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Antidote administration in mice exposed to sarin resulted in brainwave stabilization without cognitive protection: Partial neuroprotective effects of antidote in mice exposed to sarin
No full textInternational audienceResurgence of sarin use in the Syrian conflict demonstrates that chemical weapons are a vivid threat. Like other organophosphate compounds, sarin inhibits acetylcholinesterase resulting in cholinergic crisis. The current antidote therapy includes atropine (a muscarinic cholinergic antagonist) + an oxime (e.g., pralidoxime) to reactivate the inhibited cholinesterases. Long-term sequelae reported in victims of the 1995 Tokyo subway sarin attack emphasize the need to improve neuroprotection and to delineate more precise biomarkers of intoxication severity. Previously, we proposed that brain oscillations could indicate exposure severity to a sublethal dose of a neurotoxic agent. In the present study, we evaluated the effects of atropine + pralidoxime in mice exposed to a sublethal dose of sarin (0.9 LD 50 ) on changes in short-term recovery, brainwaves and behavioral patterns. We demonstrated the benefits of the antidotes on alleviation of the sarin-induced encephalopathy, stabilization of brain oscillations, and attenuation of anhedonia behavior. Nevertheless, mice exhibited work memory impairments associated with the disruption of theta oscillations during the task, the disruption of sleep architecture and the anxiety-like behavior when exposed to the non-convulsive sarin dose. These outcomes were not mitigated by atropine + pralidoxime administration. Our findings suggest that the currently recommended antidote for sarin poisoning provides only partial neuroprotection. Despite stabilizing brain waves in resting state, current antidote is not effective in preventing long-term neurobehavioral complication
Benchmark for two-dimensional large scale coherent structures in partially magnetized E×B plasmas -Community collaboration & lessons learned
No full textLow-temperature plasmas are essential to both fundamental scientific research and critical industrial applications. As in many areas of science, numerical simulations have become a vital tool for uncovering new physical phenomena and guiding technological development. Code benchmarking remains crucial for verifying implementations and evaluating performance. This work continues the Landmark benchmark initiative, a series specifically designed to support the verification of low-temperature plasma codes. In this study, seventeen simulation codes from a collaborative community of nineteen international institutions modeled a partially magnetized E×B Penning discharge. The emergence of large scale coherent structures, or rotating plasma spokes, endows this configuration with an enormous range of time scales, making it particularly challenging to simulate. The codes showed excellent agreement on the rotation frequency of the spoke as well as key plasma properties, including time-averaged ion density, plasma potential, and electron temperature profiles. Achieving this level of agreement came with challenges, and we share lessons learned on how to conduct future benchmarking campaigns. Comparing code implementations, computational hardware, and simulation runtimes also revealed interesting trends, which are summarized with the aim of guiding future plasma simulation software development.</div
Rigorous numerical computation of the Stokes multipliers for linear differential equations with single level one
No full textWe describe a practical algorithm for computing the Stokes multipliers of a linear differential equation with polynomial coefficients at an irregular singular point of single level one. The algorithm follows a classical approach based on Borel summation and numerical ODE solving, but avoids a large amount of redundant work compared to a direct implementation. It applies to differential equations of arbitrary order, with no genericity assumption, and is suited to high-precision computations. In addition, we present an open-source implementation of this algorithm in the SageMath computer algebra system and illustrate its use with several examples. Our implementation supports arbitrary-precision computations and automatically provides rigorous error bounds. The article assumes minimal prior knowledge of the asymptotic theory of meromorphic differential equations and provides an elementary introduction to the linear Stokes phenomenon that may be of independent interest
Dilute but Dense - Reversible Crosslinking Enables Water-Rich (Bio)polymer Condensates
No full textInternational audienceLiquid-liquid phase separation (LLPS) of polymers underlies the formation of biomolecular condensates and offers a versatile route to functional soft materials. Traditionally, LLPS is attributed to changes in solvent quality or associative coacervation, but here a purely entropic connectivity-driven mechanism is demonstrated: reversible crosslinking. Using coarse-grained simulations of a minimal bead-spring model in good solvent, it is shown that transient, pairwise crosslinks alone can drive phase separation at ultralow polymer densities, yielding highly swollen, water-rich condensates. The phase behavior exhibits closed-loop coexistence and re-entrant percolation. This is captured quantitatively by a mean-field Semenov-Rubinstein theory with a single fit parameter, the effective repulsion parameter. Notably, phase boundaries are largely robust to rearrangements of crosslinkable domains along the sequence; only highly blocky sequences appreciably reduce the phase separation region and can even convert condensates into micelles or connected micelle networks. These results establish an entropy-enabled mechanism for mesoscale organization and suggest routes to programmable, membraneless materials in synthetic and RNA-protein contexts
