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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.
A very sensitive X-ray investigation of the giant HII region N11 in the Large Megallanic Cloud was performed using the Chandra X-ray Observatory. The 300 ks observation reveals X-ray sources with luminosities down to 10(32) erg s(-1), increasing the number of known point sources in the field by more than a factor of five. Among these detections are 13 massive stars (3 compact groups of massive stars, 9 O stars, and one early B star) with log(L-X/L-BOL) similar to -6.5 to -7, which may suggest that they are highly magnetic or colliding-wind systems. On the other hand, the stacked signal for regions corresponding to undetected O stars yields log(L-X/L-BOL) similar to -7.3, i.e., an emission level comparable to similar Galactic stars despite the lower metallicity. Other point sources coincide with 11 foreground stars, 6 late-B/A stars in N11, and many background objects. This observation also uncovers the extent and detailed spatial properties of the soft, diffuse emission regions, but the presence of some hotter plasma in their spectra suggests contamination by the unresolved stellar population.
A putative phosphatase, LSF1 (for LIKE SEX4; previously PTPKIS2), is closely related in sequence and structure to STARCH-EXCESS4 (SEX4), an enzyme necessary for the removal of phosphate groups from starch polymers during starch degradation in Arabidopsis (Arabidopsis thaliana) leaves at night. We show that LSF1 is also required for starch degradation: lsf1 mutants, like sex4 mutants, have substantially more starch in their leaves than wild-type plants throughout the diurnal cycle. LSF1 is chloroplastic and is located on the surface of starch granules. lsf1 and sex4 mutants show similar, extensive changes relative to wild-type plants in the expression of sugar-sensitive genes. However, although LSF1 and SEX4 are probably both involved in the early stages of starch degradation, we show that LSF1 neither catalyzes the same reaction as SEX4 nor mediates a sequential step in the pathway. Evidence includes the contents and metabolism of phosphorylated glucans in the single mutants. The sex4 mutant accumulates soluble phospho- oligosaccharides undetectable in wild-type plants and is deficient in a starch granule-dephosphorylating activity present in wild-type plants. The lsf1 mutant displays neither of these phenotypes. The phenotype of the lsf1/sex4 double mutant also differs from that of both single mutants in several respects. We discuss the possible role of the LSF1 protein in starch degradation.
Changes in the steepness of river profiles or abrupt vertical steps (i.e. waterfalls) are thought to be indicative of changes in erosion rates, lithology or other factors that affect landscape evolution. These changes are referred to as knickpoints or knickzones and are pervasive in bedrock river systems. Such features are thought to reveal information about landscape evolution and patterns of erosion, and therefore their locations are often reported in the geomorphic literature. It is imperative that studies reporting knickpoints and knickzones use a reproducible method of quantifying their locations, as their number and spatial distribution play an important role in interpreting tectonically active landscapes. In this contribution we introduce a reproducible knickpoint and knickzone extraction algorithm that uses river profiles transformed by integrating drainage area along channel length (the so-called integral or chi method). The profile is then statistically segmented and the differing slopes and step changes in the elevations of these segments are used to identify knickpoints, knickzones and their relative magnitudes. The output locations of identified knickpoints and knickzones compare favourably with human mapping: we test the method on Santa Cruz Island, CA, using previously reported knickzones and also test the method against a new dataset from the Quadrilatero Ferrifero in Brazil. The algorithm allows for the extraction of varying knickpoint morphologies, including stepped, positive slope-break (concave upward) and negative slope-break knickpoints. We identify parameters that most affect the resulting knickpoint and knickzone locations and provide guidance for both usage and outputs of the method to produce reproducible knickpoint datasets.
We present results from deep observations toward the Cygnus region using 300 hr of very high energy (VHE)gamma-ray data taken with the VERITAS Cerenkov telescope array and over 7 yr of high-energy.-ray data taken with the Fermi satellite at an energy above 1 GeV. As the brightest region of diffuse gamma-ray emission in the northern sky, the Cygnus region provides a promising area to probe the origins of cosmic rays. We report the identification of a potential Fermi-LAT counterpart to VER J2031+415 (TeV J2032+4130) and resolve the extended VHE source VER J2019+368 into two source candidates (VER J2018+367* and VER J2020+368*) and characterize their energy spectra. The Fermi-LAT morphology of 3FGL J2021.0+4031e (the Gamma Cygni supernova remnant) was examined, and a region of enhanced emission coincident with VER J2019+407 was identified and jointly fit with the VERITAS data. By modeling 3FGL J2015.6+3709 as two sources, one located at the location of the pulsar wind nebula CTB 87 and one at the quasar QSO J2015+371, a continuous spectrum from 1 GeV to 10 TeV was extracted for VER J2016+371 (CTB 87). An additional 71 locations coincident with Fermi-LAT sources and other potential objects of interest were tested for VHE gamma-ray emission, with no emission detected and upper limits on the differential flux placed at an average of 2.3% of the Crab Nebula flux. We interpret these observations in a multiwavelength context and present the most detailed gamma-ray view of the region to date.
