SUMOylation regulates nucleo-cytoplasmic shuttling of Elk-1

The transcription factor Elk-1 is a nuclear target of mitogen-activated protein kinases and regulates immediate early gene activation by extracellular signals. We show that Elk-1 is also conjugated to SUMO on either lysines 230, 249, or 254. Mutation of all three sites is necessary to fully block SUMOylation in vitro and in vivo. This Elk-1 mutant, Elk-1(3R), shuttles more rapidly to nuclei of Balb/C cells fused to transfected HeLa cells. Coexpression of SUMO-1 or -2 strongly reduces shuttling by Elk-1 without affecting that of Elk-1(3R), indicating that SUMOylation regulates nuclear retention of Elk-1. Accordingly, overexpression of Elk-1(3R) in PC12 cells, where cytoplasmic relocalization of Elk-1 has been linked to differentiation, enhances neurite extension relative to Elk-1. The effect of Elk-1, but not of the 3R mutant, was blocked upon cotransfection with SUMO-1 or -2 and enhanced by coexpression with mutant Ubc-9. Thus, SUMO conjugation is a novel regulator of Elk-1 function through the control of its nuclear-cytoplasmic shuttling

Urban Climate, Human behavior & Energy consumption: from LCZ mapping to simulation and urban planning (the MapUCE project)

International audienceThe MApUCE project aims to integrate in urban policies and most relevant legal documents quantitative data from urban microclimate, climate and energy.The primary objective of this project is to obtain climate and energy quantitative data from numerical simulations, focusing on urban microclimate and building energy consumption in the residential and service sectors, which represents in France 41% of the final energy consumption. Both aspects are coupled as building energy consumption is highly meteorologically dependent (e.g. domestic heating, air-conditioning) and heat waste impact the Urban Heat Island. We propose to develop, using national databases, a generic and automated method for generating Local Climate Zones (LCZ) for all cities in France, including the urban architectural, geographical and sociological parameters necessary for energy and microclimate simulations.As will be presented, previous projects on adaptation of cities to climate change have shown that human behavior is a very potent level to address energy consumption reduction, as much as urban forms or architectural technologies. Therefore, in order to further refine the coupled urban climate and energy consumption calculations, we will develop within TEB (and its Building Energy Module) a model of energy consumer behavior.The second objective of the project is to propose a methodology to integrate quantitative data in urban policies. Lawyers analyze the potential levers in legal and planning documents. A few “best cases” are also studied, in order to evaluate their performances. Finally, based on urban planning agencies requirements, we will define vectors to include quantified energy-climate data to legal urban planning documents. These vectors have to be understandable by urban planners and contain the relevant information.To meet these challenges, the project is organized around strongly interdisciplinary partners in the following fields: law, urban climate, building energetics, architecture, sociology, geography and meteorology, as well as the national federation of urban planning agencies.In terms of results, the cross-analysis of input urban parameters and urban micro-climate-energy simulated data will be available on-line as standardized maps for each of the studied cities. The urban parameter production tool as well as the models will be available as open-source. LCZ and associated urban (and social!) indicators may be integrated within the WUDAPT database

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

Discovery and functional prioritization of Parkinson's disease candidate genes from large-scale whole exome sequencing.

BACKGROUND: Whole-exome sequencing (WES) has been successful in identifying genes that cause familial Parkinson's disease (PD). However, until now this approach has not been deployed to study large cohorts of unrelated participants. To discover rare PD susceptibility variants, we performed WES in 1148 unrelated cases and 503 control participants. Candidate genes were subsequently validated for functions relevant to PD based on parallel RNA-interference (RNAi) screens in human cell culture and Drosophila and C. elegans models. RESULTS: Assuming autosomal recessive inheritance, we identify 27 genes that have homozygous or compound heterozygous loss-of-function variants in PD cases. Definitive replication and confirmation of these findings were hindered by potential heterogeneity and by the rarity of the implicated alleles. We therefore looked for potential genetic interactions with established PD mechanisms. Following RNAi-mediated knockdown, 15 of the genes modulated mitochondrial dynamics in human neuronal cultures and four candidates enhanced α-synuclein-induced neurodegeneration in Drosophila. Based on complementary analyses in independent human datasets, five functionally validated genes-GPATCH2L, UHRF1BP1L, PTPRH, ARSB, and VPS13C-also showed evidence consistent with genetic replication. CONCLUSIONS: By integrating human genetic and functional evidence, we identify several PD susceptibility gene candidates for further investigation. Our approach highlights a powerful experimental strategy with broad applicability for future studies of disorders with complex genetic etiologies

Urban Climate, Human behavior and Energy consumption : from LCZ mapping to simulation and urban planning (the MapUCE project)

International audienc

Women’s dissatisfaction with inappropriate behavior by health care workers during childbirth care in France: A survey study

Background As part of a decades-long process of restructuring primary care, independent (also known as community) healthcare workers are being encouraged to work in groups to facilitate their coordination and continuity of care in France. French independent midwives perform about half of the early prenatal interviews that identify mothers' needs during pregnancy and then refer them to the appropriate resources. The French government, however, structured the COVID-19 pandemic response around public health institutions and did not directly mobilise these community healthcare workers during the lockdown phase. These responses have raised questions about their role within the healthcare system in crises. This survey’s main objectives were to estimate the proportion of independent midwives who experienced new difficulties in referring women to healthcare facilities or other caregivers and in collaborating with hospitals during the first stage of this pandemic. The secondary objective was to estimate the proportion, according to their mode of practice, of independent midwives who considered that all the women under their care had risked harm due to failed or delayed referral to care. Methods We conducted an online national survey addressed to independent midwives in France from 29 April to 15 May 2020, around the end of the first lockdown (17 March–11 May, 2020). Results Of the 5264 registered independent midwives in France, 1491 (28.3%) responded; 64.7% reported new or greater problems during the pandemic in referring women to health facilities or care-providers, social workers in particular, and 71.0% reported new difficulties collaborating with hospitals. Nearly half (46.2%) the respondents considered that all the women in their care had experienced, to varying degrees, a lack of or delay in care that could have affected their health. This proportion did not differ according to the midwives’ form of practice: solo practice, group practice with other midwives only, or group practice with at least two types of healthcare professionals. Conclusions The pandemic has degraded the quality of pregnant women’s care in France and challenged the French model of care, which is highly compartmentalised between an almost exclusively independent primary care (community) sector and a predominantly salaried secondary care (hospital) sector