S 47445 counteracts the behavioral manifestations and hippocampal neuroplasticity changes in bulbectomized mice

S 47445 is a positive allosteric modulator of glutamate AMPA-type receptors that possesses procognitive, neurotrophic and enhancing synaptic plasticity properties. Its chronic administration promotes antidepressant- and anxiolytic-like effects in different rodent models of depression. We have evaluated the behavioral effects of S 47445 in the bilateral olfactory bulbectomy mice model (OB) and the adaptive changes in those proteins associated to brain neuroplasticity (BDNF and mTOR pathway). Following OB surgery, adult C57BL/6J male mice were chronically administered S 47445 (1, 3 and 10?mg/kg/day; i.p.) and fluoxetine (18?mg/kg/day; i.p.), and then behaviorally tested in the open field test. Afterwards, the expression levels of BDNF, mTOR, phospho-mTOR, 4EBP1 and phospho-4EBP1 were evaluated in hippocampus and prefrontal cortex. Both drugs reduced the OB-induced locomotor activity, a predictive outcome of antidepressant efficacy, with a similar temporal pattern of action. S 47445, but not fluoxetine, showed an anxiolytic effect as reflected by an increased central activity. Chronic administration of S 47445 reversed OB-induced changes in BDNF and phopho-mTOR expression in hippocampus but not in prefrontal cortex. The chronic administration of S 47445 induced antidepressant- and anxiolytic-like effects at low-medium doses (1 and 3?mg/kg/day, i.p.) associated with the reversal of OB-induced changes in hippocampal BDNF and mTOR signaling pathways.Funding: This work was supported by the Institut de Recherches Internationales Servier and the Spanish Ministry of Economy and Competitiveness (MINECO/FEDER) (grant number SAF2015-67457-R)

Blockade of stress-induced increase of glutamate release in the rat prefrontal/frontal cortex by agomelatine involves synergy between melatonergic and 5-HT2C receptor-dependent pathways

<p>Abstract</p> <p>Background</p> <p>Agomelatine is a melatonergic receptor agonist and a 5HT_2Creceptor antagonist that has shown antidepressant efficacy. In order to analyze separately the effect of the two receptorial components, rats were chronically treated with agomelatine, melatonin (endogenous melatonergic agonist), or S32006 (5-HT_2Cantagonist), and then subjected to acute footshock-stress.</p> <p>Results</p> <p>Only chronic agomelatine, but not melatonin or S32006, completely prevented the stress-induced increase of glutamate release in the rat prefrontal/frontal cortex.</p> <p>Conclusions</p> <p>These results suggest a potential synergy between melatonergic and serotonergic pathways in the action of agomelatine.</p

Innovating carbon-capture biotechnologies through ecosystem-inspired solutions

Rising atmospheric carbon concentrations affect global health, the economy, and overall quality of life. We are fast approaching climate tipping points that must be addressed, not only by reducing emissions but also through new innovation and action toward carbon capture for sequestration and utilization (CCSU). In this perspective, we delineate next-generation biotechnologies for CCSU supported by engineering design principles derived from ecological processes inspired by three major biomes (plant-soil, deep biosphere, and marine). These are to interface with existing industrial infrastructure and, in some cases, tap into the carbon sink potential of nature. To develop ecosystem-inspired biotechnology, it is important to identify accessible control points of CO2 and CH4 within a given system as well as value-chain opportunities that drive innovation. In essence, we must supplement natural biogeochemical carbon sinks with new bioengineering solutions

Chronic treatment with agomelatine or venlafaxine reduces depolarization-evoked glutamate release from hippocampal synaptosomes

