The Influence of a Biologically Relevant Substratum Topography on Human Aortic and Umbilical Vein Endothelial Cells

AbstractA topographically patterned substrate with stochastic surface order that closely mimics the topographic features of native basement membranes has been fabricated to investigate the influence of topographic biophysical cueing on human aortic and umbilical vein endothelial cells. The stochastic substrate was fabricated by first generating a highly porous polyelectrolyte multilayer film of poly(acrylic acid) and poly(allylamine hydrochloride) followed by replicate production of this biomimetic topography via soft lithography. These substrates, which are easy to prepare and replicate, possess a number of prominent features associated with in vivo vascular basement membrane (interwoven ridges and grooves, bumps, and pores), which have typically been studied as singular features that frequently possess anisotropic surface order (e.g., alternating ridges and grooves). When compared to a flat surface of identical chemistry, these biomimetic topographies influenced a number of important cellular behaviors associated with the homeostasis and degradation of vascular tissues. These include modulating cell migration rate and directional persistence, proliferation rate, and gene expression associated with regulation and remodeling of vascular tissues as well as inflammation

Dark Stars and Boosted Dark Matter Annihilation Rates

Dark Stars (DS) may constitute the first phase of stellar evolution, powered by dark matter (DM) annihilation. We will investigate here the properties of DS assuming the DM particle has the required properties to explain the excess positron and elec- tron signals in the cosmic rays detected by the PAMELA and FERMI satellites. Any possible DM interpretation of these signals requires exotic DM candidates, with an- nihilation cross sections a few orders of magnitude higher than the canonical value required for correct thermal relic abundance for Weakly Interacting Dark Matter can- didates; additionally in most models the annihilation must be preferentially to lep- tons. Secondly, we study the dependence of DS properties on the concentration pa- rameter of the initial DM density profile of the halos where the first stars are formed. We restrict our study to the DM in the star due to simple (vs. extended) adiabatic contraction and minimal (vs. extended) capture; this simple study is sufficient to illustrate dependence on the cross section and concentration parameter. Our basic results are that the final stellar properties, once the star enters the main sequence, are always roughly the same, regardless of the value of boosted annihilation or concentration parameter in the range between c=2 and c=5: stellar mass ~ 1000M\odot, luminosity ~ 10^7 L\odot, lifetime ~ 10^6 yrs (for the minimal DM models considered here; additional DM would lead to more massive dark stars). However, the lifetime, final mass, and final luminosity of the DS show some dependence on boost factor and concentration parameter as discussed in the paper.Comment: 37 pages, 11 figure

Production of dust by massive stars at high redshift

The large amounts of dust detected in sub-millimeter galaxies and quasars at high redshift pose a challenge to galaxy formation models and theories of cosmic dust formation. At z > 6 only stars of relatively high mass (> 3 Msun) are sufficiently short-lived to be potential stellar sources of dust. This review is devoted to identifying and quantifying the most important stellar channels of rapid dust formation. We ascertain the dust production efficiency of stars in the mass range 3-40 Msun using both observed and theoretical dust yields of evolved massive stars and supernovae (SNe) and provide analytical expressions for the dust production efficiencies in various scenarios. We also address the strong sensitivity of the total dust productivity to the initial mass function. From simple considerations, we find that, in the early Universe, high-mass (> 3 Msun) asymptotic giant branch stars can only be dominant dust producers if SNe generate <~ 3 x 10^-3 Msun of dust whereas SNe prevail if they are more efficient. We address the challenges in inferring dust masses and star-formation rates from observations of high-redshift galaxies. We conclude that significant SN dust production at high redshift is likely required to reproduce current dust mass estimates, possibly coupled with rapid dust grain growth in the interstellar medium.Comment: 72 pages, 9 figures, 5 tables; to be published in The Astronomy and Astrophysics Revie

COVID-19: Rapid antigen detection for SARS-CoV-2 by lateral flow assay: A national systematic evaluation of sensitivity and specificity for mass-testing

