Structure of a tryptophanyl-tRNA synthetase containing an iron–sulfur cluster

The crystal structure of tryptophanyl-tRNA synthetase from T. maritima unexpectedly revealed an iron–sulfur cluster bound to the tRNA anticodon-binding region

Human and mouse essentiality screens as a resource for disease gene discovery

The identification of causal variants in sequencing studies remains a considerable challenge that can be partially addressed by new gene-specific knowledge. Here, we integrate measures of how essential a gene is to supporting life, as inferred from viability and phenotyping screens performed on knockout mice by the International Mouse Phenotyping Consortium and essentiality screens carried out on human cell lines. We propose a cross-species gene classification across the Full Spectrum of Intolerance to Loss-of-function (FUSIL) and demonstrate that genes in five mutually exclusive FUSIL categories have differing biological properties. Most notably, Mendelian disease genes, particularly those associated with developmental disorders, are highly overrepresented among genes non-essential for cell survival but required for organism development. After screening developmental disorder cases from three independent disease sequencing consortia, we identify potentially pathogenic variants in genes not previously associated with rare diseases. We therefore propose FUSIL as an efficient approach for disease gene discovery. Discovery of causal variants for monogenic disorders has been facilitated by whole exome and genome sequencing, but does not provide a diagnosis for all patients. Here, the authors propose a Full Spectrum of Intolerance to Loss-of-Function (FUSIL) categorization that integrates gene essentiality information to aid disease gene discovery

The IDENTIFY study: the investigation and detection of urological neoplasia in patients referred with suspected urinary tract cancer - a multicentre observational study

Objective To evaluate the contemporary prevalence of urinary tract cancer (bladder cancer, upper tract urothelial cancer [UTUC] and renal cancer) in patients referred to secondary care with haematuria, adjusted for established patient risk markers and geographical variation. Patients and Methods This was an international multicentre prospective observational study. We included patients aged ≥16 years, referred to secondary care with suspected urinary tract cancer. Patients with a known or previous urological malignancy were excluded. We estimated the prevalence of bladder cancer, UTUC, renal cancer and prostate cancer; stratified by age, type of haematuria, sex, and smoking. We used a multivariable mixed-effects logistic regression to adjust cancer prevalence for age, type of haematuria, sex, smoking, hospitals, and countries. Results Of the 11 059 patients assessed for eligibility, 10 896 were included from 110 hospitals across 26 countries. The overall adjusted cancer prevalence (n = 2257) was 28.2% (95% confidence interval [CI] 22.3–34.1), bladder cancer (n = 1951) 24.7% (95% CI 19.1–30.2), UTUC (n = 128) 1.14% (95% CI 0.77–1.52), renal cancer (n = 107) 1.05% (95% CI 0.80–1.29), and prostate cancer (n = 124) 1.75% (95% CI 1.32–2.18). The odds ratios for patient risk markers in the model for all cancers were: age 1.04 (95% CI 1.03–1.05; P < 0.001), visible haematuria 3.47 (95% CI 2.90–4.15; P < 0.001), male sex 1.30 (95% CI 1.14–1.50; P < 0.001), and smoking 2.70 (95% CI 2.30–3.18; P < 0.001). Conclusions A better understanding of cancer prevalence across an international population is required to inform clinical guidelines. We are the first to report urinary tract cancer prevalence across an international population in patients referred to secondary care, adjusted for patient risk markers and geographical variation. Bladder cancer was the most prevalent disease. Visible haematuria was the strongest predictor for urinary tract cancer

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

A prenylated dsRNA sensor protects against severe COVID-19

Inherited genetic factors can influence the severity of COVID-19, but the molecular explanation underpinning a genetic association is often unclear. Intracellular antiviral defenses can inhibit the replication of viruses and reduce disease severity. To better understand the antiviral defenses relevant to COVID-19, we used interferon-stimulated gene (ISG) expression screening to reveal that OAS1, through RNase L, potently inhibits SARS-CoV-2. We show that a common splice-acceptor SNP (Rs10774671) governs whether people express prenylated OAS1 isoforms that are membrane-associated and sense specific regions of SARS-CoV-2 RNAs, or only express cytosolic, nonprenylated OAS1 that does not efficiently detect SARS-CoV-2. Importantly, in hospitalized patients, expression of prenylated OAS1 was associated with protection from severe COVID-19, suggesting this antiviral defense is a major component of a protective antiviral response

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

Rivers need floods: Management lessons learnt from the regulation of the Norwegian salmon river, Suldalslågen

The Norwegian river Suldalslågen, known for its population of large‐sized Atlantic salmon (Salmo salar ), has been regulated for hydropower in 1966–1967 and in 1980. The initial regulation increased winter flows and reduced summer flows and major floods. The second regulation, involving abstraction of water to a power station in an adjacent fjord, led to a strong reduction in flow. In addition to implementing different flow regimes, many remedial actions have been taken, often concurrently, making it almost impossible to detect the effect of single measures. In addition, the monitoring data have not always been consistent as regards methods and scope, and also, few data are available for preregulation conditions. This highlights major challenges in the long‐term management of regulated rivers. The absence of major floods after regulation led to increased sedimentation and encouraged carpet mosses. This reduced interstitial spaces, creating a poor habitat for salmon fry and benthic invertebrates. The knowledge gained from the wide‐ranging studies of the different flow regimes have enabled the environmental authorities to devise a final regulation regime from 2012. The final flow regime focused on biological values and functions to sustain the strain of wild, large adult salmon. The catch of wild salmon >7 kg has in fact increased since 2010 and stabilized between 1 and 2 metric tons, although the yield of large salmon prior to 1994 is unknown. In addition, the increase in the catch of large salmon is based on hatchery fish. Hatchery fish have also to a large extent contributed to the increase in the total salmon catch in recent years. Thus, that the catches in Suldalslågen are now at an all‐time high is not due to improved conditions in the river but likely to hatchery fish

