Histoire du LSD. De l’ergot de seigle à l’utilisation thérapeutique

National audienceLe LSD, de l’allemand Lysergsäurediethylamid, est une substance hallucinogène utilisée à but récréatif. Également connue sous le nom d’« acide », cette molécule à propriétés psychotropes est classée en France comme un stupéfiant illicite selon l’arrêté du 22 février 1990..

Implication des récepteurs purinergiques dans l'activation de l'inflammasome NLRP3 dans les macrophages

NLRP3-inflammasome pathway activation appears as the corner stone of manyinflammatory diseases including pulmonary fibrosis, rheumatoid arthritis, gout and Crohn disease. This pathway is known to be activated by danger signals such as ATP or Monosodium urate (MSU) leading to the pro-inflammatory cytokine IL-1β release. The aim of this study is to investigate the role of purinergic receptors in the activation of NLRP3-inflammasome pathway in human macrophages. We found here that MSU or analogs of ATP (ATPγS or BzATP) induced the release of IL-1β from LPS-primed MDM obtained from buffy coat (EFS, Rennes). We observed that purinergic P2X7 receptor antagonists, cathepsin B or caspase-1 inhibitors, siRNA targeting P2Y2R or P2X7R were able to reduce the release of IL-1β from activated macrophages. Furthermore we studied the role of purinergic receptors in pro-inflammatory cytokines release, such as IL-1α or IL-6. This study suggests that P2 receptors-NLRP3 inflammasome pathway represents a novel potential therapeutic target to control inflammation in inflammatory diseases.L’inflammasome NLRP3 est très impliqué dans de nombreuses pathologies inflammatoires comme la fibrose pulmonaire, la polyarthrite rhumatoïde, la goutte ou la maladie de Crohn. Cette voie de signalisation permet la libération de la cytokine pro-inflammatoire IL-1β après activation par des signaux de danger comme l’ATP ou les cristaux d’acide urique (MSU). L’objectif de cette étude est de mieux comprendre le rôle des récepteurs purinergiques dans l’activation de l’inflammasome NLRP3 dans les macrophages humains. Nous montrons ici que le MSU ou les analogues de l’ATP (ATPγS ou BzATP) induisent la libération d’IL-1β dans des macrophages pré-activés par du LPS. Ces macrophages proviennent de la différenciation de monocytes issus de poches de sang périphérique (buffy coat) obtenues à l’EFS (Rennes). Nous observons que des antagonistes du récepteur purinergique P2X7, des inhibiteurs de la cathepsine B ou de la caspase-1 et des siRNA ciblant les récepteurs P2X7 et P2Y2 sont capables de réduire la libération d’IL-1β par les macrophages activés. De plus, dans cette étude nous mettons en évidence le rôle des récepteurs purinergiques dans la sécrétion d’autres cytokines pro-inflammatoires comme l’IL-1α ou l’IL-6. Ce travail suggère que la voie d’activation de l’inflammasome NLRP3 par les récepteurs purinergiques représente une nouvelle cible thérapeutique dans le traitement des pathologies inflammatoires

Multiphase Flow LES Study of the Fuel Split Effects on Combustion Instabilities in an Ultra Low-NOx Annular Combustor

International audienceThis paper describes the application of a coupled acoustic model/large-eddy simulation approach to assess the effect of fuel split on combustion instabilities in an industrial ultra-low-NOx annular combustor. Multiphase flow LES and an analytical model (analytical tool to analyze and control azimuthal modes in annular chambers (ATACAMAC)) to predict thermoacoustic modes are combined to reveal and compare two mechanisms leading to thermoacoustic instabilities: (1) a gaseous type in the multipoint zone (MPZ) where acoustics generates vortex shedding, which then wrinkle the flame front, and (2) a multiphase flow type in the pilot zone (PZ) where acoustics can modify the liquid fuel transport and the evaporation process leading to gaseous fuel oscillations. The aim of this paper is to investigate these mechanisms by changing the fuel split (from 5% to 20%, mainly affecting the PZ and mechanism 2) to assess which mechanism controls the flame dynamics. First, the eigenmodes of the annular chamber are investigated using an analytical model validated by 3D Helmholtz simulations. Then, multiphase flow LES are forced at the eigenfrequencies of the chamber for three different fuel split values. Key features of the flow and flame dynamics are investigated. Results show that acoustic forcing generates gaseous fuel oscillations in the PZ, which strongly depend on the fuel split parameter. However, the correlation between acoustics and the global (pilot + multipoint) heat release fluctuations highlights no dependency on the fuel split staging. It suggests that vortex shedding in the MPZ, almost not depending on the fuel split, is the main feature controlling the flame dynamics for this engin

