The KCNQ1 potassium channel is down-regulated by ubiquitylating enzymes of the Nedd4/Nedd4-like family

Objective: The voltage-gated KCNQ1 potassium channel regulates key physiological functions in a number of tissues. In the heart, KCNQ1 α-subunits assemble with KCNE1 β-subunits forming a channel complex constituting the delayed rectifier current IKs. In epithelia, KCNQ1 channels participate in controlling body electrolyte homeostasis. Several regulatory mechanisms of the KCNQ1 channel complexes have been reported, including protein kinase A (PKA)-phosphorylation and β-subunit interactions. However, the mechanisms controlling the membrane density of KCNQ1 channels have attracted less attention. Methods and results: Here we demonstrate that KCNQ1 proteins expressed in HEK293 cells are down-regulated by Nedd4/Nedd4-like ubiquitin-protein ligases. KCNQ1 and KCNQ1/KCNE1 currents were reduced upon co-expression of Nedd4-2, the isoform among the nine members of the Nedd4/Nedd4-like family displaying the highest expression level in human heart. In vivo expression of a catalytically inactive form of Nedd4-2, able to antagonize endogenous Nedd4-2 in guinea-pig cardiomyocytes, increased IKs significantly, but did not modify IK1. Concomitant with the reduction in current induced by Nedd4-2, an increased ubiquitylation as well as a decreased total level of KCNQ1 proteins were observed in HEK293 cells. Pull-down and co-immunoprecipitation experiments showed that Nedd4-2 interacts with the C-terminal part of KCNQ1. The Nedd4/Nedd4-like-mediated regulation of the KCNQ1 channel complexes is strictly dependent on a PY motif located in the distal part of the C-terminal domain. When this motif was mutated, the current and ubiquitylation levels were unaffected by Nedd4-2, and Nedd4-2 proteins were neither pulled-down nor co-immunoprecipitated. Conclusions: These results suggest that KCNQ1 internalization and stability is physiologically regulated by its Nedd4/Nedd4-like-dependent ubiquitylation. This mechanism may thereby be important in regulating the surface density of the KCNQ1 channels in cardiomyocytes and other cell type

Increase in Bone Mineral Density after Successful Parathyroidectomy for Tertiary Hyperparathyroidism after Renal Transplantation

Background: Few studies have reported changes of bone mineral density (BMD) after parathyroidectomy in patients with persistent hyperparathyroidism after renal transplantation (3 HPT). Patients and Methods: We retrospectively analyzed 14 patients who underwent successful parathyroidectomy for 3 HPT and who had available BMD data before and after parathyroidectomy. Results: Median follow-up time was 26months (IQR: 16.8-40.2). Serum calcium levels decreased significantly after parathyroidectomy (2.32 ± 0.09 versus 2.66±0.16mmol/l; p<0.01), as did PTH levels (5.1±3.0 versus 27.8±23.7pmol/l; p<0.01). Nine patients (64%) had a steroid-free immunosuppression at follow-up. Mean increase in BMD was 9.5±8.0% for the spine and 9.5±7.9% for the hip (p<0.01 for both sites). Patients with osteoporosis (T-score ≤ 2.5) or osteopenia (T-score ≤ 1) before parathyroidectomy had the biggest increase in BMD (10.7±7.7% in hip BMD and of 12.3±8.1% in spine BMD). Conclusions: Parathyroidectomy is an efficient treatment of osteoporosis and osteopenia in patients with 3 HP

Exploring manycore architectures for next-generation HPC systems through the MANGO approach

[EN] The Horizon 2020 MANGO project aims at exploring deeply heterogeneous accelerators for use in High-Performance Computing systems running multiple applications with different Quality of Service (QoS) levels. The main goal of the project is to exploit customization to adapt computing resources to reach the desired QoS. For this purpose, it explores different but interrelated mechanisms across the architecture and system software. In particular, in this paper we focus on the runtime resource management, the thermal management, and support provided for parallel programming, as well as introducing three applications on which the project foreground will be validated.This project has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 671668.Flich Cardo, J.; Agosta, G.; Ampletzer, P.; Atienza-Alonso, D.; Brandolese, C.; Cappe, E.; Cilardo, A.... (2018). Exploring manycore architectures for next-generation HPC systems through the MANGO approach. Microprocessors and Microsystems. 61:154-170. https://doi.org/10.1016/j.micpro.2018.05.011S1541706

Practical Recommendations for Optimal Thromboprophylaxis in Patients with COVID-19: A Consensus Statement Based on Available Clinical Trials.