The Alborz range of N Iran provides key information on the spatiotemporal evolution and characteristics of the Arabia-Eurasia continental collision zone. The southwestern Alborz range constitutes a transpressional duplex, which accommodates oblique shortening between Central Iran and the South Caspian Basin. The duplex comprises NW-striking frontal ramps that are kinematically linked to inherited E-W-striking, right-stepping lateral to obliquely oriented ramps. New zircon and apatite (U-Th)/He data provide a high-resolution framework to unravel the evolution of collisional tectonics in this region. Our data record two pulses of fast cooling associated with SW-directed thrusting across the frontal ramps at similar to 18-14 and 9.5-7.5 Ma, resulting in the tectonic repetition of a fossil zircon partial retention zone and a cooling pattern with a half U-shaped geometry. Uniform cooling ages of similar to 7-6 Ma along the southernmost E-W striking oblique ramp and across its associated NW-striking frontal ramps suggests that the ramp was reactivated as a master throughgoing, N-dipping thrust. We interpret this major change in fault kinematics and deformation style to be related to a change in the shortening direction from NE to N/NNE. The reduction in the obliquity of thrusting may indicate the termination of strike-slip faulting (and possibly thrusting) across the Iranian Plateau, which could have been triggered by an increase in elevation. Furthermore, we suggest that similar to 7-6-m.y.-old S-directed thrusting predated inception of the westward motion of the South Caspian Basin. Citation: Ballato, P., D. F. Stockli, M. R. Ghassemi, A. Landgraf, M. R. Strecker, J. Hassanzadeh, A. Friedrich, and S. H. Tabatabaei (2012), Accommodation of transpressional strain in the Arabia-Eurasia collision zone: new constraints from (U-Th)/He thermochronology in the Alborz mountains.
A cluster approach extended to the ONIOM methodology has been applied using several density functionals and Moller-Plesset perturbation theory (MP2) to simulate the adsorption of selected nitrogen-containing compounds [NCCs, 2,4,6-trinitrotoluene (TNT), 2,4-dinitrotoluene (DNT), 2,4-dinitroanisole (DNAN), and 3-nitro-1,2,4-triazole-5-one (NTO)] on the hydroxyated (100) surface of a-quartz. The structural properties were calculated using the M06-2X functional and 6-31G(d,p) basis set. The M06-2X-D3, PBE-D3, and MP2 methods were used to calculate the adsorption energies. Results have been compared with the data from other studies of adsorption of compounds of similar nature on silica. Effect of deformation of the silica surface and adsorbates on the binding energy values was also studied. The atoms in molecules (AIM) analysis was employed to characterize the adsorbate-adsorbent binding and to calculate the bond energies. The silica surface shows different sorption affinity toward the chemicals considered depending on their electronic structure. All target NCCs are physisorbed on the modeled silica surface. Adsorption occurs due to the formation of multiple hydrogen bonds between the functional groups of NCCs and surface silanol groups. Parallel orientation of NCCs interacting with the silica surface was found to be favorable when compared with perpendicularly oriented NCCs. NTO was found to be the most strongly adsorbed on the silica surface among all of the considered compounds. Dispersion correction was shown to play an important role in the DFT calculations of the adsorption energies of silica-NCC systems.
