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Influx-dependent Local Ca2+ Increases Regulate Myosin II and Myosin VI Activation to Promote Rupture of the Shigella-Containing Vacuole
No full textInternational audienceShigella, the causative agent of bacillary dysentery, invades epithelial cells to colonize the intestinal mucosa. During Shigella invasion, an actin coat forms around the bacteria containing vacuole, preceding vacuolar rupture and bacterial escape and replication in the cell cytosol. While critical for virulence and the subsequent bacterial infection steps, the process by which Shigella ruptures the phagocytic vacuole is poorly understood. Recent studies point to a role of trafficking, including sorting and recycling pathways in vacuolar rupture, but how these promote vacuolar rupture remains unclear. We show here that rupture of the Shigella vacuole requires Ca2+ influx and is associated with long lasting local Ca2+ increases. Influx-dependent Ca2+ increase up-regulated the formation of the actin coat associated with bacterial vacuoles, suggesting a role for this structure and actin components in vacuolar rupture. Consistently, we found that myosin II and myosin VI were involved in rupture of the Shigella vacuole in a Ca2+-dependent albeit differential manner. We found that phospho-activated myosin II associates with actin filaments in membrane ruffles distant from the bacterial vacuole. In contrast, local Ca2+ increases triggered the recruitment and formation of myosin VI patches contacting the vacuole. Inhibition of myosin VI led to an increased mobility of the bacterial vacuole associated with a delay in vacuolar rupture. The findings suggest that rupture of the Shigella-containing vacuole requires Ca2+-dependent pulling forces exerted by distal myosin II combined with the tethering of the vacuole in the actin cortex by myosin VI
Pancreatic islet organoids and organoids on-chip for type 1 diabetes
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Design of Hydrogel Microneedle Arrays for Physiology Monitoring of Farm Animals
No full textInternational audienceFor monitoring animal adaptation when facing environmental challenges, and more specifically when addressing the impacts of global warming—particularly responses to heat stress and short-term fluctuations in osmotic regulations in the different organs influencing animal physiology—there is an increasing demand for digital tools to understand and monitor a range of biomarkers. Microneedle arrays (MNAs) have recently emerged as promising devices minimally invasively penetrating human skin to access dermal interstitial fluid (ISF) to monitor deviations in physiology and consequences on health. The ISF is a blood filtrate where the concentrations of ions, low molecular weight metabolites (<70 kDa), hormones, and drugs, often closely correlate with those in blood. However, anatomical skin differences between human and farm animals, especially large animals, as well as divergent tolerances of such devices among species with behavior specificities, motivate new MNA designs. We addressed technological challenges to design higher microneedles for farm animal (pigs and cattle) measurements. We designed microneedle arrays composed of 37 microneedles, each 2.8 mm in height, using dextran-methacrylate, a photo-crosslinked biocompatible biopolymer-based hydrogel. The arrays were characterized geometrically and mechanically. Their abilities to perforate pig and cow skin were demonstrated through histological analysis. The MNAs successfully absorbed approximately 10 µL of fluid within 3 h of application
An Introduction to Modern C++ and Software Development Practices: How to be a happy programmer!
No full textInternational audienceThis book is meant as a beginner's guide to C++ programming, with a focus on acquiring a certain methodology and approach to programming which is intended to lead to the reader becoming a 'happy programmer'. It also provides a thorough introduction to modern software development using CMake.Here are a few teaser quotes from the book to give you a taste of its rather unique 'style': + Remember that anything that is the programmer’s responsibility is sure to go pear-shaped. + The aim of this book is to get you to reach the point where you spontaneously start to think “aah, this smells like a class...” + Pointers are nearly as evil as arrays + Have a nice cup of tea. Do some yoga. Never ever code in the same way again. + Anybody with a basic understanding of using a hammer can try to build a chaise longue but results will certainly vary according to the craftsman at work. + What defines a good programmer? Let's go with "person who can write some code which can efficiently deal with whatever problem needs treating while causing themselves and those around them the least pain and suffering possible" + Why do all C++ beginners rapidly arrive at the ultimate solution to any programming task: a 2-, 3-, or multi-dimensional array of pointers??