Coronavirus disease 2019 (COVID-19) has been shown to be strongly associated with increased risk for venous thromboembolism events (VTE) mainly in the inpatient but also in the outpatient setting. Pharmacologic thromboprophylaxis has been shown to offer significant benefits in terms of reducing not only VTE events but also mortality, especially in acutely ill patients with COVID-19. Although the main source of evidence is derived from observational studies with several limitations, thromboprophylaxis is currently recommended for all hospitalized patients with acceptable bleeding risk by all national and international guidelines. Recently, high quality data from randomized controlled trials (RCTs) further support the role of thromboprophylaxis and provide insights into the optimal thromboprophylaxis strategy. The aim of this statement is to systematically review all the available evidence derived from RCTs regarding thromboprophylaxis strategies in patients with COVID-19 in different settings (either inpatient or outpatient) and provide evidence-based guidance to practical questions in everyday clinical practice. Clinical questions accompanied by practical recommendations are provided based on data derived from 20 RCTs that were identified and included in the present study. Overall, the main conclusions are: (i) thromboprophylaxis should be administered in all hospitalized patients with COVID-19, (ii) an optimal dose of inpatient thromboprophylaxis is dependent upon the severity of COVID-19, (iii) thromboprophylaxis should be administered on an individualized basis in post-discharge patients with COVID-19 with high thrombotic risk, and (iv) thromboprophylaxis should not be routinely administered in outpatients. Changes regarding the dominant SARS-CoV-2 variants, the wide immunization status (increasing rates of vaccination and reinfections), and the availability of antiviral therapies and monoclonal antibodies might affect the characteristics of patients with COVID-19; thus, future studies will inform us about the thrombotic risk and the optimal therapeutic strategies for these patients

Height and body-mass index trajectories of school-aged children and adolescents from 1985 to 2019 in 200 countries and territories: a pooled analysis of 2181 population-based studies with 65 million participants

Summary Background Comparable global data on health and nutrition of school-aged children and adolescents are scarce. We aimed to estimate age trajectories and time trends in mean height and mean body-mass index (BMI), which measures weight gain beyond what is expected from height gain, for school-aged children and adolescents. Methods For this pooled analysis, we used a database of cardiometabolic risk factors collated by the Non-Communicable Disease Risk Factor Collaboration. We applied a Bayesian hierarchical model to estimate trends from 1985 to 2019 in mean height and mean BMI in 1-year age groups for ages 5–19 years. The model allowed for non-linear changes over time in mean height and mean BMI and for non-linear changes with age of children and adolescents, including periods of rapid growth during adolescence. Findings We pooled data from 2181 population-based studies, with measurements of height and weight in 65 million participants in 200 countries and territories. In 2019, we estimated a difference of 20 cm or higher in mean height of 19-year-old adolescents between countries with the tallest populations (the Netherlands, Montenegro, Estonia, and Bosnia and Herzegovina for boys; and the Netherlands, Montenegro, Denmark, and Iceland for girls) and those with the shortest populations (Timor-Leste, Laos, Solomon Islands, and Papua New Guinea for boys; and Guatemala, Bangladesh, Nepal, and Timor-Leste for girls). In the same year, the difference between the highest mean BMI (in Pacific island countries, Kuwait, Bahrain, The Bahamas, Chile, the USA, and New Zealand for both boys and girls and in South Africa for girls) and lowest mean BMI (in India, Bangladesh, Timor-Leste, Ethiopia, and Chad for boys and girls; and in Japan and Romania for girls) was approximately 9–10 kg/m2. In some countries, children aged 5 years started with healthier height or BMI than the global median and, in some cases, as healthy as the best performing countries, but they became progressively less healthy compared with their comparators as they grew older by not growing as tall (eg, boys in Austria and Barbados, and girls in Belgium and Puerto Rico) or gaining too much weight for their height (eg, girls and boys in Kuwait, Bahrain, Fiji, Jamaica, and Mexico; and girls in South Africa and New Zealand). In other countries, growing children overtook the height of their comparators (eg, Latvia, Czech Republic, Morocco, and Iran) or curbed their weight gain (eg, Italy, France, and Croatia) in late childhood and adolescence. When changes in both height and BMI were considered, girls in South Korea, Vietnam, Saudi Arabia, Turkey, and some central Asian countries (eg, Armenia and Azerbaijan), and boys in central and western Europe (eg, Portugal, Denmark, Poland, and Montenegro) had the healthiest changes in anthropometric status over the past 3·5 decades because, compared with children and adolescents in other countries, they had a much larger gain in height than they did in BMI. The unhealthiest changes—gaining too little height, too much weight for their height compared with children in other countries, or both—occurred in many countries in sub-Saharan Africa, New Zealand, and the USA for boys and girls; in Malaysia and some Pacific island nations for boys; and in Mexico for girls. Interpretation The height and BMI trajectories over age and time of school-aged children and adolescents are highly variable across countries, which indicates heterogeneous nutritional quality and lifelong health advantages and risks

