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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.
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.
The selaginella genome identifies genetic changes associated with the evolution of vascular plants
(2011)
Vascular plants appeared similar to 410 million years ago, then diverged into several lineages of which only two survive: the euphyllophytes (ferns and seed plants) and the lycophytes. We report here the genome sequence of the lycophyte Selaginella moellendorffii (Selaginella), the first nonseed vascular plant genome reported. By comparing gene content in evolutionarily diverse taxa, we found that the transition from a gametophyte- to a sporophyte-dominated life cycle required far fewer new genes than the transition from a nonseed vascular to a flowering plant, whereas secondary metabolic genes expanded extensively and in parallel in the lycophyte and angiosperm lineages. Selaginella differs in posttranscriptional gene regulation, including small RNA regulation of repetitive elements, an absence of the trans-acting small interfering RNA pathway, and extensive RNA editing of organellar genes.
This study examined changes in sweet cherry buds of ‘Summit’ cultivar in four seasons (2011/12–2014/15) with respect to the nitrogen (N) content and the profile of eight free amino acids (asparagine (Asn), aspartic acid (Asp), isoleucine (Ile), glutamine (Gln), glutamic acid (Glu), arginine (Arg), alanine (Ala), histidine (His)). The presented results are to our knowledge the first under natural conditions in fruit tree orchards with a high temporal resolution from the dormant stage until cluster development. The N content in the buds from October, during endo- and ecodormancy until the beginning of ontogenetic development was a relatively stable parameter in each of the four seasons. The N accumulation into the buds began after ‘swollen bud’ and significant differences were visible at ‘green tip’ with an N content of 3.24, 3.12, 3.08, 2.40 which increased markedly to the mean of ‘tight’ and ‘open cluster’ by 3.77%, 3.78%, 3.44% and 3.10% in 2012–2015, respectively. In the buds, levels of asparagine were higher (up to 44 mg g−1 DW−1) than aspartic acid (up to 2 mg g−1 DW−1) and aspartic acid higher than isoleucine (up to 0.83 mg g−1 DW−1). Levels of glutamine were higher (up to 25 mg g−1 DW−1) than glutamic acid (up to 20 mg g−1 DW−1). The course of the arginine content was higher in 2011/12 compared to 2012/13, 2013/14 and 2014/15 which showed only slight differences. The alanine content in the buds was denoted in the four seasons only by relatively minor changes. The histidine content was higher in 2011/12 and 2012/13 compared to 2013/14 and 2014/15 which showed a comparable pattern. For 6 amino acids (Asn, Asp, Ile, Glu, Arg, Ala), the highest content was observed in 2012/13, the warmest period between swollen bud and open cluster. However in 2014/15, the season with the lowest mean temperature of 8.8 °C, only the content of Gln was the lowest. It was not possible to explain any seasonal differences in the amino acid content by environmental factors (air temperature) on the basis of few seasons. From none of the measured free amino acids could a clear determination of the date of endodormancy release (t1) or the beginning of the ontogenetic development (t1*) be derived. Therefore, these amino acids are no suitable markers to improve phenological models for the beginning of cherry blossom.
X-ray free-electron lasers have, over the past decade, opened up the possibility of understanding the ultrafast response of matter to intense X-ray pulses. In earlier research on atoms and small molecules, new aspects of this response were uncovered, such as rapid sequences of inner-shell photoionization and Auger ionization. Here, we studied a larger molecule, buckminsterfullerene (C-60), exposed to 640 eV X-rays, and examined the role of chemical effects, such as chemical bonds and charge transfer, on the fragmentation following multiple ionization of the molecule. To provide time resolution, we performed femtosecond-resolved X-ray pump/X-ray probe measurements, which were accompanied by advanced simulations. The simulations and experiment reveal that despite substantial ionization induced by the ultrashort (20 fs) X-ray pump pulse, the fragmentation of C-60 is considerably delayed. This work uncovers the persistence of the molecular structure of C-60, which hinders fragmentation over a timescale of hundreds of femtoseconds. Furthermore, we demonstrate that a substantial fraction of the ejected fragments are neutral carbon atoms. These findings provide insights into X-ray free-electron laser-induced radiation damage in large molecules, including biomolecules.
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.
Horse domestication revolutionized warfare and accelerated travel, trade, and the geographic expansion of languages. Here, we present the largest DNA time series for a non-human organism to date, including genome-scale data from 149 ancient animals and 129 ancient genomes (>= 1-fold coverage), 87 of which are new. This extensive dataset allows us to assess the modem legacy of past equestrian civilisations. We find that two extinct horse lineages existed during early domestication, one at the far western (Iberia) and the other at the far eastern range (Siberia) of Eurasia. None of these contributed significantly to modern diversity. We show that the influence of Persian-related horse lineages increased following the Islamic conquests in Europe and Asia. Multiple alleles associated with elite-racing, including at the MSTN "speed gene," only rose in popularity within the last millennium. Finally, the development of modem breeding impacted genetic diversity more dramatically than the previous millennia of human management.
