Mexiletine Differentially Restores the Trafficking Defects Caused by Two Brugada Syndrome Mutations

The human cardiac sodium channel Nav1.5 encoded by the SCN5A gene plays a critical role in cardiac excitability and the propagation of action potentials. Nav1.5 dysfunctions due to mutations cause cardiac diseases such as the LQT3 form of long QT syndrome, conduction disorders, and Brugada syndrome (BrS). They have also recently been associated with dilated cardiomyopathy. BrS is characterized by coved ST-segment elevation on surface ECGs and lethal ventricular arrhythmias in an apparently structurally normal heart. Nav1.5 mutations that cause BrS result in a loss of channel function. Our aim was to functionally characterize two novel Nav1.5 mutations (A124D and V1378M) in BrS patients. Wild-type (WT) and mutant Nav1.5 channels were expressed in tsA201 cells in the presence of the β1-auxiliary subunit. The patch-clamp technique and immunocytochemistry approaches were used to study the mutant channels and their cellular localization. The two mutant channels displayed a dramatic reduction in current density but had normal gating properties. The reduction in current density was caused by the retention of channel proteins in the endoplasmic reticulum (ER). Mutant channel retention could be partially reversed by incubating transfected cells at 25°C and by treating them with mexiletine (for V1378M but not A124D), or with curcumin or thapsigargin, two drugs that target ER resident proteins. It is likely that the clinical phenotypes observed in these two BrS patients were related to a surface expression defect caused by ER retention

Patterns and Factors of Soil Structure Recovery as Revealed From a Tillage and Cover-Crop Experiment in a Compacted Orchard

Degraded soil structure recovery is much less documented than structure degradation and in particular compaction. In this field experiment, the effects of rotary spade tillage followed by Sorghum cover crop (cover-crop treatment) on the degraded structure of the soil from an orchard were evaluated on undisturbed soil samples collected at 5–10 cm and 20–25 cm depth, respectively, using CoreVESS visual scoring of structure quality and shrinkage analysis. The cover-crop treatment took place from April to September and despite a particularly dry climate, the development of Sorghum was good. A large and significant improvement of the structure quality scores were obtained at both depths. Similar recovery trends in the physical properties were observed at the two depths, however the changes were significant at 5–10 cm depth only and were associated with a small increase of soil organic carbon (SOC) content. Analysis of covariance revealed a significant impact of the tillage and root development on the structure recovery, larger than the effect of SOC content. The structure recovery showed an increase of the positive role of SOC content on the physical properties. This structural change pattern was similar to those reported from other structure degradation or compaction studies. The slopes of the relationship between physical properties and SOC is an indicator of structure quality in general. Though the observed final structure quality of the top layer was good, we assume that its vulnerability remains large due to its small SOC to clay ratio. Our results are in close agreement with previous studies highlighting the relationships between SOC to clay ratio and structure quality

Bismuth iron garnet: ab initio study of electronic properties

Bismuth iron garnet (BIG), i.e. Bi3Fe5O12, is a strong ferrimagnet that also possess outstanding magneto-optical properties such as the largest known Faraday rotation. These properties are related with the distribution of magnetic moments on octahedral and tetrahedral sites, the presence of spin gaps in the density of state and a strong spin-orbit coupling. In this work, first-principles ab initio calculations are performed to study the structural, electronic and magnetic properties of BIG using Density Functional Theory with Hubbard+U (DFT+U) correction including spin-orbit coupling and HSE06 hybrid functional. We found that the presence of spin gaps in the electronic structure results from the interplay between exchange and correlation effects and the crystal field strengths for tetrahedral and octahedral iron sublattices. The DFT+U treatment tends to close the spin-gaps for larger U due to over-localization effects, notably in the octahedral site. On the other hand, the hybrid functional confirms the occurrences of three spin gaps in the iron states of the conduction band as expected from optical measurements. A strong exchange splitting at the top of the valence bands associated with a lone-pair type mixture of O p and Bi s,p states is also obtained. Similar exchange splitting was not previously observed for other iron based garnets, such as for yttrium iron garnet. It follows that hole doping, as obtained by Ca substitution at Bi sites, results in a full spin polarized density at the Fermi energy. This work helps to shed more light on the theoretical comprehension of the properties of BIG and opens the route towards the use of advanced Many Body calculations to predict the magneto-optical coupling effects in BIG in a direct comparison with the experimental measurements

