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Deciphering pro‐arrhythmogenic mechanisms of EPAC in human atrial cardiomyocytes
No full textInternational audienceExchange protein directly activated by cAMP (EPAC) 1 and EPAC2 are involved in electrophysiological modulation in ventricular cardiomyocytes. Their putative contribution in supra‐ventricular arrhythmogenic processes has been suggested in animal models. However, nothing is known about the electrophysiological remodelling and the underlying signalling pathway regulated by EPACs in human atrial cardiomyocyte. Action potentials (AP) and K + currents ( I K ) were recorded with the patch‐clamp technique in enzymatically freshly isolated human atrial cardiomyocytes. Acute EPAC activation with the EPAC agonist 8‐(4‐chlorophenylthio)‐2′‐ O ‐methyl‐cAMP acetoxymethyl ester (8‐CPTAM; 10 µmol/l) lengthened APs by inhibition of the repolarizing K + currents in myocytes obtained from sinus rhythm (SR) patients. The selective EPAC1 pharmacological blocker AM‐001 (20 µmol/l) or the EPAC2 inhibitor ESI‐05 (25 µmol/l) prevented the effect of 8‐CPTAM on APs and I K , indicating that both EPAC isoforms participate in this electrophysiological regulation. Mechanistically, the effects of EPAC1 and EPAC2 proteins on the inhibition of three major components of K + currents, I to , I KDR, and I KUR , were Ca 2+ ‐independent but involved Ca 2+ /calmodulin‐dependent protein kinase II (CaMKII) and the AMP‐activated protein kinase (AMPK)–nitric oxide synthase (NOS)–protein kinase G (PKG) axis. Interestingly, immunoblot analysis showed that EPAC1 but not EPAC2 was overexpressed in the atria of atrial fibrillation (AF) patients. Finally, the application of AM‐001 consecutively to the 8‐CPTAM treatment significantly corrected the EPAC‐dependent downregulation of I K in AF cardiomyocytes. Our results uncover that EPAC activation influences I K by CaMKII and the AMPK–NOS–PKG signalling pathways in human atrial cardiomyocytes. Moreover, our findings suggest that EPAC1 over‐activation in AF cardiomyocytes promotes the electrophysiological remodelling underlying the initiation of AF. image Key points Activation of exchange proteins directly activated by cAMP (EPAC) lengthens action potentials (AP) in human atrial cardiac myocytes. This AP duration increase is mediated by an inhibition of the repolarizing K + current. Using EPAC1 and EPAC2 pharmacological inhibitors (AM‐001 and ESI‐05, respectively), we show that both EPAC1 and EPAC2 isoforms are involved in these electrophysiological effects. Mechanistically, EPAC‐induced K + current inhibition signalling involves both CaMKII and AMPK–NOS–PKG pathways. EPAC1 but not EPAC2 is overexpressed in atrial samples of patients with atrial fibrillation (AF). A selective pharmacological inhibitor of EPAC1, AM‐001 prevents the downregulation of K + current in cardiomyocytes from AF patients. Our results suggest that over‐activation of EPAC1 and its signalling represent a cellular mechanism for atrial arrythmia and might be a potential target for the treatment of AF
Landscapes at Colliders
No full textInternational audienceTheories with a large number of long-lived metastable vacua are our only concrete explanation for the puzzling value of the Cosmological Constant (CC). The energy scales where these vacua are realized are unknown. In this work, we consider the possibility that a sector of this landscape of vacua is within experimental reach and discuss its signatures at colliders. We find that striking large-multiplicity final states might have gone undetected due to their relatively small total energy. In particular, this could lead to new exotic Higgs decays, which are both intriguing and challenging to search for. In addition to a general phenomenological analysis of these theories, we also discuss an explicit model where the small values of the CC and the Higgs mass are jointly explained by Weinberg's anthropic argument and a low energy landscape
A ThDP-Dependent Enzyme with a Broad Nucleophilic Substrate Spectrum: Stereoselective Carboligation Reactions Catalyzed by Escherichia coli SucA
No full textInternational audienceMost bioactive molecules possess complex structures with multiple functionalities and chiral centers. Consequently, their synthesis often involves numerous steps, leading to low overall yields. An eco-friendly solution is to use the EcSucA enzyme, which facilitates the highly selective formation of C–C bonds, providing access to complex multifunctional motifs. Thanks to the unusual broad substrate spectrum of this carboligase, various chiral δ-hydroxy-γ-ketoacids could be produced in a single step, demonstrating that EcSucA can be efficiently integrated into total synthesis pathways
