Comment développer un antidépresseur au mécanisme d’action innovant : l’exemple de l’agomélatine

Divers axes de recherche ont été suivis pour obtenir de nouveaux traitements de la dépression plus efficaces, mieux tolérés et d’action plus rapide. Parmi ces axes de recherche, la mélatonine, synchronisateur endogène des rythmes biologiques chez les mammifères, suscite un intérêt croissant dans la mesure où la désorganisation des rythmes circadiens est caractéristique d’un grand nombre de troubles de l’humeur. L’agomélatine est un antidépresseur qui se distingue par des propriétés agonistes pour les récepteurs mélatoninergiques (MT1 et MT2) ; ses propriétés agonistes ont été confirmées lors d’études in vivo, l’agomélatine améliorant les perturbations des rythmes circadiens observés dans différents modèles animaux. La propriété antidépressive de l’agomélatine a été mise en évidence dans plusieurs modèles animaux validés, dont les tests de la nage forcée, de la résignation acquise ou du stress chronique modéré. De façon tout à fait intéressante, l’activité antidépressive de l’agomélatine ne repose pas uniquement sur une action chronobiotique : en fait, l’agomélatine présente une activité antagoniste sur les récepteurs 5-HT2C, et ce aux doses antidépressives. Par ailleurs, l’absence d’affinité de l’agomélatine vis-à-vis d’un large éventail de récepteurs lui confère un excellent profil de sécurité, particulièrement avantageux par rapport aux antidépresseurs déjà sur le marché (pas de désordres gastro-intestinaux ni de perturbations de la fonction sexuelle ou du sommeil). L’agomélatine inaugure donc un nouveau concept dans le traitement de la dépression.There are now many potentials for the development of more effective, better tolerated, and more rapidly acting antidepressants acting in association and/or beyond the monoamine hypothesis. One of these possibilities is the development of antidepressant drugs with melatonin agonist property. This holds much promise since various affective disorders, including depression, are characterized by abnormal patterns of circadian rhythms. In line with this, the melatoninergic agonist properties of agomelatine, an antidepressant with proven clinical efficacy, may represent a new concept for the treatment of depression. By way of behavioral studies in rodents, it has been shown that administration of agomelatine can mimic the action of melatonin in the synchronization of circadian rhythm patterns. Interest in agomelatine has increased in recent times due to its prospective use as a novel antidepressant agent, as demonstrated in a number of animal studies using well-validated animal models of depression (including the forced swimming test, the learned helplessness, the chronic mild stress). Interestingly, the melatoninergic agonist property of agomelatine may not, alone, be sufficient to sustain its clear antidepressant-like activity. Recent results from receptor binding and in vivo studies gave support to the notion that agomelatine’s effects are also mediated via its function as a competitive antagonist at the 5-HT2C receptor. Finally, thanks to its absence of binding with a broad range of receptors and enzymes, agomelatine is particularly safe and devoid of all the deleterious effects reported with tricyclics and SSRIs

Numerical simulation of boiling during the quenching process

National audienceDuring the thermal modelling of the quenching process, different stages of boiling need to be treated, from nucleate boiling to generation and growth of a vapour film. The interface between each phase flow is determined using a level set method. Surface tension is evaluated using the continuum surface force. The proposed approach demonstrates the capability of the model to simulate detachment of a single bubble and the generation of film vapour from a heated source. A comparison between numerical and experimental results shows a good agreement.br/>See http://hal.archives-ouvertes.fr/docs/00/59/26/76/ANNEX/r_71D43983.pd

Rhéologie de suspensions concentrées à pression imposée : un pont entre les suspensions et les écoulements granulaires

La rhéologie des suspensions concentrées reste mal comprise : faisant intervenir à la fois des interactions hydrodynamiques et de contact, ce sont des systèmes intermédiaires entre les suspensions diluées et les écoulements granulaires. Nous présentons des résultats issus d'une approche nouvelle permettant d'éviter les divergences usuellement rencontrées à fraction volumique imposée : en choisissant la pression particulaire comme paramètre de contrôle, la rhéologie s'exprime en terme de friction effective dont nous montrons la compatibilité avec l'approche classique

Les politiques de revitalisation des aires d'ancienne industrie à Londres et en Ile-de-France