Rising rural body-mass index is the main driver of the global obesity epidemic in adults

Body-mass index (BMI) has increased steadily in most countries in parallel with a rise in the proportion of the population who live in cities(.)(1,2) This has led to a widely reported view that urbanization is one of the most important drivers of the global rise in obesity(3-6). Here we use 2,009 population-based studies, with measurements of height and weight in more than 112 million adults, to report national, regional and global trends in mean BMI segregated by place of residence (a rural or urban area) from 1985 to 2017. We show that, contrary to the dominant paradigm, more than 55% of the global rise in mean BMI from 1985 to 2017-and more than 80% in some low- and middle-income regions-was due to increases in BMI in rural areas. This large contribution stems from the fact that, with the exception of women in sub-Saharan Africa, BMI is increasing at the same rate or faster in rural areas than in cities in low- and middle-income regions. These trends have in turn resulted in a closing-and in some countries reversal-of the gap in BMI between urban and rural areas in low- and middle-income countries, especially for women. In high-income and industrialized countries, we noted a persistently higher rural BMI, especially for women. There is an urgent need for an integrated approach to rural nutrition that enhances financial and physical access to healthy foods, to avoid replacing the rural undernutrition disadvantage in poor countries with a more general malnutrition disadvantage that entails excessive consumption of low-quality calories.Peer reviewe

Mécanismes d'initiation des laves torrentielles dans las Alpes françaises - Contribution à la maitrise du risque.

This research is related to the "debris flow " phenomenon with the aim of identifying necessary conditions for initiation and studying ils mechanisms, in several torrential catchments in the French Alps. . Debris flow occurrence results from a conjunction of several predisposition factors related to climatology, geology, geomorphology and hydrogeology. The triggering factor is most often water provided by violent rainstorms. The study of numerous debris flow deposits, sampled in different catchments, allow to determine two types of debris flows, granular debris flows and cohesive debris flows. Their distinction is based upon several granulometric criteria defined ori the fraction of soil inferior to 20 mm. The granulometric and geotechnical characteristics of initiation zone samples are similar to those of debris flow deposits, which implies that the granulometric sorting between source areas and deposit areas is very low. The initiation mechanisms have been identified and described considering the environmental context. They are numerous, and we established their typology. The knowledge of the initiation mechanisms and the identification of geotechnical criteria for initiation zone materials has been used to elaborate maps of " aptitude for debris flow initiation " . Regarding the initiation mechanisms and the volumes of available materials in the potential initiation zones, we have defined different debris flow scenarios, taking into account the potential damage caused on torrential fans.Ce travail concerne le phénomène "lave torrentielle" en recherchant les conditions de l'initiation et en en étudiant les mécanismes dans plusieurs bassins torrentiels des Alpes françaises. L'occurrence des laves torrentielles résulte de la conjonction de multiples facteurs de prédisposition,en rapport avec la climatologie, la géologie, la géomorphologie et l'hydrogéologie, le facteur déclenchant étant le plus souvent l'eau apportée par de violents orages. L'étude de nombreux dépôts de laves torrentielles de provenance variée a permis de déterminer l' existence de deux familles de laves torrentielles, les laves granulaires et les laves cohésives, dont la distinction est basée sur plusieurs critères granulométriques définis sur le sol écrêté à 20 mm. Les caractéristiques granulométriques et géotechniques des matériaux prélevés dans les zones d'initiation sont semblables à celles des dépôts de laves torrentielles, ce qui signifie que le tri granulométrique entre les zones sources et les zones de dépôts est très faible. Les mécanismes d'initiation ont alors été identifiés et décrits en tenant compte du contexte environnemental. lis sont multiples et nous en avons établi une typologie. La connaissance de ces mécanismes et l'identification de critères géotechniques propres aux matériaux des zones d'initiation des laves torrentielles a servi de base à l'élaboration de cartes " d'aptitude à l'initiation des laves torrentielles ". En fonction des mécanismes d'initiation et des volumes disponibles dans ces zones d'initiation potentielle, nous avons défini différents scénarios d'événements "laves torrentielles " , tenant compte des dégâts susceptibles d'être causés sur les cônes de déjection