Metal-free visible-light carbonylation of alkyl iodides to amides <i>via</i> consecutive photoinduced electron transfer
No full textInternational audienceA visible-light-driven, metal-free carbonylation of unactivated alkyl iodides is reported, enabling the directsynthesis of 35 structurally diverse amides in good to excellent yields. The reaction shows broad functional-group tolerance toward both amines and alkyl iodides, including bioisosteric motifs and complex naturalproduct derivatives, underscoring its potential for late-stage functionalization. Mechanistic investigationscombining flash photolysis, spectroelectrochemistry, irradiated thin-layer cyclic voltammetry, and EPRspectroscopy reveal a consecutive photoinduced electron transfer (ConPET) mechanism that divergesfrom conventional single-photon photoredox catalysis. DFT calculations elucidate the key radicalcarbonylation steps governing reactivity and selectivity. This sustainable and operationally simple methodoffers a transition-metal-free approach to carbonylation, expanding the toolbox for highly reducingtransformations under mild conditions
The CAISAR Platform: Extending the Reach of Machine Learning Specification and Verification
No full textThe formal specification and verification of machine learning programs saw remarkable progress in less than a decade, leading to a profusion of tools. However, diversity may lead to fragmentation, resulting in tools that are difficult to compare, except for very specific benchmarks. Furthermore, this progress is heavily geared towards the specification and verification of a certain class of property, that is, local robustness properties. But while provers are becoming more and more efficient at solving local robustness properties, even slightly more complex properties, involving multiple neural networks for example, cannot be expressed in the input languages of winners of the International Competition of Verification of Neural Networks VNN-Comp. In this tool paper, we present CAISAR, an open-source platform dedicated to machine learning specification and verification. We present its specification language, suitable for modelling complex properties on neural networks, support vector machines and boosted trees. We show on concrete use-cases how specifications written in this language are automatically translated to queries to state-of-the-art provers, notably by using automated graph editing techniques, making it possible to use their off-the-shelf versions. The artifact to reproduce the paper claims is available at the following DOI: https://doi.org/10.5281/zenodo.1520951
AI-enhanced sorting enabling direct high-purity tantalum urban mining: a novel pathway from e-waste to critical materials
No full textInternational audienceTantalum’s supply chain instability demands efficient urban mining from e-waste. Here, we present an AI-enhanced process that combines intelligent sorting with sustainable hydrometallurgy for high-yield/high-purity Ta recovery. A hybrid sorting system, cascading an interpretable convolutional neural network (CNN) with automated multi-energy X-ray transmission (MEXRT) spectroscopy, achieved 99.6 % precision and 96.9 % recall at 3000 components/hour, resolving the Ta/Nb ambiguity. Spatial activation mapping illustrated the visual sorting mechanism, facilitating feature-driven upgrading. Meanwhile, Canny edge detection and K-edge detection enabled real-time and pixel-wise spectral analysis under multi-threaded processing. Downstream, streamlined physical separation and thermodynamically guided reverse leaching selectively recovered Ta with 98.2 % efficiency under mild conditions. Advanced characterization using transmission electron microscopy and ion beam analysis revealed a quantifiable core-shell Ta/Ta2O5 structure in leached products, guiding calcination into >99.8 % pure Ta2O5. This work establishes a closed-loop urban mining framework, demonstrating how AI and tailored refining enable a circular economy for critical metals
Formulation of direct ink writing suspensions from coarse and reused B4C powders with ultra-high-temperature pressureless SPS