Reproducibility is a defining feature of science, but the extent to which it characterizes current research is unknown. We conducted replications of 100 experimental and correlational studies published in three psychology journals using high-powered designs and original materials when available. Replication effects were half the magnitude of original effects, representing a substantial decline. Ninety-seven percent of original studies had statistically significant results. Thirty-six percent of replications had statistically significant results; 47% of original effect sizes were in the 95% confidence interval of the replication effect size; 39% of effects were subjectively rated to have replicated the original result; and if no bias in original results is assumed, combining original and replication results left 68% with statistically significant effects. Correlational tests suggest that replication success was better predicted by the strength of original evidence than by characteristics of the original and replication teams.
Aus dem Inhalt: - Die Multidimensionalität der Menschenrechte – Chance oder Gefahr für den universellen Menschenrechtsschutz? - Völkerrechtliche Fragen des Einsatzes bewaffneter Drohnen: Menschenrechtsschutz versus Terrorismusbekämpfung? - Bericht über die Tätigkeit des Menschenrechtsausschusses der Vereinten Nationen im Jahre 2012 – Teil II: Individualbeschwerden
Primary cultures of cardiac muscle cells as models for investigation of protein glycosylation
(1996)
CXCL12-CXCR4 signaling controls multiple physiological processes and its dysregulation is associated with cancers and inflammatory diseases. To discover as-yet-unknown endogenous ligands of CXCR4, we screened a blood-derived peptide library for inhibitors of CXCR4-tropic HIV-1 strains. This approach identified a 16 amino acid fragment of serum albumin as an effective and highly specific CXCR4 antagonist. The endogenous peptide, termed EPI-X4, is evolutionarily conserved and generated from the highly abundant albumin precursor by pH-regulated proteases. EPI-X4 forms an unusual lasso-like structure and antagonizes CXCL12-induced tumor cell migration, mobilizes stem cells, and suppresses inflammatory responses in mice. Furthermore, the peptide is abundant in the urine of patients with inflammatory kidney diseases and may serve as a biomarker. Our results identify EPI-X4 as a key regulator of CXCR4 signaling and introduce proteolysis of an abundant precursor protein as an alternative concept for chemokine receptor regulation.
SwSt 1 (PN G001.5-06.7) is a bright and compact planetary nebula containing a late [WC]-type central star. Previous studies suggested that the nebular and stellar lines are slowly changing with time. We studied new and archival optical and ultraviolet spectra of the object. The [O III] 4959 and 5007 angstrom to H beta line flux ratios decreased between about 1976 and 1997/2015. The stellar spectrum also shows changes between these epochs. We modelled the stellar and nebular spectra observed at different epochs. The analyses indicate a drop of the stellar temperature from about 42 kK to 40.5 kK between 1976 and 1993. We do not detect significant changes between 1993 and 2015. The observations show that the star performed a loop in the H-R diagram. This is possible when a shell source is activated during its post-AGB evolution. We infer that a late thermal pulse (LTP) experienced by a massive post-AGB star can explain the evolution of the central star. Such a star does not expand significantly as the result of the LTP and does not became a born-again red giant. However, the released energy can remove the tiny H envelope of the star.
Steuern und Abgaben auf Produkte oder Verbrauch mit gesellschaftlichen Folgekosten (externe Kosten) – sogenannte Pigou- oder Lenkungssteuern – sind ein gesellschaftliches „Win-Win-Instrument“. Sie verbessern die Wohlfahrt und schützen gleichzeitig die Umwelt und das Klima. Dies wird erreicht, indem umweltschädigende Aktivitäten einen Preis bekommen, der möglichst exakt der Höhe des Schadens entspricht. Eine konsequente Bepreisung der externen Kosten nach diesem Prinzip könnte in Deutschland erhebliche zusätzliche Einnahmen erbringen: Basierend auf bisherigen Studien zu externen Kosten wären zusätzliche Einnahmen in der Größenordnung von 348 bis 564 Milliarden Euro pro Jahr (44 bis 71 Prozent der gesamten Steuereinnahmen) möglich. Die Autoren warnen allerdings, dass die Bezifferung der externen Kosten mit erheblichen Unsicherheiten verbunden ist. Damit Lenkungssteuern und -abgaben ihre positiven Lenkungs- und Wohlstandseffekte voll entfalten können, seien zudem institutionelle Reformen notwendig.
