Blood lipids are causally involved in the pathogenesis of atherosclerosis, but their role in cerebral small vessel disease remains largely elusive. Here, we explored associations of genetic ...determinants of blood lipid levels, lipoprotein particle components, and targets for lipid-modifying drugs with small vessel disease phenotypes. We selected genetic instruments for blood levels of high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides, for cholesterol and triglycerides components of size-defined lipoprotein particles, and for lipid-modifying drug targets based on published genome-wide association studies (up to 617 303 individuals). Applying two-sample Mendelian randomization approaches we investigated associations with ischaemic and haemorrhagic manifestations of small vessel disease small vessel stroke: 11 710 cases, 287 067 controls; white matter hyperintensities (WMH): 10 597 individuals; intracerebral haemorrhage: 1545 cases, 1481 controls. We applied the inverse-variance weighted method and multivariable Mendelian randomization as our main analytical approaches. Genetic predisposition to higher HDL-C levels was associated with lower risk of small vessel stroke odds ratio (OR) per standard deviation = 0.85, 95% confidence interval (CI) = 0.78-0.92 and lower WMH volume (β = -0.07, 95% CI = -0.12 to -0.02), which in multivariable Mendelian randomization remained stable after adjustments for LDL-C and triglycerides. In analyses of lipoprotein particle components by size, we found these effects to be specific for cholesterol concentration in medium-sized high-density lipoprotein, and not large or extra-large high-density lipoprotein particles. Association estimates for intracerebral haemorrhage were negatively correlated with those for small vessel stroke and WMH volume across all lipid traits and lipoprotein particle components. HDL-C raising genetic variants in the gene locus of the target of CETP inhibitors were associated with lower risk of small vessel stroke (OR: 0.82, 95% CI = 0.75-0.89) and lower WMH volume (β = -0.08, 95% CI = -0.13 to -0.02), but a higher risk of intracerebral haemorrhage (OR: 1.64, 95% CI = 1.26-2.13). Genetic predisposition to higher HDL-C, specifically to cholesterol in medium-sized high-density lipoprotein particles, is associated with both a lower risk of small vessel stroke and lower WMH volume. These analyses indicate that HDL-C raising strategies could be considered for the prevention of ischaemic small vessel disease but the net benefit of such an approach would need to be tested in a randomized controlled trial.
It is well established that nighttime radiance, measured from satellites, correlates with economic prosperity across the globe. In developing countries, areas with low levels of detected radiance ...generally indicate limited development - with unlit areas typically being disregarded. Here we combine satellite nighttime lights and the world settlement footprint for the year 2015 to show that 19% of the total settlement footprint of the planet had no detectable artificial radiance associated with it. The majority of unlit settlement footprints are found in Africa (39%), rising to 65% if we consider only rural settlement areas, along with numerous countries in the Middle East and Asia. Significant areas of unlit settlements are also located in some developed countries. For 49 countries spread across Africa, Asia and the Americas we are able to predict and map the wealth class obtained from ~2,400,000 geo-located households based upon the percent of unlit settlements, with an overall accuracy of 87%.
We present precise measurements of the growth rate of cosmic structure for the redshift range 0.1 < z < 0.9, using redshift-space distortions in the galaxy power spectrum of the WiggleZ Dark Energy ...Survey. Our results, which have a precision of around 10 per cent in four independent redshift bins, are well fitted by a flat Λ cold dark matter (ΛCDM) cosmological model with matter density parameter Ωm= 0.27. Our analysis hence indicates that this model provides a self-consistent description of the growth of cosmic structure through large-scale perturbations and the homogeneous cosmic expansion mapped by supernovae and baryon acoustic oscillations. We achieve robust results by systematically comparing our data with several different models of the quasi-linear growth of structure including empirical models, fitting formulae calibrated to N-body simulations, and perturbation theory techniques. We extract the first measurements of the power spectrum of the velocity divergence field, P
θθ(k), as a function of redshift (under the assumption that
, where g is the galaxy overdensity field), and demonstrate that the WiggleZ galaxy-mass cross-correlation is consistent with a deterministic (rather than stochastic) scale-independent bias model for WiggleZ galaxies for scales k < 0.3 h Mpc−1. Measurements of the cosmic growth rate from the WiggleZ Survey and other current and future observations offer a powerful test of the physical nature of dark energy that is complementary to distance-redshift measures such as supernovae and baryon acoustic oscillations.
The specifics of how galaxies form from, and are fuelled by, gas from the intergalactic medium remain uncertain. Hydrodynamic simulations suggest that 'cold accretion flows'--relatively cool ...(temperatures of the order of 10(4) kelvin), unshocked gas streaming along filaments of the cosmic web into dark-matter halos--are important. These flows are thought to deposit gas and angular momentum into the circumgalactic medium, creating disk- or ring-like structures that eventually coalesce into galaxies that form at filamentary intersections. Recently, a large and luminous filament, consistent with such a cold accretion flow, was discovered near the quasi-stellar object QSO UM287 at redshift 2.279 using narrow-band imaging. Unfortunately, imaging is not sufficient to constrain the physical characteristics of the filament, to determine its kinematics, to explain how it is linked to nearby sources, or to account for its unusual brightness, more than a factor of ten above what is expected for a filament. Here we report a two-dimensional spectroscopic investigation of the emitting structure. We find that the brightest emission region is an extended rotating hydrogen disk with a velocity profile that is characteristic of gas in a dark-matter halo with a mass of 10(13) solar masses. This giant protogalactic disk appears to be connected to a quiescent filament that may extend beyond the virial radius of the halo. The geometry is strongly suggestive of a cold accretion flow.
