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Abstract Various substituted aromatics have been reduced using colloidal ruthenium under H 2 pressure with good stereoselectivity (cis/trans up to 60). Interesting chemoselectivities are also observed.

As the number of women who use alcohol increases, so does the number of women who engage in alcohol abuse and develop alcohol dependence. The recent increased focus on women and gender differences in alcoholism research has largely come about following recognition that the face of alcoholism is changing, with alcoholism rates among men remaining stable and rising among women, particularly in younger women. As such, the need to understand gender differences in both acute and long-term effects of alcohol abuse has never been more critical. Gender differences in the long-term effects of chronic alcoholism on the brain and other systems are currently under debate, often with a focus on proclaiming whether men or women suffer the most impact. However, the story appears to be more complex than that. The issue of how alcoholism interacts with gender is complicated, as gender differences in many factors including alcohol metabolism, alcoholism progression, problematic drinking patterns, neurobiology, hormones, and psychiatric comorbidities will contribute to the differences in structural and functional outcomes observed experimentally across domains of inquiry. While women are now much more commonly included in studies of alcohol’s effects on the brain, there remains a need for more explicit examinations of gender effects.

The first kinase inhibitor drug approval in 2001 initiated a remarkable decade of tyrosine kinase inhibitor drugs for oncology indications, but a void exists for serine/threonine protein kinase inhibitor drugs and central nervous system indications. Stress kinases are of special interest in neurological and neuropsychiatric disorders due to their involvement in synaptic dysfunction and complex disease susceptibility. Clinical and preclinical evidence implicates the stress related kinase p38αMAPK as a potential neurotherapeutic target, but isoform selective p38αMAPK inhibitor candidates are lacking and the mixed kinase inhibitor drugs that are promising in peripheral tissue disease indications have limitations for neurologic indications. Therefore, pursuit of the neurotherapeutic hypothesis requires kinase isoform selective inhibitors with appropriate neuropharmacology features. Synaptic dysfunction disorders offer a potential for enhanced pharmacological efficacy due to stress-induced activation of p38αMAPK in both neurons and glia, the interacting cellular components of the synaptic pathophysiological axis, to be modulated. We report a novel isoform selective p38αMAPK inhibitor, MW01-18-150SRM (=MW150), that is efficacious in suppression of hippocampal-dependent associative and spatial memory deficits in two distinct synaptic dysfunction mouse models. A synthetic scheme for biocompatible product and positive outcomes from pharmacological screens are presented. The high-resolution crystallographic structure of the p38αMAPK/MW150 complex documents active site binding, reveals a potential low energy conformation of the bound inhibitor, and suggests a structural explanation for MW150's exquisite target selectivity. As far as we are aware, MW150 is without precedent as an isoform selective p38MAPK inhibitor or as a kinase inhibitor capable of modulating in vivo stress related behavior.

AbstractWater-in-oil emulsions having their aqueous internal phase gelled with starch were prepared and investigated. They were the primary emulsions required for the preparation of double w/o/w emulsions that could encapsulate hydrophilic materials inside the internal aqueous gel. The emulsification could be achieved at high temperature in spite of the high viscosity of the aqueous phase; the internal phase gelled upon cooling to room temperature. The high viscosity of the aqueous phase limited the possible concentration range of starch in the aqueous phase. The presence of starch made the surfactant demand larger for both the emulsification and the stabilization of the w/o emulsions. The larger the starch content, the larger the amount of required surfactant. One reason for the high surfactant demand was the high viscosity of the aqueous phase containing starch. Another cause of high surfactant demand was disclosed and it appeared that predominantly the interactions of the nonionic surfactants with starch retained the former inside the aqueous phase. The immobilized amount of surfactant had to be compensated by a supplementary concentration. Experimental evidence of the interactions between starch and the nonionic surfactants was given by interfacial tension measurements. Lastly, w/o/w double emulsions were prepared using the gelled w/o emulsions and a model hydrophilic molecule (caffeine) was encapsulated inside the internal gelled aqueous phase. The release rate of caffeine from the internally gelled double emulsions was slower than for the non-gelled emulsions, demonstrating the efficiency of the encapsulation and the possible control of the delivery.

Neurochirurgie - Sous presse. Epreuves corrigees par l'auteur. Disponible en ligne depuis le lundi 18 juin 2018

A dysfunctional endosomal pathway and abnormally enlarged early endosomes in neurons are an early characteristic of Down syndrome (DS) and Alzheimer’s disease (AD). We have hypothesized that endosomal material can be released by endosomal multivesicular bodies (MVBs) into the extracellular space via exosomes to relieve neurons of accumulated endosomal contents when endosomal pathway function is compromised. Supporting this, we found that exosome secretion is enhanced in the brains of DS patients and a mouse model of the disease, and by DS fibroblasts. Furthermore, increased levels of the tetraspanin CD63, a regulator of exosome biogenesis, were observed in DS brains. Importantly, CD63 knockdown diminished exosome release and worsened endosomal pathology in DS fibroblasts. Taken together, these data suggest that increased CD63 expression enhances exosome release as an endogenous mechanism mitigating endosomal abnormalities in DS. Thus, the upregulation of exosome release represents a potential therapeutic goal for neurodegenerative disorders with endosomal pathology. Electronic supplementary material The online version of this article (doi:10.1186/s40478-017-0466-0) contains supplementary material, which is available to authorized users.

Carbon monoxide (CO) at low concentrations imparts protective effects in numerous preclinical small animal models of brain injury. Evidence of protection in large animal models of cerebral injury, however, has not been tested. Neurologic deficits following open heart surgery are likely related in part to ischemia reperfusion injury that occurs during cardiopulmonary bypass surgery. Using a model of deep hypothermic circulatory arrest (DHCA) in piglets, we evaluated the effects of CO to reduce cerebral injury. DHCA and cardiopulmonary bypass (CPB) induced significant alterations in metabolic demands, including a decrease in the oxygen/glucose index (OGI), an increase in lactate/glucose index (LGI) and a rise in cerebral blood pressure that ultimately resulted in increased cell death in the neocortex and hippocampus that was completely abrogated in piglets preconditioned with a low, safe dose of CO. Moreover CO-treated animals maintained normal, pre-CPB OGI and LGI and corresponding cerebral sinus pressures with no change in systemic hemodynamics or metabolic intermediates. Collectively, our data demonstrate that inhaled CO may be beneficial in preventing cerebral injury resulting from DHCA and offer important therapeutic options in newborns undergoing DHCA for open heart surgery.

A potential benefit of alkylphosphocholines in brain tumor therapy was evaluated. The in vitro effects of the intravenously applicable erucylphosphocholine (ErPC) on proliferation, viability, morphology and cell cycle distribution of a rat glioma, four human astrocytoma/glioblastoma and a human medulloblastoma cell line were analyzed daily after continuous drug-exposure for up to six days. ErPC exerted strong cytostatic and direct cytotoxic effects on all cell lines tested at drug concentrations that are achieved in the rat brain after repeated intravenous injections of nontoxic drug doses. Concentrations of 70 microM (T98G, A172, 85HG66, 86HG39) and 110 microM (C6, D283 Med) led to complete cell death within 48-96 h. Particular characteristics of ErPC action are i) the accumulation of cells with a 4n DNA content corresponding to the G2/M-phase of the cell cycle, ii) the formation of two- and multinucleated cells and iii) the induction of apoptosis.