A catalog of genetic loci associated with kidney function from analyses of a million individuals
(2019)
Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through transancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these,147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.
We report the detection of pulsed gamma rays from the Crab pulsar at energies above 100 giga-electron volts (GeV) with the Very Energetic Radiation Imaging Telescope Array System (VERITAS) array of atmospheric Cherenkov telescopes. The detection cannot be explained on the basis of current pulsar models. The photon spectrum of pulsed emission between 100 mega-electron volts and 400 GeV is described by a broken power law that is statistically preferred over a power law with an exponential cutoff. It is unlikely that the observation can be explained by invoking curvature radiation as the origin of the observed gamma rays above 100 GeV. Our findings require that these gamma rays be produced more than 10 stellar radii from the neutron star.
We report the discovery of TeV gamma-ray emission from the Type Ia supernova remnant (SNR) G120.1+1.4, known as Tycho's SNR. Observations performed in the period 2008-2010 with the VERITAS ground-based gamma-ray observatory reveal weak emission coming from the direction of the remnant, compatible with a point source located at 00(h)25(m)27(s).0, +64 degrees 10'50 '' (J2000). The TeV photon spectrum measured by VERITAS can be described with a power law dN/dE = C(E/3.42 TeV)(-Gamma) with Gamma = 1.95 +/- 0.51(stat) +/- 0.30(sys) and C = (1.55 +/- 0.43(stat) +/- 0.47(sys)) x 10(-14) cm(-2) s(-1) TeV-1. The integral flux above 1 TeV corresponds to similar to 0.9% of the steady Crab Nebula emission above the same energy, making it one of the weakest sources yet detected in TeV gamma rays. We present both leptonic and hadronic models that can describe the data. The lowest magnetic field allowed in these models is similar to 80 mu G, which may be interpreted as evidence for magnetic field amplification.
Giant X-ray outbursts, with luminosities of about 10(37) erg s(-1), are observed roughly every five years from the nearby Be/pulsar binary 1A 0535+262. In this article, we present observations of the source with VERITAS at very high energies (VHEs; E > 100 GeV) triggered by the X-ray outburst in 2009 December. The observations started shortly after the onset of the outburst and provided comprehensive coverage of the episode, as well as the 111 day binary orbit. No VHE emission is evident at any time. We also examined data from the contemporaneous observations of 1A 0535+262 with the Fermi/Large Area Telescope at high-energy photons (E > 0.1 GeV) and failed to detect the source at GeV energies. The X-ray continua measured with the Swift/X-Ray Telescope and the RXTE/PCA can be well described by the combination of blackbody and Comptonized emission from thermal electrons. Therefore, the gamma-ray and X-ray observations suggest the absence of a significant population of non-thermal particles in the system. This distinguishes 1A 0535+262 from those Be X-ray binaries (such as PSR B1259-63 and LS I +61 degrees 303) that have been detected at GeV-TeV energies. We discuss the implications of the results on theoretical models.
GrassPlot is a collaborative vegetation-plot database organised by the Eurasian Dry Grassland Group (EDGG) and listed in the Global Index of Vegetation-Plot Databases (GIVD ID EU-00-003). GrassPlot collects plot records (releves) from grasslands and other open habitats of the Palaearctic biogeographic realm. It focuses on precisely delimited plots of eight standard grain sizes (0.0001; 0.001;... 1,000 m(2)) and on nested-plot series with at least four different grain sizes. The usage of GrassPlot is regulated through Bylaws that intend to balance the interests of data contributors and data users. The current version (v. 1.00) contains data for approximately 170,000 plots of different sizes and 2,800 nested-plot series. The key components are richness data and metadata. However, most included datasets also encompass compositional data. About 14,000 plots have near-complete records of terricolous bryophytes and lichens in addition to vascular plants. At present, GrassPlot contains data from 36 countries throughout the Palaearctic, spread across elevational gradients and major grassland types. GrassPlot with its multi-scale and multi-taxon focus complements the larger international vegetationplot databases, such as the European Vegetation Archive (EVA) and the global database " sPlot". Its main aim is to facilitate studies on the scale-and taxon-dependency of biodiversity patterns and drivers along macroecological gradients. GrassPlot is a dynamic database and will expand through new data collection coordinated by the elected Governing Board. We invite researchers with suitable data to join GrassPlot. Researchers with project ideas addressable with GrassPlot data are welcome to submit proposals to the Governing Board.
