A common TMPRSS2 variant has a protective effect against severe COVID-19

Background : The human protein transmembrane protease serine type 2 (TMPRSS2) plays a key role in SARS-CoV-2 infection, as it is required to activate the virus’ spike protein, facilitating entry into target cells. We hypothesized that naturally-occurring TMPRSS2 human genetic variants affecting the structure and function of the TMPRSS2 protein may modulate the severity of SARS-CoV-2 infection. Methods : We focused on the only common TMPRSS2 non-synonymous variant predicted to be damaging (rs12329760 C>T, p.V160M), which has a minor allele frequency ranging from from 0.14 in Ashkenazi Jewish to 0.38 in East Asians. We analysed the association between the rs12329760 and COVID-19 severity in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units recruited as part of the GenOMICC (Genetics Of Mortality In Critical Care) study. Logistic regression analyses were adjusted for sex, age and deprivation index. For in vitro studies, HEK293 cells were co-transfected with ACE2 and either TMPRSS2 wild type or mutant (TMPRSS2V160M). A SARS-CoV-2 pseudovirus entry assay was used to investigate the ability of TMPRSS2V160M to promote viral entry. Results : We show that the T allele of rs12329760 is associated with a reduced likelihood of developing severe COVID-19 (OR 0.87, 95%CI:0.79-0.97, p=0.01). This association was stronger in homozygous individuals when compared to the general population (OR 0.65, 95%CI:0.50-0.84, p=1.3 × 10−3). We demonstrate in vitro that this variant, which causes the amino acid substitution valine to methionine, affects the catalytic activity of TMPRSS2 and is less able to support SARS-CoV-2 spike-mediated entry into cells. Conclusion : TMPRSS2 rs12329760 is a common variant associated with a significantly decreased risk of severe COVID-19. Further studies are needed to assess the expression of TMPRSS2 across different age groups. Moreover, our results identify TMPRSS2 as a promising drug target, with a potential role for camostat mesilate, a drug approved for the treatment of chronic pancreatitis and postoperative reflux esophagitis, in the treatment of COVID-19. Clinical trials are needed to confirm this

Last resort beta-lactam antibiotics for treatment of New-Delhi Metallo-Beta-Lactamase producing Enterobacterales and other Difficult-to-Treat Resistance in Gram-negative bacteria: A real-life study

IntroductionNovel last resort beta-lactam antibiotics are now available for management of infections due to New-Delhi Metallo-Beta-Lactamase (NDM) producing Enterobacterales and non-fermenters with Difficult-to-Treat Resistance. However, data regarding the use of imipenem-cilastatin-relebactam (IMI-REL), cefiderocol (CFD) and ceftazidime-avibactam plus aztreonam (CAZ-AVI-ATM) are scarce in real-life settings. This study aimed to describe the use of last resort beta-lactam antibiotics, the microbiology and the outcome, in patients hospitalized in a tertiary hospital.MethodsWe conducted a monocentric observational cohort study from 2020/01/01, to 2022/08/31. We screened all patients admitted to Nimes University Hospital who have received ≥ 1 dose of last resort beta-lactam antibiotics during the study period, using the Pharmacy database. We included patients treated with IMI-REL, CFD and CAZ-AVI-ATM. The primary endpoint was the infection-free survival rate. We also calculated rates of microbiological and clinical cure, recurrent infection, death and adverse events.ResultsTwenty-seven patients were included in the study and 30 treatment courses were analyzed: CFD (N=24; 80%), CAZ-AVI-ATM (N=3; 10%) and IMI-REL (N=3; 10%). Antibiotics were used in 21 males (70%) and 9 females (30%) with a median age at 65-year-old [50-73.5] and a median Charlson index at 1 [0-2]. Almost all the patients had ≥ 1 risk factor for carbapenem resistant bacteria, a half of them was hospitalized for severe COVID-19, and most of antibiotic courses (N=26; 87%) were associated with ICU admission. In the study population, the probability of infection-free survival at day-90 after last resort beta-lactam therapy initiation was 48.4% CI95% [33.2-70.5]. Clinical failure rate was at 30%, microbiological failure rate at 33% and mortality rate at 23%. Adverse events were documented in 5 antibiotic courses (17%). In details, P. aeruginosa were mainly treated with CFD and IMI-REL, S. maltophilia with CFD and CAZ-AVI-ATM, A. baumannii with CFD, and NDM producing-K. pneumoniae with CAZ-AVI-ATM and CFD. After a treatment course with CFD, CAZ-AVI-ATM and IMI-REL, the probability of infection-free survival was 48% CI95% [10.4-73.5], 33.3% CI95% [6.7-100], 66.7% CI95% [30-100], respectively.Discussion/conclusionUse of last resort beta-lactam antimicrobials in real-life settings was a safe and efficient therapeutic option for severe infections related to Gram-negative bacteria with Difficult-to-Treat Resistance