Diverging life cycle patterns of two Diamesa species (Diptera, Chironomidae) in High Arctic streams, Svalbard

Abstract The fauna of streams in the High Arctic, dominated by chironomids, is shaped by extreme environmental conditions that represent the physiological limits for benthic invertebrates. Despite their ecological importance, little is known of chironomid life histories, development strategies and the key abiotic drivers limiting larval growth in High Arctic streams. We investigated the larval development and growth in three High Arctic rivers with contrasting water sources, thermal regimes and nutrient characteristics. Populations of the larvae of Diamesa bohemani (Goetghebuer 1932) and Diamesa aberrata (Lundbeck 1898) from two sampling occasions in July and August 2016 were morphometrically analysed to determine life history patterns and instream productivity. Water temperature differences lead to diverging development patterns on local spatial scales. The lowest larval growth was in a groundwater/snowmelt fed stream with low food concentration and quality, suggesting that stream productivity is not primarily water source dependant, but is dependent on the nutrient supply. Glacially influenced streams are clearly more productive than previously assumed, resulting in comparable secondary production to groundwater/snowmelt-fed streams

Hydropower‐driven thermal changes, biological responses and mitigating measures in northern river systems

Water temperatures control life histories and diversity of aquatic species. Hydropowerregulation, particularly in high head systems, alters natural water temperature regimes,which may have profound and long-term impacts on aquatic environments. Tempera-tures in by-pass sections and reaches affected by residual/environmental minimum flowsfluctuate more than in natural flow regimes, driven more by influence of air tempera-tures. Reaches downstream of power plant outlets tend to become warmer in winter andcolder in summer, driven by stratification behind the reservoir dam. In hydro-peaked sys-tems high-low temperature effects may thus be aggravated. We review alterations ofhydropower to natural thermal regimes, impacts on key organisms in terms of survival,development and behavioral thresholds, and potential mitigation measures, with focus onAtlantic salmon and brown trout in high northern latitude stream systems. Previous syn-theses have focused mainly on flow changes and ecological impacts. Temperature effectsmay not always be correlated with flow changes, although there are some unique chal-lenges with temperature changes in far northern latitudes, for example, related to theseasonal and colder climates. To help knowledge-based management and identify poten-tial knowledge gaps, we review how hydropower regulation may impact seasonal watertemperatures, what impacts changes to stream system temperature regimes may have tokey organisms, for example, Atlantic salmon and brown trout, and what adaptations andbehavioral variations they may exhibit to respond to changed temperature regimes, andfinally what good practices can be recommended for mitigating temperature impacts.This synthesis indicates that there are impacts to the fish and their supporting food webs,in particular related to growth and development, and the potential for negative impactsseems higher, and better studied, than positive impacts in northern river systems. Someof these impacts may be modified by directed hydropower regulation practices, but hereeffect studies and knowledge are limited.publishedVersio

Aquatic biodiversity in sedimentation ponds receiving road runoff - What are the key drivers?

This is an Accepted Manuscript of an article published by Elsevier in Science of the Total Environment, available online: https://www.elsevier.com/Recently, increased attention has been paid to biodiversity conservation provided by blue-green solutions such as engineered ponds that are primarily established for water treatment and flood control. However, little research has been done to analyse the factors that affect biodiversity in such ponds. The purpose of this study was to evaluate the influence of environmental factors on aquatic biodiversity, mainly macroinvertebrate communities, in road sedimentation ponds in order to provide a foundation for recommendations on aquatic biodiversity conservation. Multivariate statistical methods, including unconstrained and constrained analysis, were applied to examine the relationships between organisms and the water quality as well as physical factors (including plant cover). Stepwise multiple regressions indicated that the most important variables governing the variation in the biological community composition were pond size, average annual daily traffic, metals, chloride, distance to the closest pond from study pond, dissolved oxygen, hydrocarbons, and phosphorus. The presence of most taxa was positively correlated with pond size and negatively correlated with metals. Small ponds with high pollutant loadings were associated with a low diversity and dominated by a few pollution tolerant taxa such as oligochaetes. A comprehensive understanding of impacts of various environmental factors on aquatic biodiversity is important to effectively promote and conserve aquatic biodiversity in such sedimentation ponds. Our results indicate that road sedimentation ponds should be designed large enough, because large ponds are likely to provide a more heterogeneous habitat and thus contain a species rich fauna. In addition, larger ponds seem to be less contaminated due to dilution compared to smaller ponds, thereby maintaining a higher biodiversity. Finally, creating some additional ponds in the vicinity of the sedimentation ponds in areas with few water bodies would increase the connectivity that facilitates the movement of invertebrates between ponds.acceptedVersio