No full textInternational audiencePressureless of boron carbide (B4C) is very promising to produce high performance B4C parts usefull in many applications. However, processing dense, complex-shaped components from coarse B4C powders remains particularly challenging due to coarseningdriven sintering and the very high temperatures required. In this work, direct ink writing (DIW) printable B4C suspensions were formulated using a tailored anionic carboxymethylcellulose binder, specifically designed to enable rapid, high height printing of coarse B4C powders. The recyclability of defective printed parts was also investigated. Conventional dilatometric sintering confirmed that coarse B4C powders undergo extensive grain coarsening and incomplete densification at 2200 °C, and sintering aids did not yield significant improvements. To overcome these limitations, ultra-high temperature pressureless spark plasma sintering (UHTP-SPS) was applied at ~2350°C with rapid heating (200°C/min), achieving near-full densification without additives. The resulting bimodal microstructure delivered high hardness values up to 33.6 GPa while maintaining flexural strength despite grain growth. Notably, recycled-route parts showed comparable properties to conventional ones, confirming the feasibility of reusing defective components. This study establishes a promising pathway for the cost-effective and sustainable fabrication of dense B4C components from coarse powders through rapid and high-temperature sintering
Searching for Cosmological Collider in the Planck CMB Data II: collider templates and Modal analysis
No full textInternational audienceSignatures of massive particles during inflation are highly informative targets for cosmological experiments. With recent progress on both theoretical and observational frontiers, we have reached the point where these novel signals of primordial non-Gaussianities (PNG) can be systematically tested with increasingly precise data. In this paper, we present the results of improved CMB data analysis for cosmological collider signals using Planck CMB data. To set the stage, we first construct a set of simplified but characteristic collider templates which are accurate over a broad range of particle masses, spins and sound speeds. In order to break degeneracies with single-field PNG, we propose an orthogonalization scheme such that the collider templates are uncorrelated with the highly constrained equilateral and orthogonal shapes. On this basis, we deploy the Modal bispectrum estimator for the Planck analysis and perform a systematic scan of parameters to search for the most significant collider signal. The maximum signal-to-noise ratio is found to be for massive spin-0 exchange after taking into account the look-elsewhere effect. In addition, we cross-validate the Modal analysis with the CMB-BEST pipeline, which demonstrates the consistency of results across the benchmark examples of collider templates. Given the low signal-to-noise ratio regime we find at the current stage of PNG observations, we believe the orthogonalization procedure provides an optimized strategy for future tests of the cosmological collider with the ability to rule out single field inflation
Nonlinear Relativistic Tidal Response of Neutron Stars
No full textInternational audienceWe investigate the nonlinear tidal response of relativistic neutron stars by computing the fully relativistic, static, quadratic Love numbers. Using both the worldline effective field theory for extended gravitating bodies and second-order perturbations of relativistic stellar models, we derive the nonlinear tidal deformation induced by an external gravito-electric tidal field to quadratic order. Through a suitable matching procedure, we provide for the first time the leading nonlinear tidal corrections to the conservative dynamics and gravitational-wave signal of binary systems. Quadratic Love numbers are enhanced more than the linear ones in the small-compactness limit. Because of this, despite entering the gravitational-wave phase at 8th post-Newtonian (PN) order, the leading quadratic Love number can be as important as the next-to-next-to-leading order linear tidal correction, which enters at 7th PN order, and is larger than the subleading point-particle contribution entering at 4th PN order. In particular, quadratic Love numbers can be as large as ~10% of the linear Love numbers in the late inspiral phase. Our approach provides a framework to also compute the (subleading) nonlinear effects induced by magnetic tidal fields and higher multipole moments, and sets the foundations for incorporating nonlinear tidal effects in high-precision gravitational-wave modeling
Search for heavy neutral leptons in B-meson decays
No full textInternational audienceA search for long-lived heavy neutral leptons produced in B-meson decays and decaying to a final state is performed with data collected by the LHCb experiment in proton-proton collisions at a centre-of-mass energy of 13 TeV, corresponding to an integrated luminosity of . The results are interpreted in both lepton-number-conserving and lepton-number-violating scenarios. No significant excess is observed. Constraints are placed on the squared mixing element to the active muon neutrino, under the assumption that couplings to other lepton flavours are negligible, in the mass range of - GeV