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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.
We utilized femtosecond time-resolved resonant inelastic X-ray scattering and ab initio theory to study the transient electronic structure and the photoinduced molecular dynamics of a model metal carbonyl photocatalyst Fe(CO)(5) in ethanol solution. We propose mechanistic explanation for the parallel ultrafast intra-molecular spin crossover and ligation of the Fe(CO)(4) which are observed following a charge transfer photoexcitation of Fe(CO)(5) as reported in our previous study [ Wernet et al., Nature 520, 78 (2015)]. We find that branching of the reaction pathway likely happens in the (1)A(1) state of Fe(CO)(4). A sub-picosecond time constant of the spin crossover from B-1(2) to B-3(2) is rationalized by the proposed B-1(2) -> (1)A(1) -> B-3(2) mechanism. Ultrafast ligation of the B-1(2) Fe(CO)(4) state is significantly faster than the spin-forbidden and diffusion limited ligation process occurring from the B-3(2) Fe(CO)(4) ground state that has been observed in the previous studies. We propose that the ultrafast ligation occurs via B-1(2) -> (1)A(1) -> (1)A'Fe(CO)(4)EtOH pathway and the time scale of the (1)A(1) Fe(CO)(4) state ligation is governed by the solute-solvent collision frequency. Our study emphasizes the importance of understanding the interaction of molecular excited states with the surrounding environment to explain the relaxation pathways of photoexcited metal carbonyls in solution. (C) 2016 Author(s).
Marine Isotope Stage 3 (MIS 3, 57-27 ka) was characterised by numerous rapid climate oscillations (i.e., Dansgaard-Oeschger (D/O-) events), which are reflected in various climate archives. So far, MIS 3 speleothem records from central Europe have mainly been restricted to caves located beneath temperate Alpine glaciers or close to the Atlantic Ocean. Thus, MIS 3 seemed to be too cold and dry to enable speleothem growth north of the Alps in central Europe. Here we present a new speleothem record from Bunker Cave, Germany, which shows two distinct growth phases from 52.0 (+0.8, -0.5) to 50.9 (+0.6, -1.3) ka and 473 (+1.0, -0.6) to 42.8 (+/- 0.9) ka, rejecting this hypothesis. These two growth phases potentially correspond to the two warmest and most humid phases in central Europe during MIS 3, which is confirmed by pollen data from the nearby Eifel. The hiatus separating the two phases is associated with Heinrich stadial 5 (HS 5), although the growth stop precedes the onset of HS 5. The first growth phase is characterised by a fast growth rate, and Mg concentrations and Sr isotope data suggest high infiltration and the presence of soil cover above the cave. The second growth phase was characterised by drier, but still favourable conditions for speleothem growth. During this phase, the delta C-13 values show a significant decrease associated with D/O-event 12. The timing of this shift is in agreement with other MIS 3 speleothem data from Europe and Greenland ice core data. (C) 2018 Elsevier Ltd. All rights reserved.
Transition-metal complexes have long attracted interest for fundamental chemical reactivity studies and possible use in solar energy conversion(1,2). Electronic excitation, ligand loss from the metal centre, or a combination of both, creates changes in charge and spin density at the metal site(3-11) that need to be controlled to optimize complexes for photocatalytic hydrogen production(8) and selective carbon-hydrogen bond activation(9-11). An understanding at the molecular level of how transition-metal complexes catalyse reactions, and in particular of the role of the short-lived and reactive intermediate states involved, will be critical for such optimization. However, suitable methods for detailed characterization of electronic excited states have been lacking. Here we show, with the use of X-ray laser-based femtosecond-resolution spectroscopy and advanced quantum chemical theory to probe the reaction dynamics of the benchmark transition-metal complex Fe(CO)(5) in solution, that the photo-induced removal of CO generates the 16-electron Fe(CO)(4) species, a homogeneous catalyst(12,13) with an electron deficiency at the Fe centre(14,15), in a hitherto unreported excited singlet state that either converts to the triplet ground state or combines with a CO or solvent molecule to regenerate a penta-coordinated Fe species on a sub-picosecond timescale. This finding, which resolves the debate about the relative importance of different spin channels in the photochemistry of Fe(CO)(5) (refs 4, 16-20), was made possible by the ability of femtosecond X-ray spectroscopy to probe frontier-orbital interactions with atom specificity. We expect the method to be broadly applicable in the chemical sciences, and to complement approaches that probe structural dynamics in ultrafast processes.
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.
Aims. Recent magnetic field surveys in O- and B-type stars revealed that about 10% of the core-hydrogen-burning massive stars host large-scale magnetic fields. The physical origin of these fields is highly debated. To identify and model the physical processes responsible for the generation of magnetic fields in massive stars, it is important to establish whether magnetic massive stars are found in very young star-forming regions or whether they are formed in close interacting binary systems.