An Integrative Model for Soil Biogeochemistry and Methane Processes: I. Model Structure and Sensitivity Analysis

Environmental changes are anticipated to generate substantial impacts on carbon cycling in peatlands, affecting terrestrial-climate feedbacks. Understanding how peatland methane (CH4) fluxes respond to these changing environments is critical for predicting the magnitude of feedbacks from peatlands to global climate change. To improve predictions of CH4 fluxes in response to changes such as elevated atmospheric CO2 concentrations and warming, it is essential for Earth system models to include increased realism to simulate CH4 processes in a more mechanistic way. To address this need, we incorporated a new microbial-functional group-based CH4 module into the Energy Exascale Earth System land model (ELM) and tested it with multiple observational data sets at an ombrotrophic peatland bog in northern Minnesota. The model is able to simulate observed land surface CH4 fluxes and fundamental mechanisms contributing to these throughout the soil profile. The model reproduced the observed vertical distributions of dissolved organic carbon and acetate concentrations. The seasonality of acetoclastic and hydrogenotrophic methanogenesis—two key processes for CH4 production—and CH4 concentration along the soil profile were accurately simulated. Meanwhile, the model estimated that plant-mediated transport, diffusion, and ebullition contributed to ∼23.5%, 15.0%, and 61.5% of CH4 transport, respectively. A parameter sensitivity analysis showed that CH4 substrate and CH4 production were the most critical mechanisms regulating temporal patterns of surface CH4 fluxes both under ambient conditions and warming treatments. This knowledge will be used to improve Earth system model predictions of these high-carbon ecosystems from plot to regional scales

33èmes Journées Francophones des Langages Applicatifs

International audienceLes 33èmes Journées Francophones des Langages Applicatifs (JFLA) se sont tenues à Saint-Médard-d'Excideuil, plus précisément Domaine d'Essendiéras (Périgord), du mardi 28 juin 2022 au vendredi 1er juillet 2022.Les JFLA réunissent concepteurs, utilisateurs et théoriciens ; elles ont pour ambition de couvrir les domaines des langages applicatifs, de la preuve formelle, de la vérification de programmes, et des objets mathématiques qui sous-tendent ces outils. Ces domaines doivent être pris au sens large : nous souhaitons promouvoir les ponts entre les différentes thématiques.- Langages fonctionnels et applicatifs : sémantique, compilation, optimisation, typage, mesures, extensions par d'autres paradigmes.- Assistants de preuve : implémentation, nouvelles tactiques, développements présentant un intérêt technique ou méthodologique.- Logique, correspondance de Curry-Howard, réalisabilité, extraction de programmes, modèles.- Spécification, prototypage, développements formels d'algorithmes.- Vérification de programmes ou de modèles, méthode déductive, interprétation abstraite, raffinement.- Utilisation industrielle des langages fonctionnels et applicatifs, ou des méthodes issues des preuves formelles, outils pour le web.Les articles soumis aux JFLA sont relus par au moins deux personnes s'ils sont acceptés, trois personnes s'ils sont rejetés. Les critiques des relecteurs sont toujours bienveillantes et la plupart du temps encourageantes et constructives, même en cas de rejet

The Atacama Cosmology Telescope: A Measurement of the DR6 CMB Lensing Power Spectrum and its Implications for Structure Growth