Metodbeskrivningar för bergtekniska undersökningar : Analys av tänkbar väg till mer standardiserad praxis

Att förstå berggrunden och dess egenskaper är nödvändigt för att projektera anläggningar i berg, och bedöma vilka osäkerheter och risker som kan kopplas till infrastrukturprojekt, under projektering, byggande och drift. En god detaljförståelse är avgörande för bergkonstruktioners funktion (eng. servicability), säkerhet, robusthet, och varaktiga styrka (eng. durability). Även för att kunna bedöma eventuell påverkan från ett föränderligt klimat behövs god kunskap om bergets kemiska, fysikaliska och mekaniska egenskaper.  Denna kunskap uppnås genom att utföra undersökningar och mätningar av parametrar i berggrunden och i biosfären, vilka kan variera bland annat beroende på typ av projekt. Uppdraget tar avstamp i redan befintlig metodik för att undersöka och karaktärisera bergets egenskaper. Det finns både internationellt vedertagen metodik, metodik som tagits fram och anpassats för svenska ändamål (dagens praxis) och metodik som tagits fram för specifika ändamål. I det senare facket hamnar SKB:s metodbeskrivningar som tagits fram specifikt för att undersöka berggrunden i en bergvolym för planerat svenskt slutförvar för använt kärnbränsle. Dessa metoder bygger i grunden på befintlig svensk och internationell teknik, men kraven, i det här fallet, är väldigt högt ställda beroende på de konsekvenser en olycka kan få och de långa tidsperspektiven som det använda kärnbränslet skall ligga isolerat från biosfären. Detta har medfört ett behov av en hel del utvecklingsarbete och man kan betrakta flera av dessa metodiker som state-of-the-art i många avseenden. När det gäller dagens praxis har behov av förbättringar och utvecklingar identifierats för att bestämma parametrar på så likartat sätt som möjligt i infrastrukturprojekt, och i det sammanhanget är SKB:s metodbeskrivningar särskilt intressanta. Rapporten redovisar en sammanställning av några av SKB:s metodbeskrivningar och vunna erfarenheter i arbeten baserade på dessa, samt ett förslag på lämpliga sätt att göra anpassningar av SKB:s metodik för övriga bergbyggnadsbranschen. Urvalet har gjorts bland de som kan ge ett relevant underlag för att utveckla mer enhetlig metodik för bergbyggnadsbranschen i Sverige. I rapporten görs även en prioritering och redovisning av lämpliga aktiviteter för att uppnå en mer konsekvent branschpraxis.  Uppdraget svarar upp mot SGI:s tilldelade ansvar att minska risken för ras och arbeta för ett effektivare markbyggande. Även SGI:s arbete med klimatanpassning och klimatförändringars effekter på geotekniska och miljögeotekniska laster får stöd i projektresultate

A tyrosine-based sorting signal is involved in connexin43 stability and gap junction turnover

The gap junction protein connexin43 is known to have a rapid turnover, involving degradation by both the proteasomal and lysosomal systems, but the structural features of connexin43 that govern these actions are not known. The connexin43 C-terminal sequence contains a proline-rich region corresponding to the consensus of a protein-protein interaction PY-motif (xPPxY), and an overlapping putative tyrosine-based sorting signal (Yxxphi; =hydrophobic), known to play a role in the intracellular trafficking of many membrane proteins. As both motifs may control turnover of connexin43, we used a combination of metabolic radiolabelling, immuno-precipitation and functional assays to determine the possible role of these motifs in controlling degradation of human connexin43 expressed in SKHep1 cells. Mutation V289D in the tyrosine-based sorting motif increased the steady-state pool of connexin43 by approximately 3.5-fold, while mutation P283L in the PY-motif produced a comparatively modest augmentation (1.7-fold). No additive effect was observed when the overlapping tyrosine was mutated. In pulse-chase experiments, the Y286A substitution increased the half-life of connexin43 from 2 to 6 hours, indicating that the increased steady-state levels reflected reduced protein degradation. Moreover, expression at the junctional membrane, as well as gap junction-mediated intercellular communication (GJC), were nearly abolished by lysosomal inhibitors and Brefeldin A in cells expressing wild-type connexin43, but were unaffected in the tyrosine mutant. These results provide strong evidence that the tyrosine-based motif of human connexin43 is a prime determinant controlling connexin43 stability, and consequently GJC, by targeting connexin43 for degradation in the endocytic/lysosomal compartment