La présente étude concerne les relations entre les changements urbains et les politiques locales, dans deux boroughs de Londres et deux communes de la proche banlieue parisienne. L'évolution économique y a été marquée par la désindustrialisation et l'arrivée d'activités non productives, tandis que des transformations se faisaient jour sur le marché du logement. Ce changement a été accepté, voire encouragé, par les autorités locales, qu'elles soient de gauche (Islington, Montreuil) ou de droite (Wandsworth, Issy). En revanche, les politiques du logement restent plus différenciées, l'embourgeoisement (gentrification) confortant les municipalités de droite mais menaçant la base sociale et électorale de celles de gauche. Dans les deux Etats, les problèmes financiers, liés au désengagement des gouvernements centraux et à la diminution des ressources municipales, limitent les possibilités d'intervention des autorités locales, qui recourent de plus en plus au partenariat avec le secteur privé. Parmi les outils utilisés, le contrôle de l'usage du sol paraît jouer un plus grand rôle dans le cas français. Toutes les municipalités mènent une politique d'image et d'amélioration du cadre de vie, notamment pour attirer les investissements; mais alors qu'en France le cadre communal, personnalisé par le maire, est nettement valorisé, les boroughs londoniens ont été amenés à fondre leur action dans des projets plus ponctuels auxquels participe fortement le secteur privé.regeneration urbaine;Londres;banlieue parisienne;borough

Difficultés d'une nécessaire coopération entre collectivités territoriales

Le présent cahier, réalisé par l'équipe “Aménagement et collectivités territoriales” du laboratoire, analyse des tentatives de coopération que les collectivités territoriales ont menées du fait de la décentralisation et du morcellement administratif particulièrement important du territoire français. Les situations choisies recouvrent une diversité de milieux - urbain/rural - d'enjeux - technopolisation, urbanisation, développement touristique, gestion d'infrastructures - auxquels la décentralisation se trouve confrontée. Celle-ci apparaît comme une nécessité économique et politique, même si elle se constitue dans le désordre et la complexité et a encore à faire la preuve de son efficacité. La décentralisation a libéré des dynamismes, a redistribué les rôles entre les différents acteurs et décideurs, et c'est ce processus d'apprentissage de la coopération et du partenariat qui est analysé dans les différents articles qui concernent essentiellement des situations en Ile-de-France et dans le grand bassin parisiencommunauté de communes;communauté de villes; décentralisation;développement local;développement rural;district;intercommunalité;planification urbaine;tourisme;syndicat intercommunal;tecnopole

The response of the root proteome to the synthetic strigolactone GR24 in Arabidopsis

Strigolactones are plant metabolites that act as phytohormones and rhizosphere signals. Whereas most research on unraveling the action mechanisms of strigolactones is focused on plant shoots, we investigated proteome adaptation during strigolactone signaling in the roots of Arabidopsis thaliana. Through large-scale, time-resolved, and quantitative proteomics, the impact of the strigolactone analog rac-GR24 was elucidated on the root proteome of the wild type and the signaling mutant more axillary growth 2 (max2). Our study revealed a clear MAX2-dependent rac-GR24 response: an increase in abundance of enzymes involved in flavonol biosynthesis, which was reduced in the max2-1 mutant. Mass spectrometry-driven metabolite profiling and thin-layer chromatography experiments demonstrated that these changes in protein expression lead to the accumulation of specific flavonols. Moreover, quantitative RT-PCR revealed that the flavonol-related protein expression profile was caused by rac-GR24-induced changes in transcript levels of the corresponding genes. This induction of flavonol production was shown to be activated by the two pure enantiomers that together make up rac-GR24. Finally, our data provide much needed clues concerning the multiple roles played by MAX2 in the roots and a comprehensive view of the rac-GR24-induced response in the root proteome

Tritium and 14 C background levels in pristine aquatic systems and their potential sources of variability

C Aquatic systems Background levels Global fallout Regional scale a b s t r a c t Tritium and 14 C are currently the two main radionuclides discharged by nuclear industry. Tritium integrates into and closely follows the water cycle and, as shown recently the carbon cycle, as does 14 C (Eyrolle-Boyer et al., 2014a, b). As a result, these two elements persist in both terrestrial and aquatic environments according to the recycling rates of organic matter. Although on average the organically bound tritium (OBT) activity of sediments in pristine rivers does not significantly differ today (2007 e2012) from the mean tritiated water (HTO) content on record for rainwater (2.4 ± 0.6 Bq/L and 1.6 ± 0.4 Bq/L, respectively), regional differences are expected depending on the biomass inventories affected by atmospheric global fallout from nuclear testing and the recycling rate of organic matter within watersheds. The results obtained between 2007 and 2012 for 14 C show that the levels varied between 94.5 ± 1.5 and 234 ± 2.7 Bq/kg of C for the sediments in French rivers and across a slightly higher range of 199 ± 1.3 to 238 ± 3.1 Bq/kg of C for fish. This variation is most probably due to preferential uptake of some organic carbon compounds by fish restraining 14 C dilution with refractory organic carbon and/or with old carbonates both depleted in 14 C. Overall, most of these ranges of values are below the mean baseline value for the terrestrial environment (232.0 ± 1.8 Bq/kg of C in 2012, Roussel-Debet, 2014a) in relation to dilution by the carbonates and/or fossil organic carbon present in aquatic systems. This emphasises yet again the value of establishing regional baseline value ranges for these two radionuclides in order to account for palaeoclimatic and lithological variations. Besides, our results obtained from sedimentary archive investigation have confirmed the delayed contamination of aquatic sediments by tritium from the past nuclear tests atmospheric fallout, as recently demonstrated from data chronicles (Eyrolle-Boyer et al., 2014a,b). Thus Sedimentary archives can be successfully used to reconstruct past 14 C and OBT levels. Additionally, sediment repositories potentially represent significant storages of OBT that may account for in case of further remobilisation. We finally show that floods can significantly affect the OBT and 14 C levels within suspended particles or sediments depending on the origin of particles reinforcing the need to acquire baseline value range at a regional scale