How to produce green hydrogen from olivine and seawater? By ultrasound
No full textInternational audienceGreen hydrogen is a pillar for achieving global decarbonization and the reduction of greenhouse gas emissions. Here, a new, nature‐inspired process for green hydrogen production using virtually unlimited natural resources is reported. Olivine, the most abundant mineral in the Earth's upper mantle, is key to this process. It is found that 20 kHz ultrasound accelerates hydrogen production from olivine suspensions in seawater under near‐ambient conditions by almost 3000 times compared to the hydrothermal process. Strong mechanical stirring does not lead to hydrogen evolution in the temperature range of 40–90 °C. The striking effect of ultrasound is attributed to acoustic cavitation, which provides depassivation of the olivine surface, fragmentation of olivine particles, and local transient heating caused by collapsing bubbles. In principle, ultrasonic activation of the olivine/seawater system enables on‐demand hydrogen production
Explorer les limites du vivant
No full textInternational audienceEn tant qu'êtres humains, nous avons une notion de l'habitabilité qui est très influencée par notre propre place et évolution dans l’environnement terrestre..
Naturalité, problèmes de hiérarchie, et Cosmologie
No full textOur current understanding of Nature is plagued by three spectacular failures of symmetry. The theoretical estimates based on symmetry arguments for the Higgs boson mass, the cosmological constant, and the neutron electric dipole moment (EDM) exceed their experimental values by many orders of magnitude, thereby undermining the principle of naturalness. For decades, we have striven to reconcile these discrepancies, yet our most compelling proposals have failed direct experimental tests. For instance, no hints of new physics stabilizing the Higgs mass have emerged at LEP or the LHC, placing severe pressure on the most commonly considered TeV-scale physics scenarios, such as supersymmetric extensions of the Standard Model, composite Higgs frameworks, and their variants. While some reasonable options for such models still remain, it is important to explore alternative approaches. In this thesis, we examine a novel class of explanations that depart radically from symmetry-based reasoning. The most promising of these are referred to as models of cosmological naturalness, which include relaxion-type mechanisms and crunching models. We focused on the latter, in which different patches of the Universe have different parameters for the Higgs potential, but some form of dynamics makes the patches with either too small or too large Higgs vacuum expectation values (VEVs) undergo rapid collapse. Crunching models have already been successful in addressing the weak scale hierarchy problem and, remarkably, also the Strong CP problem which is known to be quite resistant to cosmological explanations. The quest to complete the Standard Model at higher energies often introduces new naturalness problems. For example, Grand Unified Theories (GUTs) introduce additional colored fields, the triplets, that merge with the Higgs doublet at high energies to a single multiplet. Yet proton‐decay constraints force the colored partners of the Higgs to lie far above the electroweak scale. This disparity undermines the original symmetry argument; one would expect the doublet and triplet masses to be comparable, since they originate from the same GUT multiplet. In this work, we extend the crunching cosmological mechanism to solve not only the electroweak hierarchy and the Strong CP problem, but also the GUT doublet-triplet splitting problem. Our model invokes two axion‐like fields whose dynamics trigger a rapid crunch at the QCD phase transition whenever either the triplets remain light or acquire a VEV, or the doublets become too heavy or fail to develop a VEV. The only trace left at low energies are these two axion-like particles. These fields couple only weakly to Standard Model states and could be probed in upcoming axion searches, or indirectly via complementary measurements of the neutron EDM and astrophysical signals of fuzzy dark