A rare coding mutation in the MAST2 gene causes venous thrombosis in a French family with unexplained thrombophilia: The Breizh MAST2 Arg89Gln variant.

Rare variants outside the classical coagulation cascade might cause inherited thrombosis. We aimed to identify the variant(s) causing venous thromboembolism (VTE) in a family with multiple relatives affected with unprovoked VTE and no thrombophilia defects. We identified by whole exome sequencing an extremely rare Arg to Gln variant (Arg89Gln) in the Microtubule Associated Serine/Threonine Kinase 2 (MAST2) gene that segregates with VTE in the family. Free-tissue factor pathway inhibitor (f-TFPI) plasma levels were significantly decreased in affected family members compared to healthy relatives. Conversely, plasminogen activator inhibitor-1 (PAI-1) levels were significantly higher in affected members than in healthy relatives. RNA sequencing analysis of RNA interference experimental data conducted in endothelial cells revealed that, of the 13,387 detected expressed genes, 2,354 have their level of expression modified by MAST2 knockdown, including SERPINE1 coding for PAI-1 and TFPI. In HEK293 cells overexpressing the MAST2 Gln89 variant, TFPI and SERPINE1 promoter activities were respectively lower and higher than in cells overexpressing the MAST2 wild type. This study identifies a novel thrombophilia-causing Arg89Gln variant in the MAST2 gene that is here proposed as a new molecular player in the etiology of VTE by interfering with hemostatic balance of endothelial cells

Artificial intelligence: The future for organic chemistry?

International audienceBased on a recent article "Predicting reaction performance in C-N cross-coupling using machine learning" appearing in Science we had decided to highlight the way forward for artificial intelligence in chemistry. Synthesis of molecules remains one of the most important challenges in organic chemistry and the standard approach involved by a chemist to solve a problem is based on experience and constitutes a repetitive, time-consuming task often resulting in non-optimized solutions. Thus, considering the recent phenomenal progresses that have been made in machine-learning, there is little doubt that these systems, once fully operational in organic chemistry, will dramatically speed up development of new drugs and will constitute the future of chemistry

Is ionic choline and geranate (CAGE) liquid caging diet-derived fat, limiting its absorption?

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Lipides peroxydés et réaction immuno-inflammatoire dans l’athérosclérose

Inflammation is now considered as a critical process that closely escorts lipid disturbances in the initiation and progression of atherosclerosis. Oxidative process, particularly oxidation of LDL, by creating neo-epitopes, is a key initiator of the inflammatory reaction as it triggers both innate and adaptive immunity. This further induces the production of pro-inflammatory cytokines and the dysregulation of endothelial and hemostatic functions leading to atherosclerotic plaque growth and rupture. The specific role of some cytokines and receptors in the dysregulation of the Th1/Th2 response is now emerging to better approach the complex mechanisms inducing disturbances of the immunoinflammatory process in atherosclerosis

Voltage-Dependent Inhibition of Glycine Receptor Channels by Niflumic Acid

Niflumic acid (NFA) is a member of the fenamate class of nonsteroidal anti-inflammatory drugs. This compound and its derivatives are used worldwide clinically for the relief of chronic and acute pain. NFA is also a commonly used blocker of voltage-gated chloride channels. Here we present evidence that NFA is an efficient blocker of chloride-permeable glycine receptors (GlyRs) with subunit heterogeneity of action. Using the whole-cell configuration of patch-clamp recordings and molecular modeling, we analyzed the action of NFA on homomeric alpha 1 Delta Ins, alpha 2B, alpha 3L, and heteromeric alpha 1 beta and alpha 2 beta GlyRs expressed in CHO cells. NFA inhibited glycine-induced currents in a voltage-dependent manner and its blocking potency in alpha 2 and alpha 3 GlyRs was higher than that in alpha 1 GlyR. The Woodhull analysis suggests that NFA blocks alpha 1 and alpha 2 GlyRs at the fractional electrical distances of 0.16 and 0.65 from the external membrane surface, respectively. Thus, NFA binding site in alpha 1 GlyR is closer to the external part of the membrane, while in alpha 2 GlyR it is significantly deeper in the pore. Mutation G254A at the cytoplasmic part of the alpha 1 GlyR pore-lining TM2 helix (level 2') increased the NFA blocking potency, while incorporation of the beta subunit did not have a significant effect. The Hill plot analysis suggests that alpha 1 and alpha 2 GlyRs are preferably blocked by two and one NFA molecules, respectively. Molecular modeling using Monte Carlo energy minimizations provides the structural rationale for the experimental data and proposes more than one interaction site along the pore where NFA can suppress the ion permeation