Comparative genome structure, secondary metabolite, and effector coding capacity across Cochliobolus pathogens.

The genomes of five Cochliobolus heterostrophus strains, two Cochliobolus sativus strains, three additional Cochliobolus species (Cochliobolus victoriae, Cochliobolus carbonum, Cochliobolus miyabeanus), and closely related Setosphaeria turcica were sequenced at the Joint Genome Institute (JGI). The datasets were used to identify SNPs between strains and species, unique genomic regions, core secondary metabolism genes, and small secreted protein (SSP) candidate effector encoding genes with a view towards pinpointing structural elements and gene content associated with specificity of these closely related fungi to different cereal hosts. Whole-genome alignment shows that three to five percent of each genome differs between strains of the same species, while a quarter of each genome differs between species. On average, SNP counts among field isolates of the same C. heterostrophus species are more than 25× higher than those between inbred lines and 50× lower than SNPs between Cochliobolus species. The suites of nonribosomal peptide synthetase (NRPS), polyketide synthase (PKS), and SSP-encoding genes are astoundingly diverse among species but remarkably conserved among isolates of the same species, whether inbred or field strains, except for defining examples that map to unique genomic regions. Functional analysis of several strain-unique PKSs and NRPSs reveal a strong correlation with a role in virulence

Histopathological findings and viral tropism in UK patients with severe fatal COVID-19: a post-mortem study

Background Severe COVID-19 has a high mortality rate. Comprehensive pathological descriptions of COVID-19 are scarce and limited in scope. We aimed to describe the histopathological findings and viral tropism in patients who died of severe COVID-19. Methods In this case series, patients were considered eligible if they were older than 18 years, with premortem diagnosis of severe acute respiratory syndrome coronavirus 2 infection and COVID-19 listed clinically as the direct cause of death. Between March 1 and April 30, 2020, full post-mortem examinations were done on nine patients with confirmed COVID-19, including sampling of all major organs. A limited autopsy was done on one additional patient. Histochemical and immunohistochemical analyses were done, and histopathological findings were reported by subspecialist pathologists. Viral quantitative RT-PCR analysis was done on tissue samples from a subset of patients. Findings The median age at death of our cohort of ten patients was 73 years (IQR 52–79). Thrombotic features were observed in at least one major organ in all full autopsies, predominantly in the lung (eight [89%] of nine patients), heart (five [56%]), and kidney (four [44%]). Diffuse alveolar damage was the most consistent lung finding (all ten patients); however, organisation was noted in patients with a longer clinical course. We documented lymphocyte depletion (particularly CD8-positive T cells) in haematological organs and haemophagocytosis. Evidence of acute tubular injury was noted in all nine patients examined. Major unexpected findings were acute pancreatitis (two [22%] of nine patients), adrenal micro-infarction (three [33%]), pericarditis (two [22%]), disseminated mucormycosis (one [10%] of ten patients), aortic dissection (one [11%] of nine patients), and marantic endocarditis (one [11%]). Viral genomes were detected outside of the respiratory tract in four of five patients. The presence of subgenomic viral RNA transcripts provided evidence of active viral replication outside the respiratory tract in three of five patients. Interpretation Our series supports clinical data showing that the four dominant interrelated pathological processes in severe COVID-19 are diffuse alveolar damage, thrombosis, haemophagocytosis, and immune cell depletion. Additionally, we report here several novel autopsy findings including pancreatitis, pericarditis, adrenal micro-infarction, secondary disseminated mucormycosis, and brain microglial activation, which require additional investigation to understand their role in COVID-19. Funding Imperial Biomedical Research Centre, Wellcome Trust, Biotechnology and Biological Sciences Research Council