We present new measurements of cosmic microwave background (CMB) lensing over $9400$ sq. deg. of the sky. These lensing measurements are derived from the Atacama Cosmology Telescope (ACT) Data Release 6 (DR6) CMB dataset, which consists of five seasons of ACT CMB temperature and polarization observations. We determine the amplitude of the CMB lensing power spectrum at $2.3\%$ precision ($43\sigma$ significance) using a novel pipeline that minimizes sensitivity to foregrounds and to noise properties. To ensure our results are robust, we analyze an extensive set of null tests, consistency tests, and systematic error estimates and employ a blinded analysis framework. The baseline spectrum is well fit by a lensing amplitude of $A_{\mathrm{lens}}=1.013\pm0.023$ relative to the Planck 2018 CMB power spectra best-fit $\Lambda$CDM model and $A_{\mathrm{lens}}=1.005\pm0.023$ relative to the $\text{ACT DR4} + \text{WMAP}$ best-fit model. From our lensing power spectrum measurement, we derive constraints on the parameter combination $S^{\mathrm{CMBL}}_8 \equiv \sigma_8 \left({\Omega_m}/{0.3}\right)^{0.25}$ of $S^{\mathrm{CMBL}}_8= 0.818\pm0.022$ from ACT DR6 CMB lensing alone and $S^{\mathrm{CMBL}}_8= 0.813\pm0.018$ when combining ACT DR6 and Planck NPIPE CMB lensing power spectra. These results are in excellent agreement with $\Lambda$CDM model constraints from Planck or $\text{ACT DR4} + \text{WMAP}$ CMB power spectrum measurements. Our lensing measurements from redshifts $z\sim0.5$--$5$ are thus fully consistent with $\Lambda$CDM structure growth predictions based on CMB anisotropies probing primarily $z\sim1100$. We find no evidence for a suppression of the amplitude of cosmic structure at low redshiftsComment: 45+21 pages, 50 figures. Prepared for submission to ApJ. Also see companion papers Madhavacheril et al and MacCrann et a

The Atacama Cosmology Telescope: High-resolution component-separated maps across one-third of the sky

Observations of the millimeter sky contain valuable information on a number of signals, including the blackbody cosmic microwave background (CMB), Galactic emissions, and the Compton-$y$ distortion due to the thermal Sunyaev-Zel'dovich (tSZ) effect. Extracting new insight into cosmological and astrophysical questions often requires combining multi-wavelength observations to spectrally isolate one component. In this work, we present a new arcminute-resolution Compton-$y$ map, which traces out the line-of-sight-integrated electron pressure, as well as maps of the CMB in intensity and E-mode polarization, across a third of the sky (around 13,000 sq.~deg.). We produce these through a joint analysis of data from the Atacama Cosmology Telescope (ACT) Data Release 4 and 6 at frequencies of roughly 93, 148, and 225 GHz, together with data from the \textit{Planck} satellite at frequencies between 30 GHz and 545 GHz. We present detailed verification of an internal linear combination pipeline implemented in a needlet frame that allows us to efficiently suppress Galactic contamination and account for spatial variations in the ACT instrument noise. These maps provide a significant advance, in noise levels and resolution, over the existing \textit{Planck} component-separated maps and will enable a host of science goals including studies of cluster and galaxy astrophysics, inferences of the cosmic velocity field, primordial non-Gaussianity searches, and gravitational lensing reconstruction of the CMB.Comment: The Compton-y map and associated products will be made publicly available upon publication of the paper. The CMB T and E mode maps will be made available when the DR6 maps are made publi

The Atacama Cosmology Telescope: DR6 Gravitational Lensing Map and Cosmological Parameters

