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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.
Many lakes exhibit seasonal stratification, during which they develop strong thermal and chemical gradients. An expansion of depth-integrated monitoring programs has provided insight into the importance of organic carbon processing that occurs below the upper mixed layer. However, the chemical and physical drivers of metabolism and metabolic coupling remain unresolved, especially in the metalimnion. In this depth zone, sharp gradients in key resources such as light and temperature co-occur with dynamic physical conditions that influence metabolic processes directly and simultaneously hamper the accurate tracing of biological activity. We evaluated the drivers of metalimnetic metabolism and its associated uncertainty across 10 stratified lakes in Europe and North America. We hypothesized that the metalimnion would contribute highly to whole-lake functioning in clear oligotrophic lakes, and that metabolic rates would be highly variable in unstable polymictic lakes. Depth-integrated rates of gross primary production (GPP) and ecosystem respiration (ER) were modelled from diel dissolved oxygen curves using a Bayesian approach. Metabolic estimates were more uncertain below the epilimnion, but uncertainty was not consistently related to lake morphology or mixing regime. Metalimnetic rates exhibited high day-to-day variability in all trophic states, with the metalimnetic contribution to daily whole-lake GPP and ER ranging from 0% to 87% and < 1% to 92%, respectively. Nonetheless, the metalimnion of low-nutrient lakes contributed strongly to whole-lake metabolism on average, driven by a collinear combination of highlight, low surface-water phosphorous concentration and high metalimnetic volume. Consequently, a single-sensor approach does not necessarily reflect whole-ecosystem carbon dynamics in stratified lakes.
Moving in the Anthropocene
(2018)
Animal movement is fundamental for ecosystem functioning and species survival, yet the effects of the anthropogenic footprint on animal movements have not been estimated across species. Using a unique GPS-tracking database of 803 individuals across 57 species, we found that movements of mammals in areas with a comparatively high human footprint were on average one-half to one-third the extent of their movements in areas with a low human footprint. We attribute this reduction to behavioral changes of individual animals and to the exclusion of species with long-range movements from areas with higher human impact. Global loss of vagility alters a key ecological trait of animals that affects not only population persistence but also ecosystem processes such as predator-prey interactions, nutrient cycling, and disease transmission.
The effects of climate and topography on soil physico-chemical and microbial parameters were studied along an extensive latitudinal climate gradient in the Coastal Cordillera of Chile (26 degrees-38 degrees S). The study sites encompass arid (Pan de Azucar), semiarid (Santa Gracia), mediterranean (La Campana) and humid (Nahuelbuta) climates and vegetation, ranging from arid desert, dominated by biological soil crusts (biocrusts), semiarid shrubland and mediterranean sclerophyllous forest, where biocrusts are present but do have a seasonal pattern to temperate-mixed forest, where biocrusts only occur as an early pioneering development stage after disturbance. All soils originate from granitic parent materials and show very strong differences in pedogenesis intensity and soil depth. Most of the investigated physical, chemical and microbiological soil properties showed distinct trends along the climate gradient. Further, abrupt changes between the arid northernmost study site and the other semi-arid to humid sites can be shown, which indicate non-linearity and thresholds along the climate gradient. Clay and total organic carbon contents (TOC) as well as Ah horizons and solum depths increased from arid to humid climates, whereas bulk density (BD), pH values and base saturation (BS) decreased. These properties demonstrate the accumulation of organic matter, clay formation and element leaching as key-pedogenic processes with increasing humidity. However, the soils in the northern arid climate do not follow this overall latitudinal trend, because texture and BD are largely controlled by aeolian input of dust and sea salts spray followed by the formation of secondary evaporate minerals. Total soil DNA concentrations and TOC increased from arid to humid sites, while areal coverage by biocrusts exhibited an opposite trend. Relative bacterial and archaeal abundances were lower in the arid site, but for the other sites the local variability exceeds the variability along the climate gradient. Differences in soil properties between topographic positions were most pronounced at the study sites with the mediterranean and humid climate, whereas microbial abundances were independent on topography across all study sites. In general, the regional climate is the strongest controlling factor for pedogenesis and microbial parameters in soils developed from the same parent material. Topographic position along individual slopes of limited length augmented this effect only under humid conditions, where water erosion likely relocated particles and elements downward. The change from alkaline to neutral soil pH between the arid and the semi-arid site coincided with qualitative differences in soil formation as well as microbial habitats. This also reflects non-linear relationships of pedogenic and microbial processes in soils depending on climate with a sharp threshold between arid and semi-arid conditions. Therefore, the soils on the transition between arid and semi-arid conditions are especially sensitive and may be well used as indicators of long and medium-term climate changes. Concluding, the unique latitudinal precipitation gradient in the Coastal Cordillera of Chile is predestined to investigate the effects of the main soil forming factor - climate - on pedogenic processes.