Air pollution is the number one environmental cause of premature deaths in Europe. Despite extensive regulations, air pollution remains a challenge, especially in urban areas. For studying summertime air quality in the Berlin–Brandenburg region of Germany, the Weather Research and Forecasting Model with Chemistry (WRF-Chem) is set up and evaluated against meteorological and air quality observations from monitoring stations as well as from a field campaign conducted in 2014. The objective is to assess which resolution and level of detail in the input data is needed for simulating urban background air pollutant concentrations and their spatial distribution in the Berlin–Brandenburg area. The model setup includes three nested domains with horizontal resolutions of 15, 3 and 1 km and anthropogenic emissions from the TNO-MACC III inventory. We use RADM2 chemistry and the MADE/SORGAM aerosol scheme. Three sensitivity simulations are conducted updating input parameters to the single-layer urban canopy model based on structural data for Berlin, specifying land use classes on a sub-grid scale (mosaic option) and downscaling the original emissions to a resolution of ca. 1 km × 1 km for Berlin based on proxy data including traffic density and population density. The results show that the model simulates meteorology well, though urban 2 m temperature and urban wind speeds are biased high and nighttime mixing layer height is biased low in the base run with the settings described above. We show that the simulation of urban meteorology can be improved when specifying the input parameters to the urban model, and to a lesser extent when using the mosaic option. On average, ozone is simulated reasonably well, but maximum daily 8 h mean concentrations are underestimated, which is consistent with the results from previous modelling studies using the RADM2 chemical mechanism. Particulate matter is underestimated, which is partly due to an underestimation of secondary organic aerosols. NOx (NO + NO2) concentrations are simulated reasonably well on average, but nighttime concentrations are overestimated due to the model's underestimation of the mixing layer height, and urban daytime concentrations are underestimated. The daytime underestimation is improved when using downscaled, and thus locally higher emissions, suggesting that part of this bias is due to deficiencies in the emission input data and their resolution. The results further demonstrate that a horizontal resolution of 3 km improves the results and spatial representativeness of the model compared to a horizontal resolution of 15 km. With the input data (land use classes, emissions) at the level of detail of the base run of this study, we find that a horizontal resolution of 1 km does not improve the results compared to a resolution of 3 km. However, our results suggest that a 1 km horizontal model resolution could enable a detailed simulation of local pollution patterns in the Berlin–Brandenburg region if the urban land use classes, together with the respective input parameters to the urban canopy model, are specified with a higher level of detail and if urban emissions of higher spatial resolution are used.
Air pollution is the number one environmental cause of premature deaths in Europe. Despite extensive regulations, air pollution remains a challenge, especially in urban areas. For studying summertime air quality in the Berlin-Brandenburg region of Germany, the Weather Research and Forecasting Model with Chemistry (WRF-Chem) is set up and evaluated against meteorological and air quality observations from monitoring stations as well as from a field campaign conducted in 2014. The objective is to assess which resolution and level of detail in the input data is needed for simulating urban background air pollutant concentrations and their spatial distribution in the Berlin-Brandenburg area. The model setup includes three nested domains with horizontal resolutions of 15, 3 and 1 km and anthropogenic emissions from the TNO-MACC III inventory. We use RADM2 chemistry and the MADE/SORGAM aerosol scheme. Three sensitivity simulations are conducted updating input parameters to the single-layer urban canopy model based on structural data for Berlin, specifying land use classes on a sub-grid scale (mosaic option) and downscaling the original emissions to a resolution of ca. 1 km x 1 km for Berlin based on proxy data including traffic density and population density. The results show that the model simulates meteorology well, though urban 2m temperature and urban wind speeds are biased high and nighttime mixing layer height is biased low in the base run with the settings described above. We show that the simulation of urban meteorology can be improved when specifying the input parameters to the urban model, and to a lesser extent when using the mosaic option. On average, ozone is simulated reasonably well, but maximum daily 8 h mean concentrations are underestimated, which is consistent with the results from previous modelling studies using the RADM2 chemical mechanism. Particulate matter is underestimated, which is partly due to an underestimation of secondary organic aerosols. NOx (NO + NO2) concentrations are simulated reasonably well on average, but nighttime concentrations are overestimated due to the model's underestimation of the mixing layer height, and urban daytime concentrations are underestimated. The daytime underestimation is improved when using downscaled, and thus locally higher emissions, suggesting that part of this bias is due to deficiencies in the emission input data and their resolution. The results further demonstrate that a horizontal resolution of 3 km improves the results and spatial representativeness of the model compared to a horizontal resolution of 15 km. With the input data (land use classes, emissions) at the level of detail of the base run of this study, we find that a horizontal resolution of 1 km does not improve the results compared to a resolution of 3 km. However, our results suggest that a 1 km horizontal model resolution could enable a detailed simulation of local pollution patterns in the Berlin-Brandenburg region if the urban land use classes, together with the respective input parameters to the urban canopy model, are specified with a higher level of detail and if urban emissions of higher spatial resolution are used.