We report on the gamma-ray activity of the blazar Mrk 501 during the first 480 days of Fermi operation. We find that the average Large Area Telescope (LAT) gamma-ray spectrum of Mrk 501 can be well described by a single power-law function with a photon index of 1.78 +/- 0.03. While we observe relatively mild flux variations with the Fermi-LAT (within less than a factor of two), we detect remarkable spectral variability where the hardest observed spectral index within the LAT energy range is 1.52 +/- 0.14, and the softest one is 2.51 +/- 0.20. These unexpected spectral changes do not correlate with the measured flux variations above 0.3 GeV. In this paper, we also present the first results from the 4.5 month long multifrequency campaign (2009 March 15-August 1) on Mrk 501, which included the Very Long Baseline Array (VLBA), Swift, RXTE, MAGIC, and VERITAS, the F-GAMMA, GASP-WEBT, and other collaborations and instruments which provided excellent temporal and energy coverage of the source throughout the entire campaign. The extensive radio to TeV data set from this campaign provides us with the most detailed spectral energy distribution yet collected for this source during its relatively low activity. The average spectral energy distribution of Mrk 501 is well described by the standard one-zone synchrotron self-Compton (SSC) model. In the framework of this model, we find that the dominant emission region is characterized by a size less than or similar to 0.1 pc (comparable within a factor of few to the size of the partially resolved VLBA core at 15-43 GHz), and that the total jet power (similar or equal to 10(44) erg s(-1)) constitutes only a small fraction (similar to 10(-3)) of the Eddington luminosity. The energy distribution of the freshly accelerated radiating electrons required to fit the time-averaged data has a broken power-law form in the energy range 0.3 GeV-10 TeV, with spectral indices 2.2 and 2.7 below and above the break energy of 20 GeV. We argue that such a form is consistent with a scenario in which the bulk of the energy dissipation within the dominant emission zone of Mrk 501 is due to relativistic, proton-mediated shocks. We find that the ultrarelativistic electrons and mildly relativistic protons within the blazar zone, if comparable in number, are in approximate energy equipartition, with their energy dominating the jet magnetic field energy by about two orders of magnitude.
Rapid decline of glomerular filtration rate estimated from creatinine (eGFRcrea) is associated with severe clinical endpoints. In contrast to cross-sectionally assessed eGFRcrea, the genetic basis for rapid eGFRcrea decline is largely unknown. To help define this, we meta-analyzed 42 genome-wide association studies from the Chronic Kidney Diseases Genetics Consortium and United Kingdom Biobank to identify genetic loci for rapid eGFRcrea decline. Two definitions of eGFRcrea decline were used: 3 mL/min/1.73m(2)/year or more ("Rapid3"; encompassing 34,874 cases, 107,090 controls) and eGFRcrea decline 25% or more and eGFRcrea under 60 mL/min/1.73m(2) at follow-up among those with eGFRcrea 60 mL/min/1.73m(2) or more at baseline ("CKDi25"; encompassing 19,901 cases, 175,244 controls). Seven independent variants were identified across six loci for Rapid3 and/or CKDi25: consisting of five variants at four loci with genome-wide significance (near UMOD-PDILT (2), PRKAG2, WDR72, OR2S2) and two variants among 265 known eGFRcrea variants (near GATM, LARP4B). All these loci were novel for Rapid3 and/or CKDi25 and our bioinformatic follow-up prioritized variants and genes underneath these loci. The OR2S2 locus is novel for any eGFRcrea trait including interesting candidates. For the five genome-wide significant lead variants, we found supporting effects for annual change in blood urea nitrogen or cystatin-based eGFR, but not for GATM or (LARP4B). Individuals at high compared to those at low genetic risk (8-14 vs. 0-5 adverse alleles) had a 1.20-fold increased risk of acute kidney injury (95% confidence interval 1.08-1.33). Thus, our identified loci for rapid kidney function decline may help prioritize therapeutic targets and identify mechanisms and individuals at risk for sustained deterioration of kidney function.