Methods. In the framework of our ESO Large Program, we carried out low-resolution spectropolarimetric observations with FORS 2 in 2013 April of the three most massive central stars in the Trifid nebula, HD 164492A, HD 164492C, and HD 164492D. These observations indicated a strong longitudinal magnetic field of about 500-600 G in the poorly studied component HD 164492C. To confirm this detection, we used HARPS in spectropolarimetric mode on two consecutive nights in 2013 June.
Results. Our HARPS observations confirmed the longitudinal magnetic field in HD 164492C. Furthermore, the HARPS observations revealed that HD 164492C cannot be considered as a single star as it possesses one or two companions. The spectral appearance indicates that the primary is most likely of spectral type B1-B1.5 V. Since in both observing nights most spectral lines appear blended, it is currently unclear which components are magnetic. Long-term monitoring using high-resolution spectropolarimetry is necessary to separate the contribution of each component to the magnetic signal. Given the location of the system HD 164492C in one of the youngest star formation regions, this system can be considered as a Rosetta Stone for our understanding of the origin of magnetic fields in massive stars.
Although quantitative isotope data from speleothems has been used to evaluate isotope-enabled model simulations, currently no consensus exists regarding the most appropriate methodology through which to achieve this. A number of modelling groups will be running isotope-enabled palaeoclimate simulations in the framework of the Coupled Model Intercomparison Project Phase 6, so it is timely to evaluate different approaches to using the speleothem data for data–model comparisons. Here, we illustrate this using 456 globally distributed speleothem δ18O records from an updated version of the Speleothem Isotopes Synthesis and Analysis (SISAL) database and palaeoclimate simulations generated using the ECHAM5-wiso isotope-enabled atmospheric circulation model. We show that the SISAL records reproduce the first-order spatial patterns of isotopic variability in the modern day, strongly supporting the application of this dataset for evaluating model-derived isotope variability into the past. However, the discontinuous nature of many speleothem records complicates the process of procuring large numbers of records if data–model comparisons are made using the traditional approach of comparing anomalies between a control period and a given palaeoclimate experiment. To circumvent this issue, we illustrate techniques through which the absolute isotope values during any time period could be used for model evaluation. Specifically, we show that speleothem isotope records allow an assessment of a model's ability to simulate spatial isotopic trends. Our analyses provide a protocol for using speleothem isotope data for model evaluation, including screening the observations to take into account the impact of speleothem mineralogy on δ18O values, the optimum period for the modern observational baseline and the selection of an appropriate time window for creating means of the isotope data for palaeo-time-slices.
Motivation: Visualizing and analysing the potential non-linear structure of a dataset is becoming an important task in molecular biology. This is even more challenging when the data have missing values. Results: Here, we propose an inverse model that performs non-linear principal component analysis (NLPCA) from incomplete datasets. Missing values are ignored while optimizing the model, but can be estimated afterwards. Results are shown for both artificial and experimental datasets. In contrast to linear methods, non-linear methods were able to give better missing value estimations for non-linear structured data. Application: We applied this technique to a time course of metabolite data from a cold stress experiment on the model plant Arabidopsis thaliana, and could approximate the mapping function from any time point to the metabolite responses. Thus, the inverse NLPCA provides greatly improved information for better understanding the complex response to cold stress
Three small stalagmites from Zoolithencave (southern Germany) show visible laminae, which consist of a clear and a brownish, pigmented layer pair. This potentially provides the opportunity to construct precise chronologies by counting annual laminae. The growth period of the three stalagmites was constrained by the C-14 bomb peak in the youngest part of all three stalagmites and C-14-dating of a piece of charcoal in the consolidated base part of stalagmite Zoo-rez-2. These data suggest an age of AD 1970 for the top laminae and a lower age limit of AD 1973-1682 or AD 1735-1778. Laminae were counted and their thickness determined on scanned thin sections of all stalagmites. On stalagmites Zoo-rez-1 and -2, three tracks were measured near the growth axes, each separated into three sections at prominent anchor laminae (I, II, III). Each section was replicated three times (a, b, c). For Zoo-rez-3, only one track was measured. The total number of laminae counted for Zoo-rez-1 ranges from 138 to 177, for Zoo-rez-2 from 119 to 145, and for Zoo-rez-3 from 159 to 166. The numbers agree well with the range constrained by the bomb peak and the age of the charcoal, which supports the annual origin of the laminae. The replicated measurements of the different tracks as well as the three different tracks on the stalagmites Zoo-rez-1 and-2 were cross-dated using the TSAP-Win (R) tree-ring software. This software is very useful for cross-dating because it enables to insert or delete missing or false laminae as well as identifying common pattern by shifting the series back and forth in time. However, visual inspection of the thin sections was necessary to confirm detection of missing or false laminae by TSAP-Win (R). For all three Zoo-rez speleothems, crossdating of the mean lamina thickness series was not possible due to a missing common pattern. The cross-dating procedure results in three refined chronologies for the three Zoo-rez stalagmites of ranging from AD 1821-1970 (Zoo-rez-1), AD 1835-1970 (Zoo-rez-2), and AD 1808-1970 (Zoo-rez-3).