Mutually Beneficial Combination of Molecular Dynamics Computer Simulations and Scattering Experiments

We showcase the combination of experimental neutron scattering data and molecular dynamics (MD) simulations for exemplary phospholipid membrane systems. Neutron and X-ray reflectometry and small-angle scattering measurements are determined by the scattering length density profile in real space, but it is not usually possible to retrieve this profile unambiguously from the data alone. MD simulations predict these density profiles, but they require experimental control. Both issues can be addressed simultaneously by cross-validating scattering data and MD results. The strengths and weaknesses of each technique are discussed in detail with the aim of optimizing the opportunities provided by this combination

Temperature Anomalies and Mortality Events in Marine Communities: Insights on Factors behind Differential Mortality Impacts in the NW Mediterranean

Two large-scale mass mortality events (MMEs) of unprecedented extent and severity affecting rocky benthic communities occurred during the summers of 1999 and 2003 along the coasts of the NW Mediterranean Sea. These mortality outbreaks were associated with positive thermal anomalies. In this study, we performed an analysis of inter-regional and inter-annual differences in temperature (T) conditions associated with MMEs of the red gorgonian Paramuricea clavata by analyzing high resolution T time series (hourly records for 3 to 8 years) from four regions of the NW Mediterranean with differing hydrological conditions and biological impacts. High resolution records allowed a detailed analysis using classical and new descriptors to characterize T anomalies. We were able to determine that the MMEs were triggered by two main types of positive thermal anomalies, with the first type being characterized by short periods (2 to 5 days) with high Mean T reaching more than 27°C in some regions and being associated with high intra-day and intra-period variability, while the second type of anomaly presented long duration (near one month) at warm T (24°C) with low intra-period variability. Inter-regional patterns arose; some regions displayed both types of anomalies, while others exhibited only one type. The results showed that T conditions should be considered as the main factor that explains the observed inter-regional and inter-annual differences in mortality impacts. In explaining these differences, the late timing of T anomalies, in addition to their magnitude was found to be determinant. Finally, by combining thermotolerance experimental data with the maximal T stress conditions observed in the four regions, we were able to determine the differential risk of mass mortality across regions. We conclude that expanding high resolution T series is important for the development of sound management and conservation plans to protect Mediterranean marine biodiversity in the face of climate change

Follow-up analyses to the O3 LIGO-Virgo-KAGRA lensing searches

Along their path from source to observer, gravitational waves may be gravitationally lensed by massive objects. This results in distortions of the observed signal which can be used to extract new information about fundamental physics, astrophysics, and cosmology. Searches for these distortions amongst the observed signals from the current detector network have already been carried out, though there have as yet been no confident detections. However, predictions of the observation rate of lensing suggest detection in the future is a realistic possibility. Therefore, preparations need to be made to thoroughly investigate the candidate lensed signals. In this work, we present some of the follow-up analyses and strategies that could be applied to assess the significance of such events and ascertain what information may be extracted about the lens-source system from such candidate signals by applying them to a number of O3 candidate events, even if these signals did not yield a high significance for any of the lensing hypotheses. For strongly-lensed candidates, we verify their significance using a background of simulated unlensed events and statistics computed from lensing catalogs. We also look for potential electromagnetic counterparts. In addition, we analyse in detail a candidate for a strongly-lensed sub-threshold counterpart that is identified by a new method. For microlensing candidates, we perform model selection using a number of lens models to investigate our ability to determine the mass density profile of the lens and constrain the lens parameters. We also look for millilensing signatures in one of the lensed candidates. Applying these additional analyses does not lead to any additional evidence for lensing in the candidates that have been examined. However, it does provide important insight into potential avenues to deal with high-significance candidates in future observations.Comment: 34 pages, 27 figure

Endogenous Retinoic Acid Activity in Principal Cells and Intercalated Cells of Mouse Collecting Duct System

Background: Retinoic acid is the bioactive derivative of vitamin A, which plays an indispensible role in kidney development by activating retinoic acid receptors. Although the location, concentration and roles of endogenous retinoic acid in postnatal kidneys are poorly defined, there is accumulating evidence linking post-natal vitamin A deficiency to impaired renal concentrating and acidifying capacity associated with increased susceptibility to urolithiasis, renal inflammation and scarring. The aim of this study is to examine the presence and the detailed localization of endogenous retinoic acid activity in neonatal, young and adult mouse kidneys, to establish a fundamental ground for further research into potential target genes, as well as physiological and pathophysiological roles of endogenous retinoic acid in the post-natal kidneys.Methodology/Principal Findings: RARE-hsp68-lacZ transgenic mice were employed as a reporter for endogenous retinoic acid activity that was determined by X-gal assay and immunostaining of the reporter gene product, beta-galactosidase. Double immunostaining was performed for beta-galactosidase and markers of kidney tubules to localize retinoic acid activity. Distinct pattern of retinoic acid activity was observed in kidneys, which is higher in neonatal and 1- to 3-week-old mice than that in 5- and 8-week-old mice. The activity was present specifically in the principal cells and the intercalated cells of the collecting duct system in all age groups, but was absent from the glomeruli, proximal tubules, thin limbs of Henle's loop and distal tubules.Conclusions/Significance: Endogenous retinoic acid activity exists in principal cells and intercalated cells of the mouse collecting duct system after birth and persists into adulthood. This observation provides novel insights into potential roles for endogenous retinoic acid beyond nephrogenesis and warrants further studies to investigate target genes and functions of endogenous retinoic acid in the kidney after birth, particularly in the collecting duct system