Rapid decline of glomerular filtration rate estimated from creatinine (eGFRcrea) is associated with severe clinical endpoints. In contrast to cross-sectionally assessed eGFRcrea, the genetic basis for rapid eGFRcrea decline is largely unknown. To help define this, we meta-analyzed 42 genome-wide association studies from the Chronic Kidney Diseases Genetics Consortium and United Kingdom Biobank to identify genetic loci for rapid eGFRcrea decline. Two definitions of eGFRcrea decline were used: 3 mL/min/1.73m(2)/year or more ("Rapid3"; encompassing 34,874 cases, 107,090 controls) and eGFRcrea decline 25% or more and eGFRcrea under 60 mL/min/1.73m(2) at follow-up among those with eGFRcrea 60 mL/min/1.73m(2) or more at baseline ("CKDi25"; encompassing 19,901 cases, 175,244 controls). Seven independent variants were identified across six loci for Rapid3 and/or CKDi25: consisting of five variants at four loci with genome-wide significance (near UMOD-PDILT (2), PRKAG2, WDR72, OR2S2) and two variants among 265 known eGFRcrea variants (near GATM, LARP4B). All these loci were novel for Rapid3 and/or CKDi25 and our bioinformatic follow-up prioritized variants and genes underneath these loci. The OR2S2 locus is novel for any eGFRcrea trait including interesting candidates. For the five genome-wide significant lead variants, we found supporting effects for annual change in blood urea nitrogen or cystatin-based eGFR, but not for GATM or (LARP4B). Individuals at high compared to those at low genetic risk (8-14 vs. 0-5 adverse alleles) had a 1.20-fold increased risk of acute kidney injury (95% confidence interval 1.08-1.33). Thus, our identified loci for rapid kidney function decline may help prioritize therapeutic targets and identify mechanisms and individuals at risk for sustained deterioration of kidney function.
We report on the VERITAS discovery of very high energy (VHE) gamma-ray emission above 200 GeV from the high-frequency-peaked BL Lac (HBL) object RX J0648.7+1516 (GB J0648+1516), associated with 1FGL J0648.8+1516. The photon spectrum above 200 GeV is fitted by a power law dN/dE = F-0(E/E-0)(-Gamma) with a photon index Gamma of 4.4 +/- 0.8(stat) +/- 0.3(syst) and a flux normalization F-0 of (2.3 +/- 0.5(stat) +/- 1.2(sys)) x 10(-11) TeV-1 cm(-2) s(-1) with E-0 = 300 GeV. No VHE variability is detected during VERITAS observations of RX J0648.7+1516 between 2010 March 4 and April 15. Following the VHE discovery, the optical identification and spectroscopic redshift were obtained using the Shane 3 m Telescope at the Lick Observatory, showing the unidentified object to be a BL Lac type with a redshift of z = 0.179. Broadband multiwavelength observations contemporaneous with the VERITAS exposure period can be used to subclassify the blazar as an HBL object, including data from the MDM observatory, Swift-UVOT, and X-Ray Telescope, and continuous monitoring at photon energies above 1 GeV from the Fermi Large Area Telescope (LAT). We find that in the absence of undetected, high-energy rapid variability, the one-zone synchrotron self-Compton (SSC) model overproduces the high-energy gamma-ray emission measured by the Fermi-LAT over 2.3 years. The spectral energy distribution can be parameterized satisfactorily with an external-Compton or lepto-hadronic model, which have two and six additional free parameters, respectively, compared to the one-zone SSC model.
Multiwavelength observations of the AGN 1ES 0414+009 with veritas, FERMI-LAT, SWIFT-XRT, AND MDM
(2012)
We present observations of the BL Lac object 1ES 0414+009 in the >200 GeV gamma-ray band by the VERITAS array of Cherenkov telescopes. 1ES 0414+009 was observed by VERITAS between 2008 January and 2011 February, resulting in 56.2 hr of good quality pointed observations. These observations resulted in a detection of 822 events from the source corresponding to a statistical significance of 6.4 standard deviations (6.4 sigma) above the background. The source flux, showing no evidence for variability, is measured as (5.2 +/- 1.1(stat) +/- 2.6(sys)) x 10(-12) photons cm(-2) s(-1) above 200 GeV, equivalent to approximately 2% of the Crab Nebula flux above this energy. The differential photon spectrum from 230 GeV to 850 GeV is well fit by a power law with a photon index of Gamma = 3.4 +/- 0.5(stat) +/- 0.3(sys) and a flux normalization of (1.6 +/- 0.3(stat) +/- 0.8(sys)) x 10(-11) photons cm(-2) s(-1) at 300 GeV. We also present multiwavelength results taken in the optical (MDM), x-ray (Swift-XRT), and GeV (Fermi-LAT) bands and use these results to construct a broadband spectral energy distribution (SED). Modeling of this SED indicates that homogenous one-zone leptonic scenarios are not adequate to describe emission from the system, with a lepto-hadronic model providing a better fit to the data.