Background: Growing compelling evidence from clinical and preclinical studies has demonstrated the primary role of alterations of glutamatergic transmission in cortical and limbic areas in the pathophysiology of mood disorders. Chronic antidepressants have been shown to dampen endogenous glutamate release from rat hippocampal synaptic terminals and to prevent the marked increase of glutamate overflow induced by acute behavioral stress in frontal/prefrontal cortex. Agomelatine, a new antidepressant endowed with MT1/MT2 agonist and 5-HT2C serotonergic antagonist properties, has shown efficacy at both preclinical and clinical levels. Results: Chronic treatment with agomelatine, or with the reference drug venlafaxine, induced a marked decrease of depolarization-evoked endogenous glutamate release from purified hippocampal synaptic terminals in superfusion. No changes were observed in GABA release. This effect was accompanied by reduced accumulation of SNARE protein complexes, the key molecular effector of vesicle docking, priming and fusion at presynaptic membranes. Conclusions: Our data suggest that the novel antidepressant agomelatine share with other classes of antidepressants the ability to modulate glutamatergic transmission in hippocampus. Its action seems to be mediated by molecular mechanisms located on the presynaptic membrane and related with the size of the vesicle pool ready for release

S 38093, a histamine H3 antagonist/inverse agonist, promotes hippocampal neurogenesis and improves context discrimination task in aged mice

Strategies designed to increase adult hippocampal neurogenesis (AHN) may have therapeutic potential for reversing memory impairments. H3 receptor antagonists/inverse agonists also may be useful for treating cognitive deficits. However, it remains unclear whether these ligands have effects on AHN. The present study aimed to investigate the effects of a 28-day treatment with S 38093, a novel brain-penetrant antagonist/inverse agonist of H3 receptors, on AHN (proliferation, maturation and survival) in 3-month-old and in aged 16-month-old mice. In addition, the effects of S 38093 treatment on 7-month-old APPSWE Tg2576 transgenic mice, a model of Alzheimer’s disease, were also assessed. In all tested models, chronic treatment with S 38093 stimulated all steps of AHN. In aged animals, S 38093 induced a reversal of age-dependent effects on hippocampal brain-derived neurotrophic factor (BDNF) BDNF-IX, BDNF-IV and BDNF-I transcripts and increased vascular endothelial growth factor (VEGF) expression. Finally, the effects of chronic administration of S 38093 were assessed on a neurogenesis-dependent “context discrimination (CS) test” in aged mice. While ageing altered mouse CS, chronic S 38093 treatment significantly improved CS. Taken together, these results provide evidence that chronic S 38093 treatment increases adult hippocampal neurogenesis and may provide an innovative strategy to improve age-associated cognitive deficits

Isoform-Specific Biased Agonism of Histamine H 3 Receptor Agonists s

ABSTRACT The human histamine H 3 receptor (hH 3 R) is subject to extensive gene splicing that gives rise to a large number of functional and nonfunctional isoforms. Despite the general acceptance that G protein-coupled receptors can adopt different ligand-induced conformations that give rise to biased signaling, this has not been studied for the H 3 R; further, it is unknown whether splice variants of the same receptor engender the same or differential biased signaling. Herein, we profiled the pharmacology of histamine receptor agonists at the two most abundant hH 3 R splice variants (hH 3 R 445 and hH 3 R 365 ) across seven signaling endpoints. Both isoforms engender biased signaling, notably for 4-[3-(benzyloxy)propyl]-1H-imidazole (proxyfan) [e.g., strong bias toward phosphorylation of glycogen synthase kinase 3b (GSK3b) via the full-length receptor] and its congener 3-(1H-imidazol-4-yl)propyl-(4-iodophenyl)-methyl ether (iodoproxyfan), which are strongly consistent with the former&apos;s designation as a &quot;protean&quot; agonist. The 80 amino acid IL3 deleted isoform hH 3 R 365 is more permissive in its signaling than hH 3 R 445 : 2-(1H-imidazol-5-yl)ethyl imidothiocarbamate (imetit), proxyfan, and iodoproxyfan were all markedly biased away from calcium signaling, and principal component analysis of the full data set revealed divergent profiles for all five agonists. However, most interesting was the identification of differential biased signaling between the two isoforms. Strikingly, hH 3 R 365 was completely unable to stimulate GSK3b phosphorylation, an endpoint robustly activated by the full-length receptor. To the best of our knowledge, this is the first quantitative example of differential biased signaling via isoforms of the same G proteincoupled receptor that are simultaneously expressed in vivo and gives rise to the possibility of selective pharmacological targeting of individual receptor splice variants

Contribution à l'étude de la pyrolyse de précurseurs organosiliciés en vue de l'élaboration de fibres base carbure ou carbonitrure de silicium

