Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Common, low-frequency, rare, and ultra-rare coding variants contribute to COVID-19 severity

The combined impact of common and rare exonic variants in COVID-19 host genetics is currently insufficiently understood. Here, common and rare variants from whole-exome sequencing data of about 4000 SARS-CoV-2-positive individuals were used to define an interpretable machine-learning model for predicting COVID-19 severity. First, variants were converted into separate sets of Boolean features, depending on the absence or the presence of variants in each gene. An ensemble of LASSO logistic regression models was used to identify the most informative Boolean features with respect to the genetic bases of severity. The Boolean features selected by these logistic models were combined into an Integrated PolyGenic Score that offers a synthetic and interpretable index for describing the contribution of host genetics in COVID-19 severity, as demonstrated through testing in several independent cohorts. Selected features belong to ultra-rare, rare, low-frequency, and common variants, including those in linkage disequilibrium with known GWAS loci. Noteworthily, around one quarter of the selected genes are sex-specific. Pathway analysis of the selected genes associated with COVID-19 severity reflected the multi-organ nature of the disease. The proposed model might provide useful information for developing diagnostics and therapeutics, while also being able to guide bedside disease management. © 2021, The Author(s)

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice

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

The effect of temperature and strain rate on the deformation behaviour, structure development and properties of biaxially stretched PET-clay nanocomposites.

International audienceThe inclusion of a synthetic fluoromica clay in PET affects its processability via biaxial stretching and stretching temperature (95 °C and 102 °C) and strain rate (1 s and 2 s) influence the structuring and properties of the stretched material. The inclusion of clay has little effect on the temperature operating window for the PET-clay but it has a major effect on deformation behavior which will necessitate the use of much higher forming forces during processing. The strain hardening behavior of both the filled and unfilled materials is well correlated with tensile strength and tensile modulus. Increasing the stretching temperature to reduce stretching forces has a detrimental effect on clay exfoliation, mechanical and O barrier properties. Increasing strain rate has a lesser effect on the strain hardening behavior of the PET-clay compared with the pure PET and this is attributed to possible adiabatic heating in the PET-clay sample at the higher strain rate. The Halpin-Tsai model is shown to accurately predict the modulus enhancement of the PET-clay materials when a modified particle modulus rather than nominal clay modulus is used

Quasi-solid state uniaxial and biaxial deformation of PET/MWCNT composites: structural evolution, electrical and mechanical properties

Composites of multi-walled carbon nanotubes (MWCNTs) and a poly(ethylene terephthalate)(PET), prepared by melt mixing, were uniaxially and biaxially deformed at 100 degrees C using a strain rate of 2 s(-1) and at stretch ratios (SR) up to 2. A hierarchical organization of randomly well dispersed and distributed agglomerates, smaller bundles and individual MWCNTs was identified in the as extruded composite from extensive microscopic examination across the length scales using polarised optical microscopy (POM), field emission scanning electron microscopy (FESEM) and high resolution transmission electron microscopy (HRTEM). Evidence from X-ray diffraction (XRD) and differential scanning calorimetry (DSC) confirmed the MWCNTs induced crystallization via a heterogeneous mechanism and altered the crystallization behaviour of PET. Uniaxial deformation of the composite materials resulted in orientation of the MWCNTs in the direction parallel to the applied strain and for biaxial deformation at an angle approaching 45 degrees to the vertical axis (extrusion direction), evidence for the latter obtained by HRTEM and from small angle X-ray scattering experiments (SAXS). In both instances, XRD and DSC confirmed the occurrence of significant strain induced crystallization resulting in large increases in tensile mechanical properties. Evidence from wide angle X-ray scattering experiments (WAXS), supported by XRD and DSC showed the overall crystalline content and degree of long-range ordering increased with MWCNT addition. The decrease in diffraction (SAXS) associated with lamella spacing implies the MWCNTs disrupt formation of lamella and reside in the inter-lamellar spacing. Annealing the composites, particularly at T-m -50 degrees C, results in an increase in PET crystalline content. Prior to deformation the MWCNTs formed an electrically conducting interconnected network throughout the PET matrix, however, this was partially destroyed when the composite was uniaxially or biaxially deformed, as the probability of conductor-conductor contacts decreased. It was possible to restore a MWCNT conducting network similar to that achieved prior to uniaxial deformation only by annealing the sample at T-m -50 degrees C

Composites of poly(ε-caprolactone) and Mo6S3I6 Nanowires

Composites of poly(ε-caprolactone) (PCL) and molybdenum sulfur iodine (MoSI) nanowires were prepared using twin-screw extrusion. Extensive microscopic examination of the composites revealed the nanowires were well dispersed in the PCL matrix, although bundles of Mo6S3I6 ropes were evident at higher loadings. Secondary electron imaging (SEI) showed the nanowires had formed an extensive network throughout the PCL matrix, resulting in increased electrical conductivity of PCL, by eight orders of magnitude, and an electrical percolation threshold of 6.5 × 10−3 vol%. Thermal analysis (DSC), WAXD, and hot stage polarized optical microscopy (HSPOM) experiments revealed Mo6S3I6 addition altered PCL crystallization kinetics, nucleation density, and crystalline content. A greater number of smaller spherulites were formed via heterogeneous nucleation. The onset of thermal decomposition (TGA) of PCL decreased by 70°C, a consequence of the thermal degradation of Mo6S3I6 to MoO3, which in turn accelerates the formation of volatile gases during the first stage of PCL decomposition

Quantitative characterization of clay dispersion in polypropylene-clay nanocomposites by combined transmission electron microscopy and optical microscopy

This paper presents a novel method to describe the microstructure of polymer/clay nanocomposites quantitatively. Based on the image analyses of transmission electron microscopy (TEM) and optical microscopy micrographs, two parameters, degree of dispersion (χ) and mean interparticle distance per unit volume of clay (λV) are proposed to describe the level of clay dispersion. The degree of dispersion gives the percentage of exfoliation, and λV is a measure of spatial separation between particles relative to clay loading. A polypropylene/clay system was chosen as an example to show the effects of processing conditions and biaxial stretching on clay dispersion using the proposed quantifiers. It provides insights into the ‘real’ clay dispersion using a combination of both microscopical and macroscopical aspects