Application of Large-Eddy simulation to rotor/stator configurations

A better understanding of unsteady flows (including turbulence) is a necessary step towards a breakthrough in the design of current gas turbine components. LES is a very promising method to improve both knowledge of complex physics and reliability of flow solver predictions. However, there is still a lack of evidences in the literature that LES is applicable for rotor/stator configurations. In that context, the objective of the present work is to investigate the capability of LES to predict the turbulent flow in rotor/stator configurations. Two methods are presented and discussed. The first application deals with the application of a dedicated in-house code, designed for LES of turbomachinery through the coupling of multi-copies of the unstructured compressible LES solver AVBP. The investigated configuration is the MT1 high-pressure transonic turbine (QinetiQ Farnborough). The configuration is computed with one scaled stator passage and two rotor passages to guaranty the periodicity and keep the solidity. LES is able to capture major unsteady flow structures and statistics of pressure profiles are in good agreement with experimental data. The analysis of the temporal evolution of signals clearly shows frequency components combined with the blade passing and the vortex shedding of stator wake. The second application relies on the use of the structured multiblock code elsA. The studied configuration is an axial single-stage compressor, operating at subsonic conditions (designed by Snecma). Steady RANS (coupled with the mixing plane approach), unsteady RANS and a LES are performed to predict the flow. Different qualities of grids are compared, from 1.5M cells/passage to 100M cells/passage (the finest mesh is made of 800M cells to represent a tenth of whole periodicity). Compressor performance and flow features as predicted with the three methods are compared with experiments

PUMAH : Pan-tilt Ultrasound Mid-Air Haptics

International audienceFocused ultrasound mid-air haptic interfaces are ideal for providing tactile feedback in Virtual Reality (VR), as they do not require the user to be tethered to, hold, or wear any device. Using an array of ultrasound emitters, they generate focused points of oscillating high pressure in mid-air, eliciting vibrotactile sensations when encountering a user's skin. These arrays feature a large vertical workspace, but are not capable of displaying stimuli far beyond their horizontal limits, severely limiting their workspace in the lateral dimensions. This demo presents the PUMAH, a low-cost 2 degrees-of-freedom robotic system rotating a focused ultrasound array around the pan and tilt axes, enabling multi-directional tactile feedback and increasing the array's workspace volume more than 14-fold

Heart failure care in low-and middle-income countries: a systematic review and meta-analysis

In a systematic review and meta-analysis, Kazem Rahimi and colleagues examine the burden of heart failure in low- and middle-income countries. Please see later in the article for the Editors' Summar

Curvature Discrimination for Dynamic Ultrasound Mid-Air Haptic Stimuli

International audienc

A cellular model to study drug-induced liver injury in nonalcoholic fatty liver disease: application to acetaminophen

International audienceObesity and nonalcoholic fatty liver disease (NAFLD) can increase susceptibility to hepatotoxicity induced by some xenobiotics including drugs, but the involved mechanisms are poorly understood. For acetaminophen (APAP), a role of hepatic cytochrome P450 2E1 (CYP2E1) is suspected since the activity of this enzyme is consistently enhanced during NAFLD. The first aim of our study was to set up a cellular model of NAFLD characterized not only by triglyceride accumulation but also by higher CYP2E1 activity. To this end, human HepaRG cells were incubated for one week with stearic acid or oleic acid, in the presence of different concentrations of insulin. Although cellular triglycerides and the expression of lipid-responsive genes were similar with both fatty acids, CYP2E1 activity was significantly increased only by stearic acid. CYP2E1 activity was reduced by insulin and this effect was reproduced in cultured primary human hepatocytes. Next, APAP cytotoxicity was assessed in HepaRG cells with or without lipid accretion and CYP2E1 induction. Experiments with a large range of APAP concentrations showed that the loss of ATP and glutathione was almost always greater in the presence of stearic acid. In cells pretreated with the CYP2E1 inhibitor chlormethiazole, recovery of ATP was significantly higher in the presence of stearate with low (2.5 mM) or high (20 mM) concentrations of APAP. Levels of APAP-glucuronide were significantly enhanced by insulin. Hence, HepaRG cells can be used as a valuable model of NAFLD to unveil important metabolic and hormonal factors which can increase susceptibility to drug-induced hepatotoxicit

High-resolution mass spectrometry identifies delayed biomarkers for improved precision in acetaminophen/paracetamol human biomonitoring

Paracetamol/acetaminophen (N-acetyl-p-aminophenol, APAP) is a top selling analgesic used in more than 600 prescription and non-prescription pharmaceuticals. To study efficiently some of the potential undesirable effects associated with increasing APAP consumption (e.g., developmental disorders, drug-induced liver injury), there is a need to improve current APAP biomonitoring methods that are limited by APAP short half-life. Here, we demonstrate using high-resolution mass spectrometry (HRMS) in several human studies that APAP thiomethyl metabolite conjugates (S-methyl-3-thioacetaminophen sulfate and S-methyl-3-thioacetaminophen sulphoxide sulfate) are stable biomarkers with delayed excretion rates compared to conventional APAP metabolites, that could provide a more reliable history of APAP ingestion in epidemiological studies. We also show that these biomarkers could serve as relevant clinical markers to diagnose APAP acute intoxication in overdosed patients, when free APAP have nearly disappeared from blood. Using in vitro liver models (HepaRG cells and primary human hepatocytes), we then confirm that these thiomethyl metabolites are directly linked to the toxic N-acetyl-p-benzoquinone imine (NAPQI) elimination, and produced via an overlooked pathway called the thiomethyl shunt pathway. Further studies will be needed to determine whether the production of the reactive hepatotoxic NAPQI metabolites is currently underestimated in human. Nevertheless, these biomarkers could already serve to improve APAP human biomonitoring, and investigate, for instance, inter-individual variability in NAPQI production to study underlying causes involved in APAP-induced hepatotoxicity. Overall, our findings demonstrate the potential of exposomics-based HRMS approach to advance towards a better precision for human biomonitoring.</p