matter.Because the axion‐like potential determines the crunching criterion, we have performed a detailed analysis of its contributions, especially coming from instantons. Instantons are classical Euclidean Yang-Mills solutions that mediate tunneling between vacua of different topological charge. At high scales, small instantons yield calculable corrections to the effective axion potential. Here, we present a general method for one‐instanton computations of this potential in any gauge theory with matter fields in arbitrary representations. By accounting for all relevant instanton effects, our framework ensures that the observed Higgs mass and its splitting from the heavy color‐triplet partners, together with the tiny neutron EDM, are not accidental but are instead the consequence of early‐Universe dynamics at energies far above current laboratory reach. This interlinks the values of the cosmological constant, the electroweak scale, and the neutron EDM, and points to the sky as the ultimate laboratory to understand their origin.Notre compréhension de la Nature se heurte à trois échecs majeurs des symétries. Les estimations théoriques fondées sur des arguments de symétrie pour la masse du boson de Higgs, la constante cosmologique et le moment dipolaire électrique du neutron dépassent de plusieurs ordres de grandeur les valeurs expérimentales, remettant en cause le principe de naturalité. Malgré des décennies d'efforts, aucune trace d'une nouvelle physique capable de stabiliser la masse du Higgs n'a été détectée ni au LEP ni au LHC, remettant en cause les extensions supersymétriques du Modèle Standard, les modèles à Higgs composite, et leurs variantes. Même si quelques pistes subsistent, il est indispensable d'explorer des approches alternatives. Cette thèse explore une nouvelle famille d'explications qui rompt radicalement avec le raisonnement purement symétrique, connue sous le nom de naturalité cosmologique. Parmi ces modèles, on trouve les mécanismes de type relaxion et les modèles de crunch. Nous nous sommes particulièrement intéressés aux seconds : dans ces scénarios, différentes régions de l'Univers naissent avec des paramètres variés pour le potentiel du Higgs, mais une certaine dynamique provoque l'effondrement rapide des zones dont la valeur moyenne du champ de Higgs (VEV) est trop faible ou trop élevée. Les modèles de crunch ont déjà démontré qu'ils pouvaient résoudre le problème de hiérarchie électrofaible et, de façon surprenante, le problème CP fort, longtemps réfractaire aux explications d'origine cosmologique. La quête de théories au-delà du Modèle Standard soulève souvent de nouveaux défis de naturalité. Par exemple, les théories de Grande Unification (GUT) introduisent des champs colorés, appelés triplets, qui s'unissent au doublet de Higgs dans un même multiplet à très haute énergie. Or, les contraintes sur la durée de vie du proton imposent que ces triplets aient des masses bien au-delà de l'échelle électrofaible. Cette disparité contredit l'idée selon laquelle doublet et triplet devraient avoir des masses comparables, car provenant tous deux du même multiplet. Nous étendons ce mécanisme pour résoudre non seulement les problèmes de hiérarchie électrofaible et CP fort, mais aussi la question de la séparation doublet-triplet en GUT. Notre modèle fait intervenir deux pseudo-axions dont la dynamique déclenche un effondrement rapide lors de la transition de phase de la QCD dès que les triplets sont légers ou acquièrent un VEV, ou que les doublets deviennent trop lourds ou n'en développent pas. À basse énergie, seuls subsistent ces deux pseudo-axions, faiblement couplés au Modèle Standard. Ils pourraient être détectés dans de futures recherches d'axions ou indirectement par la combinaison de mesures du moment dipolaire du neutron et d'observations de matière noire en astrophysique. Puisque le potentiel de ces pseudo-axions fixe le critère d'effondrement, nous avons mené une étude approfondie de toutes ses contributions, en accordant une attention particulière aux instantons. Les instantons sont des solutions euclidiennes des équations de Yang-Mills, représentant des transitions quantiques entre états