described for females of the same species while foraging for hosts. The similarities between males and females of the same species, and the conditions under which such a patch-leaving decision rule is fitted are discussed. This is the first study describing an incremental effect of mating on patch residence time in males, thus suggesting that similar information use are probably driving different organisms foraging for resource, regardless of its nature

Evolution of life-history traits and mating strategy in males: a case study on two populations of a Drosophila parasitoid.

10 pagesInternational audienc

The suggested proximate mechanism underlying decision-making in male <i>A. tabida</i>.

<p>While mating a virgin female increases the tendency to stay on the patch, consequently increasing patch residence time, re-mating an already mated female has no impact on the residence time.</p

Impact d’un amorçage olfactif sur la prise alimentaire auprès de patients Alzheimer

Dans le contexte d’une population vieillissante, la dénutrition chez les personnes âgées est devenue une préoccupation majeure de santé publique, en France comme dans la plupart des pays occidentaux (PNNS, 2011). La dénutrition correspond à un déficit des apports nutritionnels, en termes de calories et/ou de nutriments et micronutriments. Sans prise en charge, elle entraîne une diminution de la mobilité, un risque accru de chutes ou de fractures, une vulnérabilité vis-à-vis des maladies infectieuses et une aggravation des maladies chroniques. En parallèle des stratégies « nutritionnelles » (conseils nutritionnels, utilisation de compléments nutritionnels), l’objectif du programme AUPALESENS était de tester l’efficacité de stratégies « sensorielles » pour prévenir et lutter contre la dénutrition chez les seniors. Spécifiquement, ce programme a permis : -De mesurer l’impact de facteurs sensoriels, psychologiques et sociologiques sur le comportement alimentaire et le statut nutritionnel du senior. Ce travail repose sur une enquête pluridisciplinaire menée auprès de 559 français de plus de 65 ans présentant différents degrés de dépendance (personnes autonomes vivant à domicile ; personnes bénéficiant d’une aide à domicile ; personnes vivant en institution). -D’identifier des leviers permettant d’améliorer l’appétence et le plaisir associés aux repas pour les seniors dépendants. Pour ce travail, nous avons développé et testé des outils et des stratégies permettant d’améliorer 1. la qualité sensorielle des aliments proposés aux seniors (contenu de l’assiette) et 2. le contexte du repas (réappropriation du repas). -D’évaluer l’impact de leviers sensoriels sur la prise alimentaire au cours d’un repas. Pour ce travail, nous avons réalisé près de 100 repas expérimentaux au sein de différentes institutions afin de mesurer les quantités ingérées par les résidents en fonction des améliorations sensorielles proposées. Le 26 novembre 2013 s’est tenu à Dijon le colloque de restitution du programme AUPALESENS. Co-labellisé par les pôles de compétitivité Valorial® et Vitagora®, soutenu par l’Agence Nationale de la Recherche (ANR), ce programme a été coordonné par le CHU de Dijon en partenariat avec l’Inra de Dijon et l’ESA d’Angers. Aupalesens a permis de montrer que le maintien du plaisir de manger et d’être à table est une bonne stratégie sensorielle pour répondre à la problématique nutritionnelle du sujet âgé et lutter contre la dénutrition. Le vieillissement s’accompagne de changements qui peuvent influer sur le comportement alimentaire et conduire à une dénutrition. Donnée difficile à évaluer, et souvent sous-estimée, on considère que la dénutrition touche environ 15 à 40% des personnes âgées vivant en institution, et de 50% à 70% de celles hospitalisées. En partant de ce constat, et en se distinguant d’une approche exclusivement nutritionnelle, le programme de recherche Aupalesens a testé l’efficacité de stratégies « sensorielles » pour prévenir et lutter contre la dénutrition chez les seniors. Des liens forts ont ainsi été mis