Simulation models are extensively used to predict agricultural productivity and greenhouse gas emissions. However, the uncertainties of (reduced) model ensemble simulations have not been assessed ...systematically for variables affecting food security and climate change mitigation, within multi‐species agricultural contexts. We report an international model comparison and benchmarking exercise, showing the potential of multi‐model ensembles to predict productivity and nitrous oxide (N2O) emissions for wheat, maize, rice and temperate grasslands. Using a multi‐stage modelling protocol, from blind simulations (stage 1) to partial (stages 2–4) and full calibration (stage 5), 24 process‐based biogeochemical models were assessed individually or as an ensemble against long‐term experimental data from four temperate grassland and five arable crop rotation sites spanning four continents. Comparisons were performed by reference to the experimental uncertainties of observed yields and N2O emissions. Results showed that across sites and crop/grassland types, 23%–40% of the uncalibrated individual models were within two standard deviations (SD) of observed yields, while 42 (rice) to 96% (grasslands) of the models were within 1 SD of observed N2O emissions. At stage 1, ensembles formed by the three lowest prediction model errors predicted both yields and N2O emissions within experimental uncertainties for 44% and 33% of the crop and grassland growth cycles, respectively. Partial model calibration (stages 2–4) markedly reduced prediction errors of the full model ensemble E‐median for crop grain yields (from 36% at stage 1 down to 4% on average) and grassland productivity (from 44% to 27%) and to a lesser and more variable extent for N2O emissions. Yield‐scaled N2O emissions (N2O emissions divided by crop yields) were ranked accurately by three‐model ensembles across crop species and field sites. The potential of using process‐based model ensembles to predict jointly productivity and N2O emissions at field scale is discussed.
The potential of simulation models used to predict variables affecting food security and climate change mitigation has not been systematically assessed. We report an international intercomparison of 24 process‐based models for the estimation of agricultural productivity and N2O emissions (individually or as ensembles) against nine long‐term experimental datasets (rotational crops and grasslands) using a five‐stage modelling protocol. Uncalibrated multi‐model medians were within the range of observed uncertainties for grain yields (wheat, maize and rice) and N2O emissions, while were poor predictor for grasslands ANPP. N2O emissions intensities ranked accurately with reduced ensembles (three models) across stages, crop species and sites.
We present Keck Cosmic Web Imager spectroscopy of the four putative images of the lensed quasar candidate J014710+463040 recently discovered by Berghea et al. The data verify the source as a ...quadruply lensed, broad absorption-line quasar having . We detect intervening absorption in the Fe ii λλ2586, 2600, Mg ii λλ2796, 2803, and/or C iv λλ1548, 1550 transitions in eight foreground systems, three of which have redshifts consistent with the photometric-redshift estimate reported for the lensing galaxy (zL 0.57). The source images probe these absorbers over transverse physical scales of 0.3-22 kpc, permitting assessment of the variation in metal-line equivalent width as a function of sight-line separation. We measure differences in of <40% across most of the sight-line pairs subtending 8-22 kpc, suggestive of a high degree of spatial coherence for the Mg ii-absorbing material. varies by >50% over the same scales across the majority of sight-line pairs, while C iv absorption exhibits a wide range in differences of 5%-80% within transverse distances of 3 kpc. These spatial variations are consistent with those measured in intervening absorbers detected toward lensed quasars drawn from the literature, in which and vary by ≤20% in 35 7% and 47 6% of sight lines separated by <10 kpc, respectively. J014710+463040 is one of only a handful of z > 2 quadruply lensed systems for which all four source images are very bright (r = 15.4-17.7 mag) and are easily separated in ground-based seeing conditions. As such, it is an ideal candidate for higher-resolution spectroscopy probing the spatial variation in the kinematic structure and physical state of intervening absorbers.
No effective therapeutic options for patients with unresectable imatinib-resistant gastrointestinal stromal tumour are available. We did a randomised, double-blind, placebo-controlled, multicentre, ...international trial to assess tolerability and anticancer efficacy of sunitinib, a multitargeted tyrosine kinase inhibitor, in patients with advanced gastrointestinal stromal tumour who were resistant to or intolerant of previous treatment with imatinib.
Blinded sunitinib or placebo was given orally once daily at a 50-mg starting dose in 6-week cycles with 4 weeks on and 2 weeks off treatment. The primary endpoint was time to tumour progression. Intention-to-treat, modified intention-to-treat, and per-protocol analyses were done. This study is registered at
ClinicalTrials.gov, number
NCT00075218.