Enhanced Lysosomal Glycogen Breakdown is associated with Liver Tumorigenesis in Glycogen Storage Disease Type III
No full textInternational audienceBackground & Aims: Glycogen storage disease type III (GSDIII) is a rare metabolic disorder caused by mutations in the glycogen debranching enzyme (AGL), leading to hepatic glycogen accumulation, fibrosis and increased hepatocellular carcinoma (HCC) risk. This study investigates the metabolic mechanisms driving liver tumorigenesis in an Agl-/- model of GSDIII. Methods: Liver and tumor samples from 14-month-old Agl-/- and Agl+/+ mice, and liver biopsies from GSDIII patients (n=4), were analyzed using histological, biochemical and molecular approaches. Results: Agl-/- mice recapitulated key features of GSDIII, including a 3.5-fold hepatic glycogen overload (p<0.001), and chronic liver disease. More than 30% of the animals developed liver tumors, associated to a 2.5-fold increase in α-fetoprotein levels (p<0.005). Despite marked reductions in glucose (7.5-fold, p<0.0001), glucose-6 phosphate (6.2-fold, p<0.0001), lactate (8-fold, p<0.005), cholesterol (1.9-fold, p<0.001) and triglyceride levels (6.2-fold, p<0.001) in the liver, glycaemia was maintained at around 87.0±9.6 mg/dl after 6h of fasting, through activated extrahepatic, but not hepatic, gluconeogenesis. Intriguingly, most tumors exhibited lower glycogen content than surrounding tissue (3.3-fold decrease, p<0.0001), associated with increased lysosomal α-acid glucosidase activity (19.5±5.5 in tumor vs 9.9±2.0 mmol/h/mg in Agl -/-liver; p<0.0005) and the presence of glycophagosomes. PAS-negative staining in GSDIII patient HCCs supported these observations. Although YAP nuclear staining varied between tumors, overall increased YAP nuclear localization and CTGF expression suggest that Hippo/YAP pathway inhibition could contribute to tumorigenesis in GSDIII hepatocytes.Conclusions: In GSDIII, liver metabolism is characterized by the accumulation of structurally abnormal glycogen and a significant reduction of key energy substrates. In this metabolic context, enhanced lysosomal glycogen degradation may support tumor growth, highlighting a mechanistic link between glycogen metabolism and the development of liver cancer
Non-linear parabolic PDEs with rough coefficients and critical data: existence, uniqueness and regularity of weak solutions
No full textThis article investigates the well-posedness of weak solutions to non-linear parabolic PDEs driven by rough coefficients with rough initial data in critical homogeneous Besov spaces. Well-posedness is understood in the sense of existence and uniqueness of maximal weak solutions in suitable weighted -spaces in the absence of smallness conditions. We showcase our theory with an application to rough reaction--diffusion equations. Subsequent articles will treat further classes of equations, including equations of Burgers-type and quasi-linear problems, using the same approach. Our toolkit includes a novel theory of hypercontractive singular integral operators (SIOs) on weighted -spaces and a self-improving property for super-linear reverse Hölder inequalities
Vers une meilleure prise en compte du castor dans les projets de restauration des cours d'eau: État des lieux et retour d'expérience sur la Romanche Séchilienne
No full textInternational audienceEn France hexagonale, l’expansion du castor européen (Castor fiber), espèce ingénieur des écosystèmes, génère des interactions avec les projets de restauration des cours d’eau. Ces interactions sont perçues de manière positive (diversification des habitats, régénération naturelle des milieux humides) ou négative (remise en cause des objectifs de la restauration, inondations). Afin d’acquérir des connaissances sur ce phénomène et d’appuyer les gestionnaires dans leur prise en compte de l’espèce, une enquête a permis de collecter des informations sur des projets de restauration, en lien avec la présence du castor et ses conséquences pour les gestionnaires et les milieux. Vingt-deux retours d’expérience ont été collectés à ce jour, permettant de mieux comprendre la diversité des types d’interactions et des moyens déployés par les gestionnaires dans ce contexte.Un de ces retours d’expérience concerne la Romanche Séchilienne. Mené par le Syndicat Mixte des Bassins Hydrauliques de l’Isère (SYMBHI), ce projet de restauration, réalisé entre 2015 et 2018, combine des objectifs de prévention des risques d’inondations, d’amélioration du cadre de vie et de lutte contre l’érosion de la biodiversité. Le castor est très présent sur ce territoire et a ainsi fait l’objet d’une attention dès les phases précoces du projet. Il a également bénéficié d’un suivi avant et après travaux. Après une diminution post-travaux du nombre d’indices de présence détectés en 2016, l’espèce semble s’être aujourd’hui rétablie durablement sur le site. Le SYMBHI a par ailleurs élaboré des fiches permettant de faciliter la prise en compte des espèces protégées, dont le castor, dans les projets de restauratio
Investigating the ADOS-2 calibrated severity score: insights from the ELENA cohort