The complex interplay between extracellular matrix and cells in tissues

Extracellular matrix (ECM) maintains the structural integrity of tissues and regulates cell and tissue functions. ECM is comprised of fibrillar proteins, proteoglycans (PGs), glycosaminoglycans, and glycoproteins, creating a heterogeneous but well-orchestrated network. This network communicates with resident cells via cell-surface receptors. In particular, integrins, CD44, discoidin domain receptors, and cell-surface PGs and additionally voltage-gated ion channels can interact with ECM components, regulating signaling cascades as well as cytoskeleton configuration. The interplay of ECM with recipient cells is enriched by the extracellular vesicles, as they accommodate ECM, signaling, and cytoskeleton molecules in their cargo. Along with the numerous biological properties that ECM can modify, autophagy and angiogenesis, which are critical for tissue homeostasis, are included. Throughout development and disease onset and progression, ECM endures rearrangement to fulfill cellular requirements. The main responsible molecules for tissue remodeling are ECM-degrading enzymes including matrix metalloproteinases, plasminogen activators, cathepsins, and hyaluronidases, which can modify the ECM structure and function in a dynamic mode. A brief summary of the complex interplay between ECM macromolecules and cells in tissues and the contribution of ECM in tissue homeostasis and diseases is given.Extracellular matrix (ECM) maintains the structural integrity of tissues and regulates cell and tissue functions. ECM is comprised of fibrillar proteins, proteoglycans (PGs), glycosaminoglycans, and glycoproteins, creating a heterogeneous but well-orchestrated network. This network communicates with resident cells via cell-surface receptors. In particular, integrins, CD44, discoidin domain receptors, and cell-surface PGs and additionally voltage-gated ion channels can interact with ECM components, regulating signaling cascades as well as cytoskeleton configuration. The interplay of ECM with recipient cells is enriched by the extracellular vesicles, as they accommodate ECM, signaling, and cytoskeleton molecules in their cargo. Along with the numerous biological properties that ECM can modify, autophagy and angiogenesis, which are critical for tissue homeostasis, are included. Throughout development and disease onset and progression, ECM endures rearrangement to fulfill cellular requirements. The main responsible molecules for tissue remodeling are ECM-degrading enzymes including matrix metalloproteinases, plasminogen activators, cathepsins, and hyaluronidases, which can modify the ECM structure and function in a dynamic mode. A brief summary of the complex interplay between ECM macromolecules and cells in tissues and the contribution of ECM in tissue homeostasis and diseases is given

The World Health Organization ACTION-I (Antenatal CorTicosteroids for Improving Outcomes in preterm Newborns) Trial: a multi-country, multi-centre, two-arm, parallel, double-blind, placebo-controlled, individually randomized trial of antenatal corticosteroids for women at risk of imminent birth in the early preterm period in hospitals in low-resource countries

BACKGROUND: Antenatal corticosteroids (ACS) have long been regarded as a cornerstone intervention in mitigating the adverse effects of a preterm birth. However, the safety and efficacy of ACS in hospitals in low-resource countries has not been established in an efficacy trial despite their widespread use. Findings of a large cluster-randomized trial in six low- and middle-income countries showed that efforts to scale up ACS use in low-resource settings can lead to harm. There is equipoise regarding the benefits and harms of ACS use in hospitals in low-resource countries. This randomized controlled trial aims to determine whether ACS are safe and efficacious when given to women at risk of imminent birth in the early preterm period, in hospitals in low-resource countries. METHODS/DESIGN: The trial design is a parallel, two-arm, double-blind, individually randomized, placebo-controlled trial of ACS (dexamethasone) for women at risk of imminent preterm birth. The trial will recruit 6018 women in participating hospitals across five low-resource countries (Bangladesh, India, Kenya, Nigeria and Pakistan). The primary objectives are to compare the efficacy of dexamethasone with placebo on survival of the baby and maternal infectious morbidity. The primary outcomes are: 1) neonatal death (to 28 completed days of life); 2) any baby death (any stillbirth postrandomization or neonatal death); and 3) a composite outcome to assess possible maternal bacterial infections. The trial will recruit eligible, consenting pregnant women from 26 weeks 0 days to 33 weeks 6 days gestation with confirmed live fetuses, in whom birth is planned or expected within 48 h. The intervention comprises a regimen of intramuscular dexamethasone sodium phosphate. The comparison is an identical placebo regimen (normal saline). A total of 6018 women will be recruited to detect a reduction of 15% or more in neonatal deaths in a two-sided 5% significance test with 90% power (including 10% loss to follow-up). DISCUSSION: Findings of this trial will guide clinicians, programme managers and policymakers on the safety and efficacy of ACS in hospitals in low-resource countries. The trial findings will inform updating of the World Health Organization's global recommendations on ACS use. TRIAL REGISTRATION: ACTRN12617000476336 . Registered on 31 March 2017