We present cosmological constraints from a gravitational lensing mass map covering 9400 sq. deg. reconstructed from CMB measurements made by the Atacama Cosmology Telescope (ACT) from 2017 to 2021. In combination with BAO measurements (from SDSS and 6dF), we obtain the amplitude of matter fluctuations $\sigma_8 = 0.819 \pm 0.015$ at 1.8% precision, $S_8\equiv\sigma_8({\Omega_{\rm m}}/0.3)^{0.5}=0.840\pm0.028$ and the Hubble constant $H_0= (68.3 \pm 1.1)\, \text{km}\,\text{s}^{-1}\,\text{Mpc}^{-1}$ at 1.6% precision. A joint constraint with CMB lensing measured by the Planck satellite yields even more precise values: $\sigma_8 = 0.812 \pm 0.013$, $S_8\equiv\sigma_8({\Omega_{\rm m}}/0.3)^{0.5}=0.831\pm0.023$ and $H_0= (68.1 \pm 1.0)\, \text{km}\,\text{s}^{-1}\,\text{Mpc}^{-1}$. These measurements agree well with $\Lambda$CDM-model extrapolations from the CMB anisotropies measured by Planck. To compare these constraints to those from the KiDS, DES, and HSC galaxy surveys, we revisit those data sets with a uniform set of assumptions, and find $S_8$ from all three surveys are lower than that from ACT+Planck lensing by varying levels ranging from 1.7-2.1$\sigma$. These results motivate further measurements and comparison, not just between the CMB anisotropies and galaxy lensing, but also between CMB lensing probing $z\sim 0.5-5$ on mostly-linear scales and galaxy lensing at $z\sim 0.5$ on smaller scales. We combine our CMB lensing measurements with CMB anisotropies to constrain extensions of $\Lambda$CDM, limiting the sum of the neutrino masses to $\sum m_{\nu} < 0.12$ eV (95% c.l.), for example. Our results provide independent confirmation that the universe is spatially flat, conforms with general relativity, and is described remarkably well by the $\Lambda$CDM model, while paving a promising path for neutrino physics with gravitational lensing from upcoming ground-based CMB surveys.Comment: 30 pages, 16 figures, prepared for submission to ApJ. Cosmological likelihood data is here: https://lambda.gsfc.nasa.gov/product/act/actadv_prod_table.html ; likelihood software is here: https://github.com/ACTCollaboration/act_dr6_lenslike . Also see companion papers Qu et al and MacCrann et al. Mass maps will be released when papers are publishe

Differential cross section measurements for the production of a W boson in association with jets in proton–proton collisions at √s = 7 TeV

Measurements are reported of differential cross sections for the production of a W boson, which decays into a muon and a neutrino, in association with jets, as a function of several variables, including the transverse momenta (pT) and pseudorapidities of the four leading jets, the scalar sum of jet transverse momenta (HT), and the difference in azimuthal angle between the directions of each jet and the muon. The data sample of pp collisions at a centre-of-mass energy of 7 TeV was collected with the CMS detector at the LHC and corresponds to an integrated luminosity of 5.0 fb[superscript −1]. The measured cross sections are compared to predictions from Monte Carlo generators, MadGraph + pythia and sherpa, and to next-to-leading-order calculations from BlackHat + sherpa. The differential cross sections are found to be in agreement with the predictions, apart from the pT distributions of the leading jets at high pT values, the distributions of the HT at high-HT and low jet multiplicity, and the distribution of the difference in azimuthal angle between the leading jet and the muon at low values.United States. Dept. of EnergyNational Science Foundation (U.S.)Alfred P. Sloan Foundatio

Juxtaposing BTE and ATE – on the role of the European insurance industry in funding civil litigation

One of the ways in which legal services are financed, and indeed shaped, is through private insurance arrangement. Two contrasting types of legal expenses insurance contracts (LEI) seem to dominate in Europe: before the event (BTE) and after the event (ATE) legal expenses insurance. Notwithstanding institutional differences between different legal systems, BTE and ATE insurance arrangements may be instrumental if government policy is geared towards strengthening a market-oriented system of financing access to justice for individuals and business. At the same time, emphasizing the role of a private industry as a keeper of the gates to justice raises issues of accountability and transparency, not readily reconcilable with demands of competition. Moreover, multiple actors (clients, lawyers, courts, insurers) are involved, causing behavioural dynamics which are not easily predicted or influenced. Against this background, this paper looks into BTE and ATE arrangements by analysing the particularities of BTE and ATE arrangements currently available in some European jurisdictions and by painting a picture of their respective markets and legal contexts. This allows for some reflection on the performance of BTE and ATE providers as both financiers and keepers. Two issues emerge from the analysis that are worthy of some further reflection. Firstly, there is the problematic long-term sustainability of some ATE products. Secondly, the challenges faced by policymakers that would like to nudge consumers into voluntarily taking out BTE LEI