Identification du comportement mécanique dynamique de tubes d'aluminium par un essai d'expansion électromagnétique

National audienceLes vitesses de déformation mises en jeu au cours du magnétoformage sont de l'ordre de 102 à 104 s-1. La maîtrise du procédé exige donc la caractérisation des métaux dans ces conditions de déformation. Cet article présente la mise en place d'une démarche d'identification du comportement dynamique basée sur un essai d'expansion de tube instrumenté à l'aide d'un système de mesure de vitesse par interférométrie doppler-laser. Les simulations numériques sont réalisées à l'aide du code LS-Dyna®, et l'analyse inverse est menée grâce à l'interface d'optimisation LS-Opt®. Après une analyse numérique, des résultats d'identification sur tubes d'aluminium 1050-O sont présentés

Antiviral and Anti-Inflammatory Activities of Fluoxetine in a SARS-CoV-2 Infection Mouse Model

The coronavirus disease 2019 (COVID-19) pandemic continues to cause significant morbidity and mortality worldwide. Since a large portion of the world’s population is currently unvaccinated or incompletely vaccinated and has limited access to approved treatments against COVID-19, there is an urgent need to continue research on treatment options, especially those at low cost and which are immediately available to patients, particularly in low- and middle-income countries. Prior in vitro and observational studies have shown that fluoxetine, possibly through its inhibitory effect on the acid sphingomyelinase/ceramide system, could be a promising antiviral and anti-inflammatory treatment against COVID-19. In this report, we evaluated the potential antiviral and anti-inflammatory activities of fluoxetine in a K18-hACE2 mouse model of SARS-CoV-2 infection, and against variants of concern in vitro, i.e., SARS-CoV-2 ancestral strain, Alpha B.1.1.7, Gamma P1, Delta B1.617 and Omicron BA.5. Fluoxetine, administrated after SARS-CoV-2 infection, significantly reduced lung tissue viral titres and expression of several inflammatory markers (i.e., IL-6, TNFα, CCL2 and CXCL10). It also inhibited the replication of all variants of concern in vitro. A modulation of the ceramide system in the lung tissues, as reflected by the increase in the ratio HexCer 16:0/Cer 16:0 in fluoxetine-treated mice, may contribute to explain these effects. Our findings demonstrate the antiviral and anti-inflammatory properties of fluoxetine in a K18-hACE2 mouse model of SARS-CoV-2 infection, and its in vitro antiviral activity against variants of concern, establishing fluoxetine as a very promising candidate for the prevention and treatment of SARS-CoV-2 infection and disease pathogenesis

Designing Focused Chemical Libraries Enriched in Protein-Protein Interaction Inhibitors using Machine-Learning Methods

Protein-protein interactions (PPIs) may represent one of the next major classes of therapeutic targets. So far, only a minute fraction of the estimated 650,000 PPIs that comprise the human interactome are known with a tiny number of complexes being drugged. Such intricate biological systems cannot be cost-efficiently tackled using conventional high-throughput screening methods. Rather, time has come for designing new strategies that will maximize the chance for hit identification through a rationalization of the PPI inhibitor chemical space and the design of PPI-focused compound libraries (global or target-specific). Here, we train machine-learning-based models, mainly decision trees, using a dataset of known PPI inhibitors and of regular drugs in order to determine a global physico-chemical profile for putative PPI inhibitors. This statistical analysis unravels two important molecular descriptors for PPI inhibitors characterizing specific molecular shapes and the presence of a privileged number of aromatic bonds. The best model has been transposed into a computer program, PPI-HitProfiler, that can output from any drug-like compound collection a focused chemical library enriched in putative PPI inhibitors. Our PPI inhibitor profiler is challenged on the experimental screening results of 11 different PPIs among which the p53/MDM2 interaction screened within our own CDithem platform, that in addition to the validation of our concept led to the identification of 4 novel p53/MDM2 inhibitors. Collectively, our tool shows a robust behavior on the 11 experimental datasets by correctly profiling 70% of the experimentally identified hits while removing 52% of the inactive compounds from the initial compound collections. We strongly believe that this new tool can be used as a global PPI inhibitor profiler prior to screening assays to reduce the size of the compound collections to be experimentally screened while keeping most of the true PPI inhibitors. PPI-HitProfiler is freely available on request from our CDithem platform website, www.CDithem.com

Implication des voies de signalisation des protéines JNK et SMAD dans l'apoptose régulée par le TGF-b1

Le TGF-beta appartient à une famille de médiateurs locaux impliqués dans le contrôle de la prolifération et de la différenciation des cellules ainsi que dans l'apoptose. Ce facteur agit en s'associant à des récepteurs transmembranaires et conduit à l'activation de différentes voies de signalisation cellulaire; L'une de ces voies implique les protéines Smad2 et Smad3. Suite à la stimulation de la voie des protéines Smad par le TGF-beta1, des boucles de régulation négative sont stimulées afin d'inactiver cette voie de signalisation cellulaire. Une de ces boucles est la translocation de la protéine Smad7 du noyau vers le cytoplasme et sa fixation au récepteur du TGF-beta1, empêchant la phosphorylation des protéines Smad2 et Smad3 par le récepteur. Le TGF-beta1 initie une deuxième voie de signalisation, la voie des GTPases de la famille Rho et déclenche la cascade d'activation des protéines kinases JNK...The TGF-beta plays an important role in constraining cellular proliferation and in regulating the cell cycle, but is also a potent inducer of apoptosis. TGF-beta1 initiates signaling throgh transmembrane receptors and activates various cellular pathways. Smad and JNK proteins have been identified as essential downstream elements of the signal transduction pathways that are required for TGF-bata1 signaling. Smad2 and Smad3, are directly activated by ligand-activated receptor. One negative feedback loop may control TGF-beta response, the involvement of Smad7, which localizes in the nucleus but translocates to the cytoplasm after TGF-beta1 stimulation. Smad7 can exert its inhibitory function by binding to TGF-beta1 receptor, thereby blocking the receptor-regulated Smad from interacting with the receptor...PARIS-BIUP (751062107) / SudocSudocFranceF

Using BRET to study chemical compound-induced disruptions of the p53-HDM2 interactions in live cells.