312 patients were randomised in a 2:1 ratio to receive sunitinib (n=207) or placebo (n=105); the trial was unblinded early when a planned interim analysis showed significantly longer time to tumour progression with sunitinib. Median time to tumour progression was 27·3 weeks (95% CI 16·0–32·1) in patients receiving sunitinib and 6·4 weeks (4·4–10·0) in those on placebo (hazard ratio 0·33; p<0·0001). Therapy was reasonably well tolerated; the most common treatment-related adverse events were fatigue, diarrhoea, skin discolouration, and nausea.
We noted significant clinical benefit, including disease control and superior survival, with sunitinib compared with placebo in patients with advanced gastrointestinal stromal tumour after failure and discontinuation of imatinab. Tolerability was acceptable.
Coronavirus disease-2019 (COVID-19) is primarily a respiratory disease, however, an increasing number of reports indicate that SARS-CoV-2 infection can also cause severe neurological manifestations, ...including precipitating cases of probable Parkinson's disease. As microglial NLRP3 inflammasome activation is a major driver of neurodegeneration, here we interrogated whether SARS-CoV-2 can promote microglial NLRP3 inflammasome activation. Using SARS-CoV-2 infection of transgenic mice expressing human angiotensin-converting enzyme 2 (hACE2) as a COVID-19 pre-clinical model, we established the presence of virus in the brain together with microglial activation and NLRP3 inflammasome upregulation in comparison to uninfected mice. Next, utilising a model of human monocyte-derived microglia, we identified that SARS-CoV-2 isolates can bind and enter human microglia in the absence of viral replication. This interaction of virus and microglia directly induced robust inflammasome activation, even in the absence of another priming signal. Mechanistically, we demonstrated that purified SARS-CoV-2 spike glycoprotein activated the NLRP3 inflammasome in LPS-primed microglia, in a ACE2-dependent manner. Spike protein also could prime the inflammasome in microglia through NF-κB signalling, allowing for activation through either ATP, nigericin or α-synuclein. Notably, SARS-CoV-2 and spike protein-mediated microglial inflammasome activation was significantly enhanced in the presence of α-synuclein fibrils and was entirely ablated by NLRP3-inhibition. Finally, we demonstrate SARS-CoV-2 infected hACE2 mice treated orally post-infection with the NLRP3 inhibitory drug MCC950, have significantly reduced microglial inflammasome activation, and increased survival in comparison with untreated SARS-CoV-2 infected mice. These results support a possible mechanism of microglial innate immune activation by SARS-CoV-2, which could explain the increased vulnerability to developing neurological symptoms akin to Parkinson's disease in COVID-19 infected individuals, and a potential therapeutic avenue for intervention.
Stereoscopic 3D (S3D) displays provide an additional sense of depth compared to non-stereoscopic displays by sending slightly different images to the two eyes. But conventional S3D displays do not ...reproduce all natural depth cues. In particular, focus cues are incorrect causing mismatches between accommodation and vergence: The eyes must accommodate to the display screen to create sharp retinal images even when binocular disparity drives the eyes to converge to other distances. This mismatch causes visual discomfort and reduces visual performance. We propose and assess two new techniques that are designed to reduce the vergence-accommodation conflict and thereby decrease discomfort and increase visual performance. These techniques are much simpler to implement than previous conflict-reducing techniques. The first proposed technique uses variable-focus lenses between the display and the viewer's eyes. The power of the lenses is yoked to the expected vergence distance thereby reducing the mismatch between vergence and accommodation. The second proposed technique uses a fixed lens in front of one eye and relies on the binocularly fused percept being determined by one eye and then the other, depending on simulated distance. We conducted performance tests and discomfort assessments with both techniques and compared the results to those of a conventional S3D display. The first proposed technique, but not the second, yielded clear improvements in performance and reductions in discomfort. This dynamic-lens technique therefore offers an easily implemented technique for reducing the vergence-accommodation conflict and thereby improving viewer experience.
Transfer RNA (tRNA) utilizes multiple properties of abundance, modification, and aminoacylation in translational regulation. These properties were typically studied one-by-one; however, recent ...advance in high throughput tRNA sequencing enables their simultaneous assessment in the same sequencing data. How these properties are coordinated at the transcriptome level is an open question. Here, we develop a single-read tRNA analysis pipeline that takes advantage of the pseudo single-molecule nature of tRNA sequencing in NGS libraries. tRNAs are short enough that a single NGS read can represent one tRNA molecule, and can simultaneously report on the status of multiple modifications, aminoacylation, and fragmentation of each molecule. We find correlations among modification-modification, modification-aminoacylation and modification-fragmentation. We identify interdependencies among one of the most common tRNA modifications, m1A58, as coordinators of tissue-specific gene expression. Our method, SingLe-read Analysis of Crosstalks (SLAC), reveals tRNAome-wide networks of modifications, aminoacylation, and fragmentation. We observe changes of these networks under different stresses, and assign a function for tRNA modification in translational regulation and fragment biogenesis. SLAC leverages the richness of the tRNA-seq data and provides new insights on the coordination of tRNA properties.
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