Analysis of the OSSEs with multi-platform in situ data and impact on fine-scale structures

This report includes recommendations for the planification of in situ experiments aimed to reconstruct fine-scale ocean currents (~20 km), such as those that will be conducted to validate SWOT satellite observations

Fine Mapping of Genetic Variants in BIN1, CLU, CR1 and PICALM for Association with Cerebrospinal Fluid Biomarkers for Alzheimer's Disease

Recent genome-wide association studies of Alzheimer's disease (AD) have identified variants in BIN1, CLU, CR1 and PICALM that show replicable association with risk for disease. We have thoroughly sampled common variation in these genes, genotyping 355 variants in over 600 individuals for whom measurements of two AD biomarkers, cerebrospinal fluid (CSF) 42 amino acid amyloid beta fragments (Aβ42) and tau phosphorylated at threonine 181 (ptau181), have been obtained. Association analyses were performed to determine whether variants in BIN1, CLU, CR1 or PICALM are associated with changes in the CSF levels of these biomarkers. Despite adequate power to detect effects as small as a 1.05 fold difference, we have failed to detect evidence for association between SNPs in these genes and CSF Aβ42 or ptau181 levels in our sample. Our results suggest that these variants do not affect risk via a mechanism that results in a strong additive effect on CSF levels of Aβ42 or ptau181

Discutindo a educação ambiental no cotidiano escolar: desenvolvimento de projetos na escola formação inicial e continuada de professores

A presente pesquisa buscou discutir como a Educação Ambiental (EA) vem sendo trabalhada, no Ensino Fundamental e como os docentes desta escola compreendem e vem inserindo a EA no cotidiano escolar., em uma escola estadual do município de Tangará da Serra/MT, Brasil. Para tanto, realizou-se entrevistas com os professores que fazem parte de um projeto interdisciplinar de EA na escola pesquisada. Verificou-se que o projeto da escola não vem conseguindo alcançar os objetivos propostos por: desconhecimento do mesmo, pelos professores; formação deficiente dos professores, não entendimento da EA como processo de ensino-aprendizagem, falta de recursos didáticos, planejamento inadequado das atividades. A partir dessa constatação, procurou-se debater a impossibilidade de tratar do tema fora do trabalho interdisciplinar, bem como, e principalmente, a importância de um estudo mais aprofundado de EA, vinculando teoria e prática, tanto na formação docente, como em projetos escolares, a fim de fugir do tradicional vínculo “EA e ecologia, lixo e horta”.Facultad de Humanidades y Ciencias de la Educació

Data from: Seed dispersal syndromes in the Madagascan flora: the unusual importance of primates

