The Very Large Array Sky Survey (VLASS) is a synoptic, all-sky radio sky survey with a unique combination of high angular resolution ( 2 5), sensitivity (a 1 goal of 70 Jy/beam in the coadded data), ...full linear Stokes polarimetry, time domain coverage, and wide bandwidth (2-4 GHz). The first observations began in 2017 September, and observing for the survey will finish in 2024. VLASS will use approximately 5500 hr of time on the Karl G. Jansky Very Large Array (VLA) to cover the whole sky visible to the VLA (decl. > −40°), a total of 33 885 deg 2 . The data will be taken in three epochs to allow the discovery of variable and transient radio sources. The survey is designed to engage radio astronomy experts, multi-wavelength astronomers, and citizen scientists alike. By utilizing an "on the fly" interferometry mode, the observing overheads are much reduced compared to a conventional pointed survey. In this paper, we present the science case and observational strategy for the survey, and also results from early survey observations.
B cells are important in the pathogenesis of many, and perhaps all, immune-mediated diseases. Each B cell expresses a single B cell receptor (BCR)
, and the diverse range of BCRs expressed by the ...total B cell population of an individual is termed the 'BCR repertoire'. Our understanding of the BCR repertoire in the context of immune-mediated diseases is incomplete, and defining this could provide new insights into pathogenesis and therapy. Here, we compared the BCR repertoire in systemic lupus erythematosus, anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, Crohn's disease, Behçet's disease, eosinophilic granulomatosis with polyangiitis, and immunoglobulin A (IgA) vasculitis by analysing BCR clonality, use of immunoglobulin heavy-chain variable region (IGHV) genes and-in particular-isotype use. An increase in clonality in systemic lupus erythematosus and Crohn's disease that was dominated by the IgA isotype, together with skewed use of the IGHV genes in these and other diseases, suggested a microbial contribution to pathogenesis. Different immunosuppressive treatments had specific and distinct effects on the repertoire; B cells that persisted after treatment with rituximab were predominately isotype-switched and clonally expanded, whereas the inverse was true for B cells that persisted after treatment with mycophenolate mofetil. Our comparative analysis of the BCR repertoire in immune-mediated disease reveals a complex B cell architecture, providing a platform for understanding pathological mechanisms and designing treatment strategies.
Impact of Boreal Forest Fire on Climate Warming Randerson, J.T; Liu, H; Flanner, M.G ...
Science (American Association for the Advancement of Science),
11/2006, Volume:
314, Issue:
5802
Journal Article
Peer reviewed
Open access
We report measurements and analysis of a boreal forest fire, integrating the effects of greenhouse gases, aerosols, black carbon deposition on snow and sea ice, and postfire changes in surface ...albedo. The net effect of all agents was to increase radiative forcing during the first year (34 ± 31 Watts per square meter of burned area), but to decrease radiative forcing when averaged over an 80-year fire cycle (-2.3 ± 2.2 Watts per square meter) because multidecadal increases in surface albedo had a larger impact than fire-emitted greenhouse gases. This result implies that future increases in boreal fire may not accelerate climate warming.
Previous studies have reported national and regional Global Burden of Disease (GBD) estimates for the UK. Because of substantial variation in health within the UK, action to improve it requires ...comparable estimates of disease burden and risks at country and local levels. The slowdown in the rate of improvement in life expectancy requires further investigation. We use GBD 2016 data on mortality, causes of death, and disability to analyse the burden of disease in the countries of the UK and within local authorities in England by deprivation quintile.
We extracted data from the GBD 2016 to estimate years of life lost (YLLs), years lived with disability (YLDs), disability-adjusted life-years (DALYs), and attributable risks from 1990 to 2016 for England, Scotland, Wales, Northern Ireland, the UK, and 150 English Upper-Tier Local Authorities. We estimated the burden of disease by cause of death, condition, year, and sex. We analysed the association between burden of disease and socioeconomic deprivation using the Index of Multiple Deprivation. We present results for all 264 GBD causes of death combined and the leading 20 specific causes, and all 84 GBD risks or risk clusters combined and 17 specific risks or risk clusters.