en évidence entre dépendance alimentaire, perte d’autonomie, diminution des capacités sensorielles, plaisir alimentaire et dénutrition. Un risque accru de dénutrition lié à la perte d’autonomie alimentaire Les scientifiques ont mesuré l’impact des facteurs sensoriels, psychologiques et sociologiques sur le comportement alimentaire et le statut nutritionnel du senior. Ce travail repose sur une enquête pluridisciplinaire menée auprès de 559 français de plus de 65 ans présentant différents degrés de dépendance (personnes autonomes vivant à domicile, personnes bénéficiant d’une aide à domicile, personnes vivant en institution). La mise en place des aides chez les personnes en perte d’autonomie est incontournable mais pose la question du bénéfice réel apporté sur l’état nutritionnel par la délégation de tout ou partie des activités culinaires. En effet, 46% des personnes âgées bénéficiant d'une aide pour leur alimentation (à domicile ou en institution) sont dénutries ou à risque de dénutrition, contre seulement 4 à 16% des personnes ne bénéficiant pas d'une aide pour leur alimentation. Des leviers pour améliorer l’appétence et le plaisir associés aux repas des seniors dépendants L’acte alimentaire ne se limitant pas à la satisfaction d’un besoin physiologique, mais étant intimement lié à la dimension plaisir, l’équipe du programme Aupalesens a développé et testé des outils et des stratégies permettant d’améliorer à la fois la qualité sensorielle des aliments proposés aux seniors (contenu de l’assiette) et le contexte du repas, en passant notamment par la réappropriation du repas. Près de 100 repas expérimentaux ont été réalisés au sein de différentes institutions afin de mesurer les quantités ingérées par les résidents en fonction des améliorations sensorielles proposées. La mise à disposition de condiments à table s’est révélée être une stratégie efficace pour augmenter le plaisir à manger. La présence de deux légumes plutôt qu’un seul dans l’assiette a permis d’augmenter la consommation de viande des résidents testés d’environ 32%. L’amélioration organoleptique des plats et l’introduction de variété sensorielle dans l’environnement des repas ont chacune entraîné une augmentation significative des quantités consommées et de l’appréciation du repas. En revanche, ces deux leviers n’ont pas d’effet cumulatif. Projet ambitieux et pluridisciplinaire, le programme Aupalesens a permis d’ouvrir une nouvelle aire dans la lutte contre la dénutrition des seniors dépendants, en montrant avant tout qu’une bonne alimentation consiste non seulement à satisfaire leurs besoins nutritionnels, mais aussi à leur proposer des plats qu’ils consomment… avec plaisir. A la suite du colloque AUPALESENS, l’Inra organisait également en partenariat avec Vitagora®, le 27 novembre 2013, un Carrefour de l’Innovation Agronomique à Dijon sur la thématique « L'alimentation des seniors et le bien vieillir », dont la restitution vidéo est accessible sur le site institutionnel (inra.fr). AUPALESENS a été financé par l’Agence Nationale de la Recherche (ANR). Ce programme a rassemblé 7 organismes de recherche publique : le CHU de Dijon Service de Médecine Interne Gériatrie, l’ESA d’Angers, l’unité Sensométrie et Chimiométrie de Nantes (ONIRIS/Inra), l’unité LARGECIA de Nantes (ONIRIS), l’unité Aliss (Inra, Paris), l’UMR CSGA (Inra, CNRS, Université de Bourgogne, Dijon), le Service d’endocrinologie et diabétologie du CHU d’Angers, et le Département de psychologie des âges de la vie de l’Université François Rabelais (Tours). Sept structures privées ont également été impliquées : Les Repas Santé (Beaune), Livrac groupe Terrena (Haute Goulaine), Frutarom (Dijon), Lactalis (Retiers), Cecab D’aucy (Saint Thurien), Entremont Alliance (Malestroit). AUPALESENS est un programme labellisé par Valorial® et Vitagora® deux pôles de compétitivité guidant ses acteurs scientifiques et industriels vers des projets collaboratifs débouchant sur des produits et services innovant visant la conquête de marchés alimentaires en France et à l’export