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- rapid eGFRcrea decline (2)
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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.
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.
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.
Aims/hypothesis Paternal high-fat diet prior to mating programmes impaired glucose tolerance in female offspring. We examined whether the metabolic consequences in offspring could be abolished by folate treatment of either the male rats before mating or the corresponding female rats during pregnancy. Methods Male F0 rats were fed either control diet or high-fat, high-sucrose and high-salt diet (HFSSD), with or without folate, before mating. Male rats were mated with control-diet-fed dams. After mating, the F0 dams were fed control diet with or without folate during pregnancy.
Transition path dynamics have been widely studied in chemical, physical, and technological systems. Mostly, the transition path dynamics is obtained for smooth barrier potentials, for instance, generic inverse-parabolic shapes. We here present analytical results for the mean transition path time, the distribution of transition path times, the mean transition path velocity, and the mean transition path shape in a rough inverted parabolic potential function under the driving of Gaussian white noise. These are validated against extensive simulations using the forward flux sampling scheme in parallel computations. We observe how precisely the potential roughness, the barrier height, and the noise intensity contribute to the particle transition in the rough inverted barrier potential.
Aims/hypothesis It was shown that maternal endothelial nitric oxide synthase (eNOS) deficiency causes fatty liver disease and numerically lower fasting glucose in female wild-type offspring, suggesting that parental genetic variants may influence the offspring's phenotype via epigenetic modifications in the offspring despite the absence of a primary genetic defect. The aim of the current study was to analyse whether paternal eNOS deficiency may cause the same phenotype as seen with maternal eNOS deficiency. Methods Heterozygous (+/-) male eNOS (Nos3) knockout mice or wild-type male mice were bred with female wild-type mice. The phenotype of wild-type offspring of heterozygous male eNOS knockout mice was compared with offspring from wild-type parents. Results Global sperm DNA methylation decreased and sperm microRNA pattern altered substantially. Fasting glucose and liver glycogen storage were increased when analysing wild-type male and female offspring of +/- eNOS fathers. Wild-type male but not female offspring of +/- eNOS fathers had increased fasting insulin and increased insulin after glucose load. Analysing candidate genes for liver fat and carbohydrate metabolism revealed that the expression of genes encoding glucocorticoid receptor (Gr; also known as Nr3c1) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (Pgc1a; also known as Ppargc1a) was increased while DNA methylation of Gr exon 1A and Pgc1a promoter was decreased in the liver of male wild-type offspring of +/- eNOS fathers. The endocrine pancreas in wild-type offspring was not affected. <br /> Conclusions/interpretation Our study suggests that paternal genetic defects such as eNOS deficiency may alter the epigenome of the sperm without transmission of the paternal genetic defect itself. In later life wild-type male offspring of +/- eNOS fathers developed increased fasting insulin and increased insulin after glucose load. These effects are associated with increased Gr and Pgc1a gene expression due to altered methylation of these genes.
The aims of this study were to identify areas of wind erosion and dust deposition and to quantify the effects of different grazing intensities on soil redistribution rates in grasslands based on the Cs-137 technique. Because the method uses a reference inventory as threshold for erosion or deposition, the classification of any other site as source or sink for dust depends on the accurate selection of this reference site.
Measurements of Cs-137 inventories and depth distributions were carried out at pasture sites with predominant species of Stipa grandis and Leymus chinensis which are grazed with different intensities. Additional measurements were made at arable land, plant-covered sand dunes and alluvial plains. Wind-induced soil erosion and dust deposition rates were calculated from Cs-137 inventories by means of the "Profile-Distribution" and the "Mass Balance II" models.
The selection of the reference site was based on fluid dynamical and process-determining parameters. The chosen site should meet the following four conditions: (i) located at a summit position with obviously low deposition rates, (ii) sufficient vegetation cover to prevent wind erosion, (iii) plane to exclude water erosion and (iv) in the wind/dust shadow of a higher elevation. The measured reference inventory of Cs-137 was 1967(+/- 102) Bqm(-2) located at a summit position of moderately grazed Leymus chinensis steppe. The Cs-137 inventories at other sites ranged from 1330 Bqm(-2) at heavily grazed sites to 5119 Bqm(-2) at river deposits, representing annual average soil losses of up to 130 tkm(-2) and deposits of up to 540 tkm(-2), respectively. The calculated annual averages of dust depositions at ungrazed Leymus chinensis sites were related to the dust storm frequencies of the last 50 years resulting in a description of the temporal variability of annual dust depositions from about 154 tkm(-2) in the 1960s to 26 tkm(-2) at recent times. Based on this quantification already 80% of the total dust depositions can be related to the 20 years between the 1960s and the end of the 1970s and only 20% to the time between 1980 and 2001.
Cs-137 technique is a promising method to assess the effect of grazing intensity and land use types on the spatial variability of wind-induced soil and dust redistribution processes in semi-arid grasslands. However, considerable efforts are needed to identify a reliable reference site, because erosion and deposition induced by wind may occur at the same places. The combination of the dust deposition rates derived from Cs-137 profile data with the dust storm frequencies is helpful for a better reconstruction of the temporal variability of dust deposition and wind erosion in this region. The calculated recent deposition rates of about 20 tkm(-2) are in good agreement with data of other authors.
The photochemical ring-opening of 1,3-cyclohexadiene imaged by ultrafast electron diffraction
(2019)
The ultrafast photoinduced ring-opening of 1,3-cyclohexadiene constitutes a textbook example of electrocyclic reactions in organic chemistry and a model for photobiological reactions in vitamin D synthesis. Although the relaxation from the photoexcited electronic state during the ring-opening has been investigated in numerous studies, the accompanying changes in atomic distance have not been resolved. Here we present a direct and unambiguous observation of the ring-opening reaction path on the femtosecond timescale and subangstrom length scale using megaelectronvolt ultrafast electron diffraction. We followed the carbon-carbon bond dissociation and the structural opening of the 1,3-cyclohexadiene ring by the direct measurement of time-dependent changes in the distribution of interatomic distances. We observed a substantial acceleration of the ring-opening motion after internal conversion to the ground state due to a steepening of the electronic potential gradient towards the product minima. The ring-opening motion transforms into rotation of the terminal ethylene groups in the photoproduct 1,3,5-hexatriene on the subpicosecond timescale.
The climate conditions during Marine Isotope Stage (MIS) 3 were similar to present-day conditions, but whether humidity then exceeded present levels is debated, and the driving mechanisms of palaeoclimate evolution since MIS 3 remain unclear. Here, we use pollen data from Wulagai Lake, Inner Mongolia, to reconstruct vegetation and climate changes since the middle MIS 3. The steppe biome is reconstructed as the first dominant biome and the desert biome as the second, and the results show that the vegetation was steppe over the last 43,800 years. Poaceae, Artemisia, Caryophyllaceae and Humulus were abundant from middle to late MIS 3, indicating humid climate conditions. As drought-tolerant species such as Hippophae, Nitraria and Chenopodiaceae spread during MIS 2, the climate became arid. The Holocene is characterized by the dominance of steppe with mixed coniferous-broadleaved forests in the Greater Hinggan Range, and the desert biome retains high affinity scores, indicating that the climate was semi-arid. The climate from middle to late MIS 3 was wetter than in the Holocene; this shift was related to changes in the Northern Hemisphere's solar insolation and ice volume. The humid conditions during MIS 3 were attributed to strong ice–albedo feedback, which led to evaporation that was less than the precipitation. The enhanced evaporation caused by increased solar insolation and decreased ice volume might have exceeded the precipitation during the Holocene and resulted in low effective humidity in the Wulagai Lake basin.