Background Lateral flow device (LFD) viral antigen immunoassays have been developed around the world as diagnostic tests for SARS-CoV-2 infection. They have been proposed to deliver an infrastructure-light, cost-economical solution giving results within half an hour. Methods LFDs were initially reviewed by a Department of Health and Social Care team, part of the UK government, from which 64 were selected for further evaluation from 1st August to 15th December 2020. Standardised laboratory evaluations, and for those that met the published criteria, field testing in the Falcon-C19 research study and UK pilots were performed (UK COVID-19 testing centres, hospital, schools, armed forces). Findings 4/64 LFDs so far have desirable performance characteristics (orient Gene, Deepblue, Abbott and Innova SARS-CoV-2 Antigen Rapid Qualitative Test). All these LFDs have a viral antigen detection of >90% at 100,000 RNA copies/ml. 8951 Innova LFD tests were performed with a kit failure rate of 5.6% (502/8951, 95% CI: 5.1–6.1), false positive rate of 0.32% (22/6954, 95% CI: 0.20–0.48). Viral antigen detection/sensitivity across the sampling cohort when performed by laboratory scientists was 78.8% (156/198, 95% CI 72.4–84.3). Interpretation Our results suggest LFDs have promising performance characteristics for mass population testing and can be used to identify infectious positive individuals. The Innova LFD shows good viral antigen detection/sensitivity with excellent specificity, although kit failure rates and the impact of training are potential issues. These results support the expanded evaluation of LFDs, and assessment of greater access to testing on COVID-19 transmission. Funding Department of Health and Social Care. University of Oxford. Public Health England Porton Down, Manchester University NHS Foundation Trust, National Institute of Health Research

Finding Diagnostically Useful Patterns in Quantitative Phenotypic Data.

Trio-based whole-exome sequence (WES) data have established confident genetic diagnoses in ∼40% of previously undiagnosed individuals recruited to the Deciphering Developmental Disorders (DDD) study. Here we aim to use the breadth of phenotypic information recorded in DDD to augment diagnosis and disease variant discovery in probands. Median Euclidean distances (mEuD) were employed as a simple measure of similarity of quantitative phenotypic data within sets of ≥10 individuals with plausibly causative de novo mutations (DNM) in 28 different developmental disorder genes. 13/28 (46.4%) showed significant similarity for growth or developmental milestone metrics, 10/28 (35.7%) showed similarity in HPO term usage, and 12/28 (43%) showed no phenotypic similarity. Pairwise comparisons of individuals with high-impact inherited variants to the 32 individuals with causative DNM in ANKRD11 using only growth z-scores highlighted 5 likely causative inherited variants and two unrecognized DNM resulting in an 18% diagnostic uplift for this gene. Using an independent approach, naive Bayes classification of growth and developmental data produced reasonably discriminative models for the 24 DNM genes with sufficiently complete data. An unsupervised naive Bayes classification of 6,993 probands with WES data and sufficient phenotypic information defined 23 in silico syndromes (ISSs) and was used to test a "phenotype first" approach to the discovery of causative genotypes using WES variants strictly filtered on allele frequency, mutation consequence, and evidence of constraint in humans. This highlighted heterozygous de novo nonsynonymous variants in SPTBN2 as causative in three DDD probands

Targeted Next-Generation Sequencing Analysis of 1,000 Individuals with Intellectual Disability.

To identify genetic causes of intellectual disability (ID), we screened a cohort of 986 individuals with moderate to severe ID for variants in 565 known or candidate ID-associated genes using targeted next-generation sequencing. Likely pathogenic rare variants were found in ∼11% of the cases (113 variants in 107/986 individuals: ∼8% of the individuals had a likely pathogenic loss-of-function [LoF] variant, whereas ∼3% had a known pathogenic missense variant). Variants in SETD5, ATRX, CUL4B, MECP2, and ARID1B were the most common causes of ID. This study assessed the value of sequencing a cohort of probands to provide a molecular diagnosis of ID, without the availability of DNA from both parents for de novo sequence analysis. This modeling is clinically relevant as 28% of all UK families with dependent children are single parent households. In conclusion, to diagnose patients with ID in the absence of parental DNA, we recommend investigation of all LoF variants in known genes that cause ID and assessment of a limited list of proven pathogenic missense variants in these genes. This will provide 11% additional diagnostic yield beyond the 10%-15% yield from array CGH alone.Action Medical Research (SP4640); the Birth Defect Foundation (RG45448); the Cambridge National Institute for Health Research Biomedical Research Centre (RG64219); the NIHR Rare Diseases BioResource (RBAG163); Wellcome Trust award WT091310; The Cell lines and DNA bank of Rett Syndrome, X-linked mental retardation and other genetic diseases (member of the Telethon Network of Genetic Biobanks (project no. GTB12001); the Genetic Origins of Congenital Heart Disease Study (GO-CHD)- funded by British Heart Foundation (BHF)This is the final version of the article. It first appeared from Wiley via http://dx.doi.org/10.1002/humu.2290