Recent experiments using time- and angle-resolved two-photon photoemission (2PPE) spectroscopy at metal/polar adsorbate interfaces succeeded in time-dependent analysis of the process of electron solvation. A fully quantum mechanical, two-dimensional simulation of this process, which explicitly includes laser excitation, is presented here, confirming the origin of characteristic features, such as the experimental observation of an apparently negative dispersion. The inference of the spatial extent of the localized electron states from the angular dependence of the 2PPE spectra has been found to be non-trivial and system-dependent. (C) 2005 American Institute of Physics
Tula virus (TULV) is a vole-associated hantavirus with low or no pathogenicity to humans. In the present study, 686 common voles (Microtus arvalis), 249 field voles (Microtus agrestis) and 30 water voles (Arvicola spec.) were collected at 79 sites in Germany, Luxembourg and France and screened by RT-PCR and TULV-IgG ELISA. TULV-specific RNA and/or antibodies were detected at 43 of the sites, demonstrating a geographically widespread distribution of the virus in the studied area. The TULV prevalence in common voles (16.7 %) was higher than that in field voles (9.2 %) and water voles (10.0 %). Time series data at ten trapping sites showed evidence of a lasting presence of TULV RNA within common vole populations for up to 34 months, although usually at low prevalence. Phylogenetic analysis demonstrated a strong genetic structuring of TULV sequences according to geography and independent of the rodent species, confirming the common vole as the preferential host, with spillover infections to co-occurring field and water voles. TULV phylogenetic clades showed a general association with evolutionary lineages in the common vole as assessed by mitochondrial DNA sequences on a large geographical scale, but with local-scale discrepancies in the contact areas.
Oxide/water interfaces are ubiquitous in a wide variety of applications and the environment. Despite this ubiquity, and attendant decades of study, gaining molecular level insight into water/oxide interaction has proven challenging. In part, this challenge springs from a lack of tools to concurrently characterize changes in surface structure (i.e., water/oxide interaction from the perspective of the solid) and O-H population and local environment (i.e., water/oxide interaction from the water perspective). Here, we demonstrate the application of surface specific vibrational spectroscopy to the characterization of the interaction of the paradigmatic alpha-Al2O3(0001) surface and water. By probing both the interfacial Al-O (surface phonon) and O-H spectral response, we characterize this interaction from both perspectives. Through electronic structure calculation, we assign the interfacial Al-O response and rationalize its changes on surface dehydroxylation and reconstruction. Because our technique is all-optical and interface specific, it is equally applicable to oxide surfaces in vacuum, ambient atmospheres and at the solid/liquid interface. Application of this approach to additional alumina surfaces and other oxides thus seems likely to significantly expand our understanding of how water meets oxide surfaces and thus the wide variety of phenomena this interaction controls. (C) 2015 AIP Publishing LLC.
alpha-Al2O3 surfaces are common in both engineered applications and the environment. Much prior work indicates that their properties, e.g., reactivity, polarity, and charge, change dramatically on interaction with water. Perhaps the simplest question that can be asked of alpha-Al2O3/water interaction is how a single water molecule interacts with the most stable alpha-Al2O3 surface: the alpha-Al2O3(0001). Over the last 15 years, a series of theoretical studies have found that water dissociatively adsorbs on alpha-Al2O3(0001) through two channels. However, to our knowledge no experimental evidence of these dissociation pathways has appeared. By combining sample preparation via supersonic molecular beam dosing, sample characterization via coherent, surface specific vibrational spectroscopy and electronic structure theory, we report the first experimental observation of reaction products of each, theoretically predicted, dissociation channel. These results thus overcome a 15 year old experiment/theory disconnect and make possible a variety of intriguing experiments that promise to provide significant new insights into water/Al2O3 and water/oxide interaction more generally.
On their way from inland to the ocean, flowing water bodies, their constituents and their biotic communities are ex-posed to complex transport and transformation processes. However, detailed process knowledge as revealed by La-grangian measurements adjusted to travel time is rare in large rivers, in particular at hydrological extremes. To fill this gap, we investigated autotrophic processes, heterotrophic carbon utilization, and micropollutant concentrations applying a Lagrangian sampling design in a 600 km section of the River Elbe (Germany) at historically low discharge. Under base flow conditions, we expect the maximum intensity of instream processes and of point source impacts. Phy-toplankton biomass and photosynthesis increased from upstream to downstream sites but maximum chlorophyll con-centration was lower than at mean discharge. Concentrations of dissolved macronutrients decreased to almost complete phosphate depletion and low nitrate values. The longitudinal increase of bacterial abundance and production was less pronounced than in wetter years and bacterial community composition changed downstream. Molecular analyses revealed a longitudinal increase of many DOM components due to microbial production, whereas saturated lipid-like DOM, unsaturated aromatics and polyphenols, and some CHOS surfactants declined. In decomposition exper-iments, DOM components with high O/C ratios and high masses decreased whereas those with low O/C ratios, low masses, and high nitrogen content increased at all sites. Radiocarbon age analyses showed that DOC was relatively old (890-1870 years B.P.), whereas the mineralized fraction was much younger suggesting predominant oxidation of algal lysis products and exudates particularly at downstream sites. Micropollutants determining toxicity for algae (terbuthylazine, terbutryn, isoproturon and lenacil), hexachlorocyclohexanes and DDTs showed higher concentrations from the middle towards the downstream part but calculated toxicity was not negatively correlated to phytoplankton. Overall, autotrophic and heterotrophic process rates and micropollutant concentrations increased from up-to down-stream reaches, but their magnitudes were not distinctly different to conditions at medium discharges.