Secondary Phases Quantification and Fracture Toughness at Cryogenic Temperature of Austenitic Stainless Steel Welds for High-Field Superconducting Magnets

The ITER magnet system is based on the “cable-in-conduit” conductor concept, which consists of various types of stainless steel jackets filled with superconducting strands. The jackets provide high strength and fracture toughness to counteract the high stress imposed by, amongst others, electromagnetic loads at cryogenic temperature. Material properties of austenitic stainless steel at cryogenic temperature are known to some extent, but only partial information is available for their welds, particularly in combination with weld fillers envisaged for cryogenic service. When a full inspection of the welded components is not possible, it becomes of special interest an assessment of its fracture toughness under close-to-service conditions if a fracture mechanics’ design approach is to be adopted. In absence of defects, brittle secondary phases are generally held responsible of the loss of ductility and toughness which is to be expected after postweld heat treatments. Their quantification becomes thus essential in order to explain the negative impact in fracture toughness after unavoidable thermal treatments. This paper investigates fracture toughness behavior at 7 K of AISI 316L and AISI 316LN tungsten inert gas welds using two fillers adapted to cryogenic service, EN 1.4453 and JK2LB. Additionally, the effect of such an aforementioned heat treatment, here the Nb$_3$Sn reaction heat treatment (650° for 200 h) on fracture toughness of the welds is evaluated. A correlation between the evolution of properties and the quantity of secondary phases as a result of the above treatment is provided

Measuring global ocean heat content to estimate the earth energy imbalance

The energy radiated by the Earth toward space does not compensate the incoming radiation from the Sun leading to a small positive energy imbalance at the top of the atmosphere (0.4–1 Wm–2). This imbalance is coined Earth’s Energy Imbalance (EEI). It is mostly caused by anthropogenic greenhouse gas emissions and is driving the current warming of the planet. Precise monitoring of EEI is critical to assess the current status of climate change and the future evolution of climate. But the monitoring of EEI is challenging as EEI is two orders of magnitude smaller than the radiation fluxes in and out of the Earth system. Over 93% of the excess energy that is gained by the Earth in response to the positive EEI accumulates into the ocean in the form of heat. This accumulation of heat can be tracked with the ocean observing system such that today, the monitoring of Ocean Heat Content (OHC) and its long-term change provide the most efficient approach to estimate EEI. In this community paper we review the current four state-of-the-art methods to estimate global OHC changes and evaluate their relevance to derive EEI estimates on different time scales. These four methods make use of: (1) direct observations of in situ temperature; (2) satellite-based measurements of the ocean surface net heat fluxes; (3) satellite-based estimates of the thermal expansion of the ocean and (4) ocean reanalyses that assimilate observations from both satellite and in situ instruments. For each method we review the potential and the uncertainty of the method to estimate global OHC changes. We also analyze gaps in the current capability of each method and identify ways of progress for the future to fulfill the requirements of EEI monitoring. Achieving the observation of EEI with sufficient accuracy will depend on merging the remote sensing techniques with in situ measurements of key variables as an integral part of the Ocean Observing System

Deep Sequencing Analyses of Low Density Microbial Communities: Working at the Boundary of Accurate Microbiota Detection

Introduction: Accurate analyses of microbiota composition of low-density communities (10 3 –10 4 bacteria/sample) can be challenging. Background DNA from chemicals and consumables, extraction biases as well as differences in PCR efficiency can significantly interfere with microbiota assessment. This study was aiming to establish protocols for accurate microbiota analysis at low microbial density. Methods: To examine possible effects of bacterial density on microbiota analyses we compared microbiota profiles of seria