The leading causes of age-adjusted YLLs in all UK countries in 2016 were ischaemic heart disease, lung cancers, cerebrovascular disease, and chronic obstructive pulmonary disease. Age-standardised rates of YLLs for all causes varied by two times between local areas in England according to levels of socioeconomic deprivation (from 14 274 per 100 000 population 95% uncertainty interval 12 791–15 875 in Blackpool to 6888 6145–7739 in Wokingham). Some Upper-Tier Local Authorities, particularly those in London, did better than expected for their level of deprivation. Allowing for differences in age structure, more deprived Upper-Tier Local Authorities had higher attributable YLLs for most major risk factors in the GBD. The population attributable fractions for all-cause YLLs for individual major risk factors varied across Upper-Tier Local Authorities. Life expectancy and YLLs have improved more slowly since 2010 in all UK countries compared with 1990–2010. In nine of 150 Upper-Tier Local Authorities, YLLs increased after 2010. For attributable YLLs, the rate of improvement slowed most substantially for cardiovascular disease and breast, colorectal, and lung cancers, and showed little change for Alzheimer's disease and other dementias. Morbidity makes an increasing contribution to overall burden in the UK compared with mortality. The age-standardised UK DALY rate for low back and neck pain (1795 1258–2356) was higher than for ischaemic heart disease (1200 1155–1246) or lung cancer (660 642–679). The leading causes of ill health (measured through YLDs) in the UK in 2016 were low back and neck pain, skin and subcutaneous diseases, migraine, depressive disorders, and sense organ disease. Age-standardised YLD rates varied much less than equivalent YLL rates across the UK, which reflects the relative scarcity of local data on causes of ill health.
These estimates at local, regional, and national level will allow policy makers to match resources and priorities to levels of burden and risk factors. Improvement in YLLs and life expectancy slowed notably after 2010, particularly in cardiovascular disease and cancer, and targeted actions are needed if the rate of improvement is to recover. A targeted policy response is also required to address the increasing proportion of burden due to morbidity, such as musculoskeletal problems and depression. Improving the quality and completeness of available data on these causes is an essential component of this response.
Bill & Melinda Gates Foundation and Public Health England.
Aims
To perform meta‐analyses of studies evaluating the risk of pre‐eclampsia in high‐risk insulin‐resistant women taking metformin prior to, or during pregnancy.
Methods
A search was conducted of ...the Medline, EMBASE, Web of Science and Scopus databases. Both randomized controlled trials and prospective observational cohort studies of metformin treatment vs. placebo/control or insulin either prior to or during pregnancy were selected. The main outcome measure was the incidence of pre‐eclampsia in each treatment group.
Results
Overall, in five randomized controlled trials comparing metformin treatment (n = 611) with placebo/control (n = 609), no difference in the risk of pre‐eclampsia was found combined/pooled risk ratio (RR), 0.86 (95% CI 0.33–2.26); P = 0.76; I2 = 66%. Meta‐analysis of four cohort studies again showed no significant effect RR, 1.21 (95% CI 0.56–2.61); P = 0.62; I2 = 30%. A meta‐analysis of eight randomized controlled trials comparing metformin (n = 838) with insulin (n = 836), however, showed a reduced risk of pre‐eclampsia with metformin RR, 0.68 (95% CI 0.48–0.95); P = 0.02; I2 = 0%. No heterogeneity was present in the metformin vs. insulin analysis of randomized controlled trials, whereas high levels of heterogeneity were present in studies comparing metformin with placebo/control. Pre‐eclampsia was a secondary outcome in most of the studies. The mean weight gain from time of enrolment to delivery was lower in the metformin group (P = 0.05, metformin vs. placebo; P = 0.004, metformin vs. insulin).
Conclusions
In studies randomizing pregnant women to glucose‐lowering therapy, metformin was associated with lower gestational weight gain and a lower risk of pre‐eclampsia compared with insulin.
What's new?
This study shows that metformin with and without insulin treatment is associated with a lower incidence of pre‐eclampsia than insulin treatment alone in women with gestational diabetes mellitus or Type 2 diabetes; this is probably linked to reduced weight gain during pregnancy in those taking metformin.
In other high‐risk pregnancies where hypoglycaemic agents are not essential, metformin does not appear to be beneficial.
Clinical guidelines, which recommend insulin as the first‐line treatment in pregnancies complicated by diabetes, should be reviewed in light of these findings, and adequately designed randomized controlled trials with pre‐eclampsia as a primary outcome carried out.
Structured diffuse auroras are often observed near magnetic local noon (MLN), but their generation mechanisms are poorly understood. We have found that two types of structured diffuse auroras with ...obviously different dynamical properties often coexist near MLN. One type usually drifts from low to high latitude with higher speed and shows pulsation. The other type is always adjacent to the discrete aurora oval and drifts together with nearby discrete aurora with much lower speed. Using coordinated observations from MMS and ground all‐sky imagers, we found that the two types of diffuse auroras are well correlated with number density increase of O+ (from the ionosphere) and of He2+ (from magnetosheath) ions, respectively. These observations indicate that mangetosheath particles penetrated into the magnetosphere also can play an important role for producing the dayside diffuse aurora. In addition, for the first time, electron cyclotron harmonic waves are observed associated with dayside diffuse aurora.