A nova is a cataclysmic event on the surface of a white dwarf in a binary system that increases the overall brightness by several orders of magnitude. Although binary systems with a white dwarf are expected to be overabundant in globular clusters compared with in the Galaxy, only two novae from Galactic globular clusters have been observed. We present the discovery of an emission nebula in the Galactic globular cluster M 22 (NGC 6656) in observations made with the integral-field spectrograph MUSE. We extracted the spectrum of the nebula and used the radial velocity determined from the emission lines to confirm that the nebula is part of NGC 6656. Emission-line ratios were used to determine the electron temperature and density. It is estimated to have a mass of 1-17 x 10(-5) M-circle dot. This mass and the emission-line ratios indicate that the nebula is a nova remnant. Its position coincides with the reported location of a "guest star", an ancient Chinese term for transients, observed in May 48 BCE. With this discovery, this nova may be one of the oldest confirmed extra-solar events recorded in human history.
This paper reconsiders the explanation of economic policy from an evolutionary economics perspective. It contrasts the neoclassical equilibrium notions of market and government failure with the dominant evolutionary neo-Schumpeterian and Austrian-Hayekian perceptions. Based on this comparison, the paper criticizes the fact that neoclassical reasoning still prevails in non-equilibrium evolutionary economics when economic policy issues are examined. This is more than surprising, since proponents of evolutionary economics usually view their approach as incompatible with its neoclassical counterpart. In addition, it is shown that this "fallacy of failure thinking" even finds its continuation in the alternative concept of "system failure" with which some evolutionary economists try to explain and legitimate policy interventions in local, regional or national innovation systems. The paper argues that in order to prevent the otherwise fruitful and more realistic evolutionary approach from undermining its own criticism of neoclassical economics and to create a consistent as well as objective evolutionary policy framework, it is necessary to eliminate the equilibrium spirit. Finally, the paper delivers an alternative evolutionary explanation of economic policy which is able to overcome the theory-immanent contradiction of the hitherto evolutionary view on this subject.
Background: To determine the general appearance of normal axillary lymph nodes (LNs) in real-time tissue sonoelastography and to explore the method's potential value in the prediction of LN metastases.
Methods: Axillary LNs in healthy probands (n=165) and metastatic LNs in breast cancer patients (n=15) were examined with palpation, B-mode ultrasound, Doppler and sonoelastography (assessment of the elasticity of the cortex and the medulla). The elasticity distributions were compared and sensitivity (SE) and specificity (SP) were calculated. In an exploratory analysis, positive and negative predictive values (PPV, NPV) were calculated based upon the estimated prevalence of LN metastases in different risk groups.
Results: In the elastogram, the LN cortex was significantly harder than the medulla in both healthy (p=0.004) and metastatic LNs (p=0.005). Comparing healthy and metastatic LNs, there was no difference in the elasticity distribution of the medulla (p=0.281), but we found a significantly harder cortex in metastatic LNs (p=0.006). The SE of clinical examination, B-mode ultrasound, Doppler ultrasound and sonoelastography was revealed to be 13.3%, 40.0%, 14.3% and 60.0%, respectively, and SP was 88.4%, 96.8%, 95.6% and 79.6%, respectively. The highest SE was achieved by the disjunctive combination of B-mode and elastographic features (cortex >3mm in B-mode or blue cortex in the elastogram, SE=73.3%). The highest SP was achieved by the conjunctive combination of B-mode ultrasound and elastography (cortex >3mm in B-mode and blue cortex in the elastogram, SP=99.3%).
Conclusions: Sonoelastography is a feasible method to visualize the elasticity distribution of LNs. Moreover, sonoelastography is capable of detecting elasticity differences between the cortex and medulla, and between metastatic and healthy LNs. Therefore, sonoelastography yields additional information about axillary LN status and can improve the PPV, although this method is still experimental.
Objectives-The purpose of this study was to determine the dependence of breast tissue elasticity on the menstrual cycle of healthy volunteers by means of real-time sonoelastography.
Methods-Twenty-two healthy volunteers (aged 18-33 years) were examined once weekly during two consecutive menstrual cycles using sonoelastography. Group 1 (n = 10) was not taking hormonal medication; group 2 (n = 12) was taking oral contraceptives.
Results-The breast parenchyma appeared softer than the dermis and harder than the adipose tissue, and elasticity varied over the menstrual cycle and between groups. Group 1 (no hormone intake) showed continuously increasing elasticity with relatively soft breast parenchyma in the menstrual and follicular phases and harder parenchyma in the luteal phase (P = .012). Group 2 (oral contraceptives) showed no statistically significant changes in breast parenchymal elasticity according to sonoelastography. The parenchyma was generally softer in group 1 compared with group 2 throughout the menstrual cycle (P = .033). The dermis, the subcutaneous adipose tissue, and the pectoralis major muscle showed no changes in elasticity. Comparison of measurements made during the first and the second menstrual cycles showed similar patterns of elasticity in both groups.
Conclusions-Sonoelastography is a reproducible method that can be used to determine the dependence of breast parenchyma elasticity on the menstrual cycle and on the intake of hormonal contraceptives.