Groundwater Isolation Governs Chemistry and Microbial Community Structure along Hydrologic Flowpaths

International audienceThis study deals with the effects of hydrodynamic functioning of hard-rock aquifers on microbial communities. In hard-rock aquifers, the heterogeneous hydrologic circulation strongly constrains groundwater residence time, hydrochemistry, and nutrient supply. Here, residence time and a wide range of environmental factors were used to test the influence of groundwater circulation on active microbial community composition, assessed by high throughput sequencing of 16S rRNA. Groundwater of different ages was sampled along hydrogeologic paths or loops, in three contrasting hard-rock aquifers in Brittany (France). Microbial community composition was driven by groundwater residence time and hydrogeologic loop position. In recent groundwater, in the upper section of the aquifers or in their recharge zone, surface water inputs caused high nitrate concentration and the predominance of putative denitrifiers. Although denitrification does not seem to fully decrease nitrate concentrations due to low dissolved organic carbon concentrations, nitrate input has a major effect on microbial communities. The occurrence of taxa possibly associated with the application of organic fertilizers was also noticed. In ancient isolated groundwater, an ecosystem based on Fe(II)/Fe(III) and S/SO4 redox cycling was observed down to several 100 of meters below the surface. In this depth section, microbial communities were dominated by iron oxidizing bacteria belonging to Gallionellaceae. The latter were associated to old groundwater with high Fe concentrations mixed to a small but not null percentage of recent groundwater inducing oxygen concentrations below 2.5 mg/L. These two types of microbial community were observed in the three sites, independently of site geology and aquifer geometry, indicating hydrogeologic circulation exercises a major control on microbial communities

Peptidomimetic antibiotics disrupt the lipopolysaccharide transport bridge of drug-resistant Enterobacteriaceae

The rise of antimicrobial resistance poses a substantial threat to our health system, and, hence, development of drugs against novel targets is urgently needed. The natural peptide thanatin kills Gram-negative bacteria by targeting proteins of the lipopolysaccharide transport (Lpt) machinery. Using the thanatin scaffold together with phenotypic medicinal chemistry, structural data, and a target-focused approach, we developed antimicrobial peptides with drug-like properties. They exhibit potent activity against Enterobacteriaceae both in vitro and in vivo while eliciting low frequencies of resistance. We show that the peptides bind LptA of both wild-type and thanatin-resistant Escherichia coli and Klebsiella pneumoniae strains with low-nanomolar affinities. Mode of action studies revealed that the antimicrobial activity involves the specific disruption of the Lpt periplasmic protein bridge

Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification

The multifactorial likelihood analysis method has demonstrated utility for quantitative assessment of variant pathogenicity for multiple cancer syndrome genes. Independent data types currently incorporated in the model for assessing BRCA1 and BRCA2 variants include clinically calibrated prior probability of pathogenicity based on variant location and bioinformatic prediction of variant effect, co-segregation, family cancer history profile, co-occurrence with a pathogenic variant in the same gene, breast tumor pathology, and case-control information. Research and clinical data for multifactorial likelihood analysis were collated for 1,395 BRCA1/2 predominantly intronic and missense variants, enabling classification based on posterior probability of pathogenicity for 734 variants: 447 variants were classified as (likely) benign, and 94 as (likely) pathogenic; and 248 classifications were new or considerably altered relative to ClinVar submissions. Classifications were compared with information not yet included in the likelihood model, and evidence strengths aligned to those recommended for ACMG/AMP classification codes. Altered mRNA splicing or function relative to known nonpathogenic variant controls were moderately to strongly predictive of variant pathogenicity. Variant absence in population datasets provided supporting evidence for variant pathogenicity. These findings have direct relevance for BRCA1 and BRCA2 variant evaluation, and justify the need for gene-specific calibration of evidence types used for variant classification

Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification

Abstract The multifactorial likelihood analysis method has demonstrated utility for quantitative assessment of variant pathogenicity for multiple cancer syndrome genes. Independent data types currently incorporated in the model for assessing BRCA1 and BRCA2 variants include clinically calibrated prior probability of pathogenicity based on variant location and bioinformatic prediction of variant effect, co-segregation, family cancer history profile, co-occurrence with a pathogenic variant in the same gene, breast tumor pathology, and case-control information. Research and clinical data for multifactorial likelihood analysis were collated for 1395 BRCA1/2 predominantly intronic and missense variants, enabling classification based on posterior probability of pathogenicity for 734 variants: 447 variants were classified as (likely) benign, and 94 as (likely) pathogenic; 248 classifications were new or considerably altered relative to ClinVar submissions. Classifications were compared to information not yet included in the likelihood model, and evidence strengths aligned to those recommended for ACMG/AMP classification codes. Altered mRNA splicing or function relative to known non-pathogenic variant controls were moderately to strongly predictive of variant pathogenicity. Variant absence in population datasets provided supporting evidence for variant pathogenicity. These findings have direct relevance for BRCA1 and BRCA2 variant evaluation, and justify the need for gene-specific calibration of evidence types used for variant classification. This article is protected by copyright. All rights reserved.Peer reviewe

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Adult Oligodentrocyte Precursor Cells Differentiate Into Schwann Cells Following Transplantation Into Ethidium Bromide-Induced Demyelination in the Adult Rat Spinal Cord

Experimental models of spinal cord demyelination in which astrocytes are lost are primarily remyelinated by Schwann cells (SC). The source of remyelinating SCs in astrocyte-ablated spinal cord lesions has been attributed to invasion from peripheral nerve roots and peripherally innervated spinal vasculature. Recent studies, however, have demonstrated potential for postnatal CNS-derived precursors to differentiate into SCs. Moreover, we recently demonstrated adult oligodendrocyte precursor cell (OPC) recruitment in areas which eventually undergo SC remyelination after ethidium bromide (EB)-induced demyelination. To determine if adult OPCs are capable of mediating SC remyelination, purified OPCs from spinal cords of adult human-placental alkaline phosphatase (hPAP) expressing rats were obtained by immunopanning with the A2B5 antibody. FACS analysis of OPCs revealed that most cells expressed A2B5 (98%), O4 (81%), and NG2 (93%). No cells expressed the SC marker p75 indicating a lack of Schwann cell lineage contamination. OPCs were transplanted acutely (3 dpi) into EB-lesioned rat spinal cords. Immunohistochemistry for hPAP demonstrated survival and integration of transplanted OPCs within EB lesions five weeks after injury. Characteristic ringlike patterns of hPAP+ processes ensheathing NF+ axons were observed. Engrafted cells did not express markers for OPCs or astrocytes. Interestingly a significant proportion of hPAP+ processes co-labeled with the Schwann cell-specific myelin protein P0. Electron microscopic immunohistochemistry demonstrated transplanted cells ensheathing axons with a characteristic Schwann cell morphology. Present data suggest that the macroglial-free environment of acute EB lesions promotes Schwann cell-like differentiation of adult OPCs and elucidates a surprising potential for these cells

Unsupervised spectral pattern recognition by Self Organizing Maps (SOM) analysis for site effects estimation: a review

A reliable determination of the unsteady aerodynamic loads acting on the blades is essential to predict the aeroelastic stability of vibrating compressor cascades with accuracy. At transonic flow conditions, the vibration of the shock may change the blade aeroelastic behavior. Numerical tools still have difficulties to capture the physics associated to this effect. In order to increase the prediction’s accuracy, high quality experimental data at high spatial resolution is therefore required to enable the calibration and validation of these tools. Within the frame of the European project FUTURE, experimental aeroelastic investigations were performed on a transonic compressor cascade in the Non-Rotating Annular Test Facility at EPFL. Associated to the measurements, the numerical flutter prediction procedure was applied. This paper focuses on the experimental results. The experimental database gained during the project is presented and aims at helping the aeroelastic community to develop and improve their flutter prediction capabilities. The test model consists of twenty prismatic blades. Each blade of the cascade assembly was mounted on an elastic spring element enabling harmonic bending vibrations in the twenty possible cascade’s travelling wave modes. Large efforts were made to improve the measuring techniques and to provide high quality data at relatively high spatial resolution. For various sub- and transonic flow conditions, steady-state and unsteady blade surface pressure distributions were measured to evaluate the local contributions to the blade stability in terms of local aerodynamic work. The blade global aerodynamic stability is determined applying an integration of all unsteady pressure signals measured over the airfoil

Insight into microbial diversity and functions in hard-rock aquifers through high throughput sequencing

International audienc

High-thoughput sequencing to access microbial diversity and functions in hard-rock aquifers

International audienc