Key Points
Two types of structured diffuse auroras observed near magnetic local noon with obviously different dynamical properties are identified
Types 1 and 2 are associated with number density increase of O+ from the magnetosphere and of He2+ from the magnetosheath, respectively
For the first time, ECH waves, but no whistler mode chorus waves, were observed associated with dayside diffuse auroras
Radiotherapy is an effective treatment of intermediate/high-risk locally advanced prostate cancer, however, >30% of patients relapse within 5 years. Clinicopathological parameters currently fail to ...identify patients prone to systemic relapse and those whom treatment intensification may be beneficial. The purpose of this study was to independently validate the performance of a 70-gene Metastatic Assay in a cohort of diagnostic biopsies from patients treated with radical radiotherapy and androgen deprivation therapy.
A bridging cohort of prostate cancer diagnostic biopsy specimens was profiled to enable optimization of the Metastatic Assay threshold before further independent clinical validation in a cohort of diagnostic biopsies from patients treated with radical radiotherapy and androgen deprivation therapy. Multivariable Cox proportional hazard regression analysis was used to assess assay performance in predicting biochemical failure-free survival (BFFS) and metastasis-free survival (MFS).
Gene expression analysis was carried out in 248 patients from the independent validation cohort and the Metastatic Assay applied. Ten-year MFS was 72% for Metastatic Assay positive patients and 94% for Metastatic Assay negative patients HR = 3.21 (1.35–7.67); P=0.003. On multivariable analysis the Metastatic Assay remained predictive for development of distant metastases HR = 2.71 (1.11–6.63); P=0.030. The assay retained independent prognostic performance for MFS when assessed with the Cancer of the Prostate Assessment Score (CAPRA) HR = 3.23 (1.22–8.59); P=0.019 whilst CAPRA itself was not significant HR = 1.88, (0.52–6.77); P=0.332. A high concordance 100% (61.5–100) for the assay result was noted between two separate foci taken from 11 tumours, whilst Gleason score had low concordance.
The Metastatic Assay demonstrated significant prognostic performance in patients treated with radical radiotherapy both alone and independent of standard clinical and pathological variables. The Metastatic Assay could have clinical utility when deciding upon treatment intensification in high-risk patients. Genomic and clinical data are available as a public resource.
The type III secretion system (T3SS) is a virulence mechanism employed by Gram-negative pathogens. The T3SS forms a proteinaceous channel that projects a needle into the extracellular medium where it ...interacts with the host cell to deliver virulence factors. Enteropathogenic Escherichia coli (EPEC) is unique in adopting a needle extension to the T3SS—a filament formed by EspA—which is absolutely required for efficient colonization of the gut. Here, we describe the cryoelectron microscopy structure of native EspA filaments from EPEC at 3.6-Å resolution. Within the filament, positively charged residues adjacent to a hydrophobic groove line the lumen of the filament in a spiral manner, suggesting a mechanism of substrate translocation mediated via electrostatics. Using structure-guided mutagenesis, in vivo studies corroborate the role of these residues in secretion and translocation function. The high-resolution structure of the EspA filament could aid in structure-guided drug design of antivirulence therapeutics.
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•Structure of native EspA adopts a unique fold compared with other T3SS tip proteins•Native EspA adopts a different conformation from the chaperone-bound state•The EspA structure reveals an electropositive pattern within its lumen•In vivo studies show that electrostatics play a crucial role in function
EPEC pathogenicity is dependent on a syringe-like nanomachine, the T3SS, including its long needle extension EspA. Lyons et al. characterize the cryo-EM-derived structure of the EspA filament purified from EPEC. Structure-guided mutagenesis and in vivo studies reveal a mechanism of substrate translocation through this essential extracellular conduit to the infected host.
Summary
Both cat breeders and the lay public have interests in the origins of their pets, not only in the genetic identity of the purebred individuals, but also in the historical origins of common ...household cats. The cat fancy is a relatively new institution with over 85% of its 40–50 breeds arising only in the past 75 years, primarily through selection on single‐gene aesthetic traits. The short, yet intense cat breed history poses a significant challenge to the development of a genetic marker–based breed identification strategy. Using different breed assignment strategies and methods, 477 cats representing 29 fancy breeds were analysed with 38 short tandem repeats, 148 intergenic and five phenotypic single nucleotide polymorphisms. Results suggest the frequentist method of Paetkau (single nucleotide polymorphisms = 0.78, short tandem repeats = 0.88) surpasses the Bayesian method of Rannala and Mountain (single nucleotide polymorphisms = 0.56, short tandem repeats = 0.83) for accurate assignment of individuals to the correct breed. Additionally, a post‐assignment verification step with the five phenotypic single nucleotide polymorphisms accurately identified between 0.31 and 0.58 of the misassigned individuals raising the sensitivity of assignment with the frequentist method to 0.89 and 0.92 for single nucleotide polymorphisms and short tandem repeats respectively. This study provides a novel multistep assignment strategy and suggests that, despite their short breed history and breed family groupings, a majority of cats can be assigned to their proper breed or population of origin, that is, race.
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