de vide de charges topologiques différentes. À haute énergie, ils procurent des corrections calculables au potentiel effectif des axions. Nous présentons ici une méthode générale pour effectuer ces calculs dans toute théorie de jauge, quel que soit le contenu en champs de matière.En tenant compte de l'ensemble de ces effets, notre cadre garantit que la masse observée du boson de Higgs, son écart vis-à-vis de ses partenaires colorés et le très faible moment dipolaire du neutron ne sont pas un hasard, mais la conséquence d'une dynamique de l'Univers primordial à des énergies bien supérieures à celles accessibles en laboratoire. Cette approche relie intimement la constante cosmologique, l'échelle électrofaible et le moment dipolaire du neutron, faisant du ciel le laboratoire ultime pour en comprendre l'origine
Caractérisation fonctionnelle des signaux calciques induits par Escherichia coli entéropathogène (EPEC) dans les cellules épithéliales
No full textEnteropathogenic Escherichia coli (EPEC) manipulates host signaling pathways to colonize intestinal epithelial cells. This study investigates how EPEC alters epithelial calcium (Ca²˖) signaling and its downstream effects on inflammation and mitochondrial function.We found EPEC triggers distinct, transient Ca²˖ signals initiated by extracellular ATP (eATP), likely released via the Type III Secretion System (T3SS) translocon pore. Ca²˖ responses varied significantly in amplitude and occurred in a subset of infected cells, indicating precise T3SS regulation. Deletion of EspC—a bacterial protease that negatively regulates T3SS translocon—greatly increased the proportion of cells exhibiting frequent Ca²˖ signals. Additionally, we identified novel, brief (<10s) and low-amplitude global Ca²˖ transients, termed Coordinated Ca²˖ Responses from IP3R Clusters (CCRICs). Unlike conventional localized "puffs," these involved simultaneous activation of IP₃ receptor clusters driven by minimal IP₃ concentrations, validated through computational modeling and low-level eATP mimicking experiments.Low-dose eATP significantly delayed TNFα-induced NF-κB activation, reflected by slower IκBα degradation and reduced p65 phosphorylation. Correspondingly, NF-κB p65 exhibited lower O-GlcNAcylation upon TNFα stimulation with eATP compared to TNFα alone; chelating intracellular Ca²˖ with BAPTA-AM prevented this effect, suggesting that CCRICs modulate NF-κB activation through reduced O-GlcNAcylation.EPEC infection also caused marked mitochondrial fragmentation, but ectopic expression of the mitochondrial- targeting effector Map alone did not. However, Map expression altered Ca²˖ dynamics, resulting in fewer cytosolic Ca²˖ oscillations and slower return to baseline. These altered dynamics corresponded with reduced mitochondrial Ca²˖ uptake, lower amplitude mitochondrial Ca²˖ transients, and delayed decay, indicating impaired cytosolic-mitochondrial Ca²˖ coupling.Our findings uncover novel aspects of Ca²˖ signaling hijacked by EPEC to suppress inflammation and alter organelle function.Escherichia coli entéropathogène (EPEC) manipule les voies de signalisation de l'hôte pour coloniser les cellules épithéliales intestinales. Cette étude examine comment EPEC modifie la signalisation calcique épithéliale (Ca² ˖) et ses effets en aval sur l'inflammation et la fonction mitochondriale.Nous avons constaté qu'EPEC déclenche des signaux Ca²˖ distincts et transitoires initiés par l'ATP extracellulaire (eATP), probablement libéré via le pore du translocon du système de sécrétion de type III (T3SS). Les réponses Ca²˖ variaient significativement en amplitude et se produisaient dans un sous- ensemble de cellules infectées, indiquant une régulation précise du T3SS. La suppression d'EspC, une protéase bactérienne qui régule négativement le translocon du T3SS, a fortement augmenté la proportion de cellules présentant des signaux Ca²˖ fréquents. De plus, nous avons identifié de nouveaux transitoires globaux de Ca²˖, brefs (< 10 s) et de faible amplitude, appelés réponses coordonnées de Ca²˖ à partir de groupes élémentaires (CCRIC). Contrairement aux bouffées localisées classiques, celles-ci impliquaient une