Madagascar is one of the most threatened biodiversity hotspots, and protection of its biodiversity is becoming increasingly urgent as deforestation of the island continues. For the long-term success of conservation efforts it is essential that key ecological processes, such as seed dispersal, are protected and restored. Therefore, the identification of ecological gaps is a vital task. For Madagascar, only little is known about plant–animal interactions, and traditional methods of ecological research are too time-consuming to provide crucial information about breakdowns in these interactions. To identify likely dispersal gaps we therefore used a theoretical approach to analyse plant–disperser interactions in Madagascar. We used data science tools to impute missing data on relevant plant traits to subsequently predict the most likely dispersal agents for each of Madagascar’s endemic plant species. We found that 38% of the endemic species (N = 8,784) are endozoochorous, and among these 26–41% display a primate syndrome and 17–19% a bird syndrome (depending on the definition of syndromes). This lower percentage of endozoochorous species and higher percentage of species with a primate syndrome in Madagascar compared to other tropical areas reflects the unusual disperser guild on the island. Only five bird species but 20 lemur species are frugivorous, and 16 of those lemur species are currently threatened with extinction. The disappearance of frugivorous lemurs would significantly change the vegetation dynamics of Madagascar’s ecosystems, and a high proportion of Madagascar’s endemic plants would enter an extinction vortex

Decoupling Fluorescence and Photochromism in Bifunctional Azo Derivatives for Bulk Emissive Structures

Bifunctional molecules that combine independent pushpull fluorophores and azo photochromes have been synthesized to create fluorescent structures upon light-induced migration in neat thin films. Their photochromic and emissive properties have been systematically investigated and interpreted in light of those of the corresponding model compounds. Fluorescence lifetimes and photoisomerization and fluorescence quantum yields have been determined in toluene solution. Kinetic analyses of the femtosecond transient absorption spectra reveal that the fluorophores evolve in a few picoseconds into a distorted intramolecular charge-transfer excited state, strongly stabilized in energy. Radiative relaxation to the ground state occurred competitively with the energy-transfer process to the azo moiety. Introduction of a 10 angstrom-long rigid and nonconjugated bridge between the photoactive units efficiently inhibits the energy transfer while it imparts enhanced free volume, which favors photoactivated molecular migration in the solid state

AN ALTERNATIVE SIMPLE APPROACH FOR THE MODELLING OF FUEL ASSEMBLIES WITH MISSING FUEL RODS

International audienceThis paper presents a discussion about an alternative calculation scheme that can be used to model nuclear fuel assemblies under water. In criticality Monte-Carlo multigroup calculations performed by French industrials, heterogeneous media (such as fuel assemblies or more generally any type of arrays of fissile material in water) are mostly modelled as a homogeneous medium whose nuclear cross sections are adjusted to match those of the original heterogeneous system. These cross sections are obtained using a preliminary flux calculation based on deterministic methods. For a fuel assembly, the simplest deterministic method is to consider a simple cell (fuel oxide cylinder surrounded by clad and water) with a moderation ratio determined by considering that the water around fuel rods and inside empty slots is homogeneously distributed all over the assembly section. This simplified calculation scheme, very useful for parametric studies and for modelling missing fuel rods which position is not known, allows fast multigroup calculations and only requires knowing the number of fuel rods in the section. However, in some cases, this simplified approach can lead to underestimate the assembly reactivity. Indeed, the moderation ratio is generally heterogeneous within the assembly section, particularly for boiling water reactor types assemblies for which empty slots are unequally dispatched within their section. Moreover, the modelling of the water located outside of the assembly section can lead to mis-estimate the moderation of the external fuel rods. The purpose of this paper is to present an alternative simple approach to use preliminary deterministic calculations to generate homogeneous cross sections for multigroup Monte Carlo codes, in order to avoid two dimensional deterministic calculations which limit the parametric studies possibilities and are computer-time consuming. This paper will firstly remind generalities about the problematics regarding missing fuel rods in fuel assembly modelling. Then, results obtained with the alternative calculation scheme will be presented, with an explanation of the discrepancies compared to other calculation schemes. At last, a discussion about the bounding trait of this alternative scheme and the parameters that can have an influence on its behaviour will be presented

Madagascan plant traits

Data on traits of endemic Madagascan plant species before and after imputation of missing values (using multivariate imputations by chained equations). Data were compiled from the literature, public databases (Madagascar Catalogue, 2013) and examination of herbarium specimens at the Royal Botanic Gardens, Kew (2,519 specimens) and at the Muséum National d’Histoire Naturelle, Paris (364 specimens)