The objective of this work was to deepen the knowledge of the transformation of organosilicon precursors of polycarbosilazane types (PCSZ) into ceramics based on silicon carbide or carbonitride. The production of ceramic filamentary cylindrical specimens was intended to allow a better understanding of the phenomena occurring during the cross-linking, pyrolysis and ceramization stages. Correlations had to be established between the chemical composition, microstructure, chemical stability and mechanical behaviour of ceramics obtained. This study was structured around four main themes: (i) the implementation of a methodology for obtaining filament specimens from a commercial polycarbosilane (PCS). The mechanical and electrical characteristics of these specimens have been related to the microstructural and chemical variations occurring during pyrolysis. (ii) the identification of the various steps and mechanisms involved in the pyrolysis of a new polycarbosilazane (PCSZ), as well as the role of bound nitrogen on the thermal stability and microstructure of pyrolysates. (iii) the production of filament specimens from a PCSZ whose oxygen level could be modulated by various cross-linking methods made it possible to highlight the role of oxygen and bound nitrogen, as well as the pyrolysis atmosphere on the thermal stability, microstructure and mechanical behaviour of the filaments. (iv) the kinetic and physico-chemical study of the oxidation of ex-PCSZ filaments.Ce travail avait pour objectif d'approfondir la connaissance de la transformation de précurseurs organosiliciés de types polycarbosilazane (PCSZ) en céramiques à base de carbure ou de carbonitrure de silicium. L'obtention d'éprouvettes cylindriques filamentaires céramiques devait permettre une meilleure compréhension des phénomènes se passant au cours des étapes de réticulation, de pyrolyse et de céramisation. Des corrélations devaient être établies entre la composition chimique, la microstructure, la stabilité chimique et le comportement mécanique des céramiquesobtenues. Cette étude s'est articulée autour de quatre thèmes principaux: (i) la mise en place d'une méthodologie d'obtention d'éprouvettes filamentaires à partir d'un polycarbosilane, commercial (PCS). Les caractéristiques mécaniques et électriques de ces éprouvettes ont été reliées aux variations microstructurales et chimique se produisant au cours de la pyrolyse. (ii) la mise en évidence des diverses étapes et des mécanismes intervenant lors de la pyrolyse d'un nouveau polycarbosilazane (PCSZ), ainsi que du rôle de l'azote lié sur la stabilité thermique et la microstructure des pyrolysats. (iii) l'obtention d'éprouvettes filamentaires à partir d'un PCSZ dont le taux d'oxygène a pu être modulé par diverses méthodes de réticulations a permis de mettre en évidence le rôle de l'oxygène et de l'azote lié, ainsi que l'atmosphère de pyrolyse sur la stabilité thermique, la microstructure et le comportement mécanique des filaments. (iv) l'étude cinétique et physico-chimique de l'oxydation de filaments ex-PCSZ

Contribution à l'étude de la pyrolyse de précurseurs organosiliciés en vue de l'élaboration de fibres base carbure ou carbonitrure de silicium