activation simultanée des groupes de récepteurs IP₃, induite par des concentrations minimales d'IP₃, validée par modélisation informatique et des expériences de simulation de l'eATP à faible dose. L'eATP à faible dose a significativement retardé l'activation de NF-κB induite par le TNFα, ce qui s'est traduit par une dégradation plus lente de l'IκBα et une phosphorylation réduite de p65. De même, la p65 de NF-κB a présenté une O- GlcNAcylation plus faible lors de la stimulation par le TNFα avec l'eATP qu'avec le TNFα seul ; la chélation du Ca²˖ intracellulaire avec BAPTA-AM a empêché cet effet, suggérant que les CCRIC modulent l'activation de NF-κB par une O- GlcNAcylation réduite.L'infection par EPEC a également entraîné une fragmentation mitochondriale marquée, contrairement à l'expression ectopique de l'effecteur Map, ciblant les mitochondries, à elle seule. Cependant, l'expression de Map a modifié la dynamique du Ca²˖, entraînant une diminution des oscillations du Ca²˖ cytosolique et un retour plus lent à la valeur initiale. Cette altération de la dynamique correspondait à une réduction de la captation du Ca²˖ mitochondrial, à des transitoires mitochondriaux de moindre amplitude et à une décroissance retardée, indiquant une altération du couplage Ca²˖ cytosolique-mitochondrial.Nos résultats révèlent de nouveaux aspects de la signalisation du Ca²˖ détournée par EPEC pour supprimer l'inflammation et altérer la fonction des organites
Reversibility of FUS-aided blood-tumor barrier opening for the delivery of therapeutics
No full textInternational audienceFocused ultrasound (FUS) offers reversible disruption of the blood-brain barrier (BBB), which enables drug delivery to the brain. However, the impact of FUS on the blood-tumor barrier (BTB) remains largely misunderstood. The reversibility of FUS-induced BTB opening was monitored using PET imaging in a glioblastoma model. C57Bl/6 mice with bilateral GL261-GFP tumors received FUS specifically targeting the right hemisphere, followed by injections of the BBB permeability marker [ 18 F]Fluoro-deoxysorbitol (183 Da) or the radiolabeled antibody [ 18 F]avelumab (150 kDa). PET acquisitions were performed after 1h, 24h and 72h post-FUS. The uptake of [ 18 F]avelumab and [ 18 F]Fluoro-deoxysorbitol was increased immediately after FUS. At 24h post-FUS, BTB permeability returned to baseline as evidenced by consistent [ 18 F]avelumab distribution volumes (V T ) between tumors. By 72h, increased radiotracer uptake indicated tumor progression. These findings highlight the potential of FUS to enhance the brain delivery of therapeutics while preserving the BTB integrity over time
Sensitivity analysis of load profiles: implications for resource adequacy in future power system
No full textInternational audienceEnsuring the reliability of future electricity systems requires more than matching annual energy needs—it demands understanding when electricity is used. Traditional resource adequacy (RA) assessmentsrely on Monte Carlo simulations across many climatic years to capture inter-annual variability, but oftenassume fixed demand profiles. This overlooks how even small structural shifts—such as increased heatpump use or changing EV charging patterns—can significantly alter system stress and operationaloutcomes. This study quantifies the sensitivity of RA metrics to such variations. Using ANTARESSimulator and French TSO projections, a European electricity model for 2050 is developed and testedunder three scenarios with equal annual demand but different hourly profiles: a reference case, a wintercase (2–10% more winter demand), and a peak case (5–20% more peak-hour demand). Results show a4% winter load increase triples LOLD hours, and 8% causes tenfold more unsupplied energy.Importantly, most stress concentrates in just a few critical climatic years. Identifying these years usingsimple indicators—like residual load or wind capacity factor—could reduce computational burdenwithout losing key adequacy insights. This study emphasizes that alongside inter-annual variability,accounting for load shape sensitivity is essential for robust and reliable RA assessments in a changingenergy system