Pf7: an open dataset of Plasmodium falciparum genome variation in 20,000 worldwide samples

We describe the MalariaGEN Pf7 data resource, the seventh release of Plasmodium falciparum genome variation data from the MalariaGEN network.  It comprises over 20,000 samples from 82 partner studies in 33 countries, including several malaria endemic regions that were previously underrepresented.  For the first time we include dried blood spot samples that were sequenced after selective whole genome amplification, necessitating new methods to genotype copy number variations.  We identify a large number of newly emerging crt mutations in parts of Southeast Asia, and show examples of heterogeneities in patterns of drug resistance within Africa and within the Indian subcontinent.  We describe the profile of variations in the C-terminal of the csp gene and relate this to the sequence used in the RTS,S and R21 malaria vaccines.  Pf7 provides high-quality data on genotype calls for 6 million SNPs and short indels, analysis of large deletions that cause failure of rapid diagnostic tests, and systematic characterisation of six major drug resistance loci, all of which can be freely downloaded from the MalariaGEN website

Para-infectious brain injury in COVID-19 persists at follow-up despite attenuated cytokine and autoantibody responses

To understand neurological complications of COVID-19 better both acutely and for recovery, we measured markers of brain injury, inflammatory mediators, and autoantibodies in 203 hospitalised participants; 111 with acute sera (1–11 days post-admission) and 92 convalescent sera (56 with COVID-19-associated neurological diagnoses). Here we show that compared to 60 uninfected controls, tTau, GFAP, NfL, and UCH-L1 are increased with COVID-19 infection at acute timepoints and NfL and GFAP are significantly higher in participants with neurological complications. Inflammatory mediators (IL-6, IL-12p40, HGF, M-CSF, CCL2, and IL-1RA) are associated with both altered consciousness and markers of brain injury. Autoantibodies are more common in COVID-19 than controls and some (including against MYL7, UCH-L1, and GRIN3B) are more frequent with altered consciousness. Additionally, convalescent participants with neurological complications show elevated GFAP and NfL, unrelated to attenuated systemic inflammatory mediators and to autoantibody responses. Overall, neurological complications of COVID-19 are associated with evidence of neuroglial injury in both acute and late disease and these correlate with dysregulated innate and adaptive immune responses acutely

Effect of remote ischaemic conditioning on clinical outcomes in patients with acute myocardial infarction (CONDI-2/ERIC-PPCI): a single-blind randomised controlled trial.

BACKGROUND: Remote ischaemic conditioning with transient ischaemia and reperfusion applied to the arm has been shown to reduce myocardial infarct size in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). We investigated whether remote ischaemic conditioning could reduce the incidence of cardiac death and hospitalisation for heart failure at 12 months. METHODS: We did an international investigator-initiated, prospective, single-blind, randomised controlled trial (CONDI-2/ERIC-PPCI) at 33 centres across the UK, Denmark, Spain, and Serbia. Patients (age >18 years) with suspected STEMI and who were eligible for PPCI were randomly allocated (1:1, stratified by centre with a permuted block method) to receive standard treatment (including a sham simulated remote ischaemic conditioning intervention at UK sites only) or remote ischaemic conditioning treatment (intermittent ischaemia and reperfusion applied to the arm through four cycles of 5-min inflation and 5-min deflation of an automated cuff device) before PPCI. Investigators responsible for data collection and outcome assessment were masked to treatment allocation. The primary combined endpoint was cardiac death or hospitalisation for heart failure at 12 months in the intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT02342522) and is completed. FINDINGS: Between Nov 6, 2013, and March 31, 2018, 5401 patients were randomly allocated to either the control group (n=2701) or the remote ischaemic conditioning group (n=2700). After exclusion of patients upon hospital arrival or loss to follow-up, 2569 patients in the control group and 2546 in the intervention group were included in the intention-to-treat analysis. At 12 months post-PPCI, the Kaplan-Meier-estimated frequencies of cardiac death or hospitalisation for heart failure (the primary endpoint) were 220 (8·6%) patients in the control group and 239 (9·4%) in the remote ischaemic conditioning group (hazard ratio 1·10 [95% CI 0·91-1·32], p=0·32 for intervention versus control). No important unexpected adverse events or side effects of remote ischaemic conditioning were observed. INTERPRETATION: Remote ischaemic conditioning does not improve clinical outcomes (cardiac death or hospitalisation for heart failure) at 12 months in patients with STEMI undergoing PPCI. FUNDING: British Heart Foundation, University College London Hospitals/University College London Biomedical Research Centre, Danish Innovation Foundation, Novo Nordisk Foundation, TrygFonden