International audienceModification of protein-protein interactions (PPIs) holds promise for novel rational drug design. Disrupting or modifying protein interactions offer new challenges in terms of chemical compound libraries and techniques for compound validation. As proteins interact with several partners in different allosteric conformation in pathological and tissue specific fashions it is difficult to predict the in vivo effect of PPI acting compounds identified by in vitro screening assays. It is therefore desirable to develop techniques that rapidly allow cell-based validation of protein interacting compounds. The binding of the p53 tumour suppressor to the HDM2 E3 ubiquitin ligase is important for controlling p53 activity and several compounds, such as Nutlin-3, have been designed to bind a hydrophobic pocket in the N-terminus of HDM2 to prevent the interaction with p53 in order to stabilize and activate downstream p53 pathways. We have used the p53-HDM2 interaction as a model system to explore the Bioluminescence Resonance Energy Transfer (BRET) technique for validating compounds that disrupt protein-protein interactions in living cells

Antagonistes de Bcl-2, thérapies anticancéreuses alternatives

La mort cellulaire programmée ou apoptose est un processus nécessaire au développement embryonnaire normal et au maintien de l'homéostasie tissulaire. L'apoptose a été décrite comme étroitement liée à diverses voies essentielles de signalisation. L'identification de points de contrôles critiques de la mort cellulaire est un enjeu majeur pour la connaissance générale de la biologie cellulaire mais surtout elle permettrait de fournir des cibles pour de nouvelles thérapies, en particulier en oncologie. Il est désormais admis que des altérations dans l'exécution de l'apoptose peuvent avoir une influence majeure sur l'initiation et/ou la progression tumorale ainsi que sur la chimiorésistance. Les protéines de la famille Bcl-2 sont des acteurs intracellulaires essentiels dans la machinerie apoptotique. Cette famille de protéines contient à la fois des membres antiapoptotiques et pro-apoptotiques qui interagissent pour réguler l'apoptose. L'inhibition de l'hétérodimérisation entre membres pro- et anti-apoptotiques est suffisante pour promouvoir l'apoptose chez des cellules de mammifères. De petites molécules ou des peptidomimétiques, inhibant l'hétérodimérisation entre les membres de la famille Bcl-2, représentent un prototype thérapeutique pour cibler la cascade apoptotique car ils induisent la mort cellulaire par activation directe de la voie apoptotique mitochondriale. De nombreuses données suggèrent que ces petites molécules antagonistes de Bcl-2 pourraient être des outils de choix pour induire l'apoptose préférentiellement dans les cellules néoplasiques

A coupled experimental/numerical approach for the characterization of material behavior at high strain-rate using electromagnetic tube expansion testing

International audienceHigh speed forming processes such as magnetic pulse forming are gaining interest in the sheet metal industry. Their design and development require specific effort on numerical modelling as well as on the characterization of the high strain-rate mechanical behaviour of metals. Standard dynamic tests (SHPB, plate impact, simple tension…) are limited in their representativeness of the deformation modes encountered in high speed processes. The present study describes how the electromagnetic tube expansion test can be used as a high strain-rate test for the identification of material constitutive parameters. Through numerical analysis, the deformation mode and the sensitivity of radial expansion to material constitutive behaviour are depicted. Then, the material parameter identification methodology is applied to annealed 1050 aluminium tubes. It is shown that the test is capable of highlighting the strain-rate sensitivity of behaviour, in spite of relatively high sensitivity to measurement uncertainties

Determination of high strain-rate behavior of metals: applications to magnetic pulse forming and electrohydraulic forming

International audienceThe design of processes like magnetic pulse forming and electrohydraulic forming involves multiphysical couplings that require numerical simulation, and knowledge on dynamic behaviour of metals. The forming process is completed in about 100 μs, so that the workpiece material deforms at strain-rates between 100 and 10 000 s-1. In this range, the mechanical behaviour can be significantly different than that in quasi-static conditions. It is often noticed that the strength and the formability are higher. The main goal of this study is to use an electromagnetically driven test on tubes or sheets to identify the constitutive behaviour of the workpiece material. In the case of tube, an industrial helix coil is used as inductor. Simulations with the code LS-Dyna® permit to find a configuration where the tube deforms homogeneously enough to allow axisymmetric modelling of the setup. The coil current is measured and used as an input for the simulations. The radial expansion velocity is measured with a Photon Doppler Velocimeter. The parameter identification is lead with the optimization software LS-Opt®. LS-Dyna axisymmetric simulations are launched which different set of parameters for the constitutive behaviour, until the computed expansion velocity fits the experimental velocity. The optimization algorithm couples a gradient method and a global method to avoid local minima. Numerical studies show that for the Johnson-Cook constitutive model, two or three experiments at different energies are required to identify the expected parameters. The method is applied to Al1050 tubes, as received and annealed. The parameters for the Johnson-Cook and Zerilli-Armstrong models are identified. The dynamic constitutive behaviour is compared to that measured on quasi-static tensile tests, and exhibits a strong sensitivity to strain-rate. The final strains are also significantly higher at high velocity, which is one of the major advantages of this kind of processes

Identification du comportement mécanique dynamique de métaux par un essai d'expansion électromagnétique de tube

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