Supernova remnants: the X-ray perspective

Supernova remnants are beautiful astronomical objects that are also of high scientific interest, because they provide insights into supernova explosion mechanisms, and because they are the likely sources of Galactic cosmic rays. X-ray observations are an important means to study these objects.And in particular the advances made in X-ray imaging spectroscopy over the last two decades has greatly increased our knowledge about supernova remnants. It has made it possible to map the products of fresh nucleosynthesis, and resulted in the identification of regions near shock fronts that emit X-ray synchrotron radiation. In this text all the relevant aspects of X-ray emission from supernova remnants are reviewed and put into the context of supernova explosion properties and the physics and evolution of supernova remnants. The first half of this review has a more tutorial style and discusses the basics of supernova remnant physics and thermal and non-thermal X-ray emission. The second half offers a review of the recent advances.The topics addressed there are core collapse and thermonuclear supernova remnants, SN 1987A, mature supernova remnants, mixed-morphology remnants, including a discussion of the recent finding of overionization in some of them, and finally X-ray synchrotron radiation and its consequences for particle acceleration and magnetic fields.Comment: Published in Astronomy and Astrophysics Reviews. This version has 2 column-layout. 78 pages, 42 figures. This replaced version has some minor language edits and several references have been correcte

Prevalence and architecture of de novo mutations in developmental disorders.

The genomes of individuals with severe, undiagnosed developmental disorders are enriched in damaging de novo mutations (DNMs) in developmentally important genes. Here we have sequenced the exomes of 4,293 families containing individuals with developmental disorders, and meta-analysed these data with data from another 3,287 individuals with similar disorders. We show that the most important factors influencing the diagnostic yield of DNMs are the sex of the affected individual, the relatedness of their parents, whether close relatives are affected and the parental ages. We identified 94 genes enriched in damaging DNMs, including 14 that previously lacked compelling evidence of involvement in developmental disorders. We have also characterized the phenotypic diversity among these disorders. We estimate that 42% of our cohort carry pathogenic DNMs in coding sequences; approximately half of these DNMs disrupt gene function and the remainder result in altered protein function. We estimate that developmental disorders caused by DNMs have an average prevalence of 1 in 213 to 1 in 448 births, depending on parental age. Given current global demographics, this equates to almost 400,000 children born per year

Self-Reported Wisdom and Happiness: An Empirical Investigation

Possible tensions between wisdom and happiness have been extensively debated in philosophy. Some regard wisdom as the 'supreme part of happiness', whereas other think that a more accurate and wiser view on reality might reduce happiness. Analyzing a Dutch internet survey of 7037 respondents, we discovered that wisdom and happiness were modestly positively related. Wisdom, measured with the Three-Dimensional Wisdom Scale (3D-WS), explained 9.2% of the variation in hedonic happiness. The correlation with the reflective dimension of wisdom was the strongest. In addition, wisdom was more important for happiness among adults with only an elementary education. Our results suggest that happiness and wisdom do not conflict

Dust in Supernovae and Supernova Remnants II: Processing and survival

Observations have recently shown that supernovae are efficient dust factories, as predicted for a long time by theoretical models. The rapid evolution of their stellar progenitors combined with their efficiency in precipitating refractory elements from the gas phase into dust grains make supernovae the major potential suppliers of dust in the early Universe, where more conventional sources like Asymptotic Giant Branch (AGB) stars did not have time to evolve. However, dust yields inferred from observations of young supernovae or derived from models do not reflect the net amount of supernova-condensed dust able to be expelled from the remnants and reach the interstellar medium. The cavity where the dust is formed and initially resides is crossed by the high velocity reverse shock which is generated by the pressure of the circumstellar material shocked by the expanding supernova blast wave. Depending on grain composition and initial size, processing by the reverse shock may lead to substantial dust erosion and even complete destruction. The goal of this review is to present the state of the art about processing and survival of dust inside supernova remnants, in terms of theoretical modelling and comparison to observations