The objective of this work was to deepen the knowledge of the transformation of organosilicon precursors of polycarbosilazane types (PCSZ) into ceramics based on silicon carbide or carbonitride. The production of ceramic filamentary cylindrical specimens was intended to allow a better understanding of the phenomena occurring during the cross-linking, pyrolysis and ceramization stages. Correlations had to be established between the chemical composition, microstructure, chemical stability and mechanical behaviour of ceramics obtained. This study was structured around four main themes: (i) the implementation of a methodology for obtaining filament specimens from a commercial polycarbosilane (PCS). The mechanical and electrical characteristics of these specimens have been related to the microstructural and chemical variations occurring during pyrolysis. (ii) the identification of the various steps and mechanisms involved in the pyrolysis of a new polycarbosilazane (PCSZ), as well as the role of bound nitrogen on the thermal stability and microstructure of pyrolysates. (iii) the production of filament specimens from a PCSZ whose oxygen level could be modulated by various cross-linking methods made it possible to highlight the role of oxygen and bound nitrogen, as well as the pyrolysis atmosphere on the thermal stability, microstructure and mechanical behaviour of the filaments. (iv) the kinetic and physico-chemical study of the oxidation of ex-PCSZ filaments.Ce travail avait pour objectif d'approfondir la connaissance de la transformation de précurseurs organosiliciés de types polycarbosilazane (PCSZ) en céramiques à base de carbure ou de carbonitrure de silicium. L'obtention d'éprouvettes cylindriques filamentaires céramiques devait permettre une meilleure compréhension des phénomènes se passant au cours des étapes de réticulation, de pyrolyse et de céramisation. Des corrélations devaient être établies entre la composition chimique, la microstructure, la stabilité chimique et le comportement mécanique des céramiquesobtenues. Cette étude s'est articulée autour de quatre thèmes principaux: (i) la mise en place d'une méthodologie d'obtention d'éprouvettes filamentaires à partir d'un polycarbosilane, commercial (PCS). Les caractéristiques mécaniques et électriques de ces éprouvettes ont été reliées aux variations microstructurales et chimique se produisant au cours de la pyrolyse. (ii) la mise en évidence des diverses étapes et des mécanismes intervenant lors de la pyrolyse d'un nouveau polycarbosilazane (PCSZ), ainsi que du rôle de l'azote lié sur la stabilité thermique et la microstructure des pyrolysats. (iii) l'obtention d'éprouvettes filamentaires à partir d'un PCSZ dont le taux d'oxygène a pu être modulé par diverses méthodes de réticulations a permis de mettre en évidence le rôle de l'oxygène et de l'azote lié, ainsi que l'atmosphère de pyrolyse sur la stabilité thermique, la microstructure et le comportement mécanique des filaments. (iv) l'étude cinétique et physico-chimique de l'oxydation de filaments ex-PCSZ

Hydrodemetallisation des fractions lourdes petrolieres

SIGLECNRS TD 14559 / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc

Un regard psycho-socio-environnemental sur les risques côtiers : une étude de cas en France et au Canada

Over the last few decades, the occupation of coastal areas has intensified throughout the world (Meur-Ferec & Morel, 2004). These areas have become increasingly artificial, whether due to the development of tourist infrastructures or the multiplication of second homes. In a context marked by climate change, manifested among other things by a rise in sea level, these areas are subject to new challenges in terms of adaptation (IPCC, 2019).The issue of coastal risks (submersion and marine erosion) is a pressing one and concerns different sectors of society, whether it be the economic sphere (e.g. maintaining the tourist offer), the political world (e.g. managing urbanization and risks) or civil society (e.g. the users and inhabitants of these areas).Our research focuses on the social representations of these risks, mobilized by the individuals who live and/or work in these coastal territories. It was conducted in an international context, in several territories at risk in France and Canada. Different survey techniques were used: interviews, questionnaires, word association tasks, and content analysis of press articles. Our results show, contrary to the dominant scientific considerations which claim to give an objective and realistic evaluation of the dangers, the existence of a social construction of the risk dependent on an environmental and sociocultural context.Au cours des dernières décennies, l’occupation des territoires côtiers s’est intensifiée partout dans le monde (Meur-Férec & Morel, 2004). Ces espaces ont connu une artificialisation croissante, que ce soit du fait du développement des infrastructures touristiques ou encore de la multiplication des résidences secondaires. Dans un contexte marqué par le changement climatique, se manifestant entre autres par une hausse du niveau marin, ces espaces sont soumis à de nouveaux défis en termes d’adaptation (GIEC, 2019). La question des risques côtiers (submersion et érosion marine) se pose avec acuité et concerne différents pans de la société, que ce soit la sphère économique (ex. maintien de l’offre touristique), le monde politique (ex. gestion de l’urbanisation et des risques) ou encore la société civile (ex. les usagers et habitants de ces espaces). Notre recherche s’intéresse aux représentations sociales de ces risques, mobilisées par les individus qui vivent et/ou travaillent sur ces territoires côtiers. Elle a été menée dans un cadre international, dans plusieurs territoires à risque en France et au Canada. Différentes techniques d’enquête ont été mobilisées : entretien, questionnaire, tâche d’association de mots, analyse de contenu d’articles de presse. Nos résultats montrent, contrairement aux considérations scientifiques dominantes qui affirment donner une évaluation objective et réaliste des dangers, l’existence d’une construction sociale du risque dépendante d’un contexte environnemental et socioculturel