No full textInternational audienceIntroduction The Autism Diagnostic Observation Schedule (ADOS-2) is widely used to assess Autism Spectrum Disorder (ASD) symptom severity. To allow comparisons across modules and developmental levels, the Calibrated Severity Score (ADOS-CSS) was developed. However, concerns have been raised about potential changes in the measurement signal introduced by the calibration process, which may alter the signal captured by the ADOS-2 raw scores (ADOS-RS). Methods Using longitudinal data from the ELENA cohort ( N = 145 children with ASD assessed at baseline and after 3 years), we examined the psychometric properties of the ADOS-CSS and ADOS-RS. The Social Responsiveness Scale (SRS-2) was used as an external reference. Bootstrap resampling was used to estimate means and 95% confidence intervals (CIs). Results Variance explained by module, age, and IQ was higher for the ADOS-RS (R 2 = 0.45, 95% CI: 0.38–0.52) than for the ADOS-CSS (R 2 = 0.16, 95% CI: 0.10–0.24). Stability of ASD severity scores over time was lower for the ADOS-CSS ( ρ = 0.34, 95% CI: 0.23–0.45) than for the ADOS-RS ( ρ = 0.60, 95% CI: 0.51–0.68). Correlations with SRS-2 scores were consistently lower for ADOS-CSS ( ρ = 0.14, 95% CI: 0.06–0.22) than for ADOS-RS ( ρ = 0.24, 95% CI: 0.17–0.32). Similar patterns were observed for change scores (Δ indicating score differences between baseline and follow-up): ΔSRS-2 correlated more strongly with ΔADOS-RS ( ρ = 0.19, 95% CI: 0.09–0.28) than with ΔADOS-CSS ( ρ = 0.13, 95% CI: 0.06–0.21). Differences between ADOS modules were reflected in SRS-2 and ADOS-RS, but markedly attenuated in ADOS-CSS, suggesting that calibration reduces module-related variance but also induces changes in the measurement signal that may affect sensitivity to individual differences. Discussion While the ADOS-CSS facilitates standardized comparisons across modules, clinicians and researchers should be aware of potential distortions in the measurement signal associated with the calibration process. Clinical Trial Registration NCT02625116
Structural and dynamical heterogeneities at the nanoscale in alkali/earth alkaline ionic liquid electrolytes: experiment and molecular simulation
No full textInternational audienceIonic liquids (ILs) are versatile solvents for a wide range of substances, including alkali and alkaline earth salts. Mixtures of ILs and these salts are promising electrolytes for Li and post-Li batteries, offering unique properties such as stability and viscosity. These characteristics stem from the multiscale coupling between structural and dynamical aspects of ILs. We focus in this study on a family of electrolytes based on the iconic IL 1-butyl-3-methylimidazolium trifluoromethylsulfonimide (BMImTFSI), in which alkali (Li+, Na+, K+, Cs+) and alkaline earth (Mg2+) TFSI salts are dissolved. First, we demonstrate how classical molecular dynamics (MD) allows reproducing structural scattering features and self-diffusion coefficients, as measured by wide angle X-ray scattering and pulsed field gradient NMR. With this approach, we show that MD also helps to decipher the subtle differences between electrolytes in which alkali or earth alkaline ions are dissolved. Second, molecular dynamics analyses based on a single particle tracking strategy allows unravelling the correlations between structural and dynamical heterogeneities in a multiscale approach (from coordination spheres/fs to nanosegregation/hundreds of ns), therefore evidencing a large distribution of dynamics and the presence of clusters with long lifetime. All these results sort out time/temperature equivalence, which appears as a key to understand the behavior of nanostructured fluids
RetroRules 2026: an expanded database combining biochemical and organic reaction templates for pathway discovery
No full textInternational audienceRetroRules (https://retrorules.org) is an open resource of reaction templates, which are generic reaction representations that describe the atomic transformations underlying biochemical reactions. These templates are key to supporting metabolic pathway discovery, reaction prediction, and enzyme engineering. The 2026 release updates biochemical sources (MetaNetX, Rhea) and newly integrates organic chemistry reactions (USPTO), extending the scope of the database beyond enzymatic systems. The template encoding has been simplified by using implicit hydrogens and minimal atomic descriptors, resulting in faster and more compact representations. Radius range now spans 0–10, allowing finer control of reaction specificity. In addition, mass-imbalanced reactions are included, expanding the coverage of biochemically relevant transformations. Reaction mapping now relies on the transformer-based tool RXNMapper, improving accuracy. RetroRules 2026 comprises 1 174 216 templates derived from 92 698 reactions, covering 5796 fourth-level EC numbers. A redesigned website, updated Online Template Generator, and OpenAPI-defined API enable multi-criteria exploration (dataset, radius, and EC number), visualization, and data export in multiple formats. Sequence annotations from UniProt were refreshed and summarized as a normalized sequence-support score for ranking. Together, these updates establish RetroRules as a cross-domain resource bridging biochemistry and organic chemistry, offering broader coverage, controllable specificity, and enhanced usability for high-throughput pathway design, reaction prediction, and enzyme engineering