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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.
Background:
COVID-19 has infected millions of people worldwide and is responsible for several hundred thousand fatalities. The COVID-19 pandemic has necessitated thoughtful resource allocation and early identification of high-risk patients. However, effective methods to meet these needs are lacking.
Objective:
The aims of this study were to analyze the electronic health records (EHRs) of patients who tested positive for COVID-19 and were admitted to hospitals in the Mount Sinai Health System in New York City; to develop machine learning models for making predictions about the hospital course of the patients over clinically meaningful time horizons based on patient characteristics at admission; and to assess the performance of these models at multiple hospitals and time points.
Methods:
We used Extreme Gradient Boosting (XGBoost) and baseline comparator models to predict in-hospital mortality and critical events at time windows of 3, 5, 7, and 10 days from admission. Our study population included harmonized EHR data from five hospitals in New York City for 4098 COVID-19-positive patients admitted from March 15 to May 22, 2020. The models were first trained on patients from a single hospital (n=1514) before or on May 1, externally validated on patients from four other hospitals (n=2201) before or on May 1, and prospectively validated on all patients after May 1 (n=383). Finally, we established model interpretability to identify and rank variables that drive model predictions.
Results:
Upon cross-validation, the XGBoost classifier outperformed baseline models, with an area under the receiver operating characteristic curve (AUC-ROC) for mortality of 0.89 at 3 days, 0.85 at 5 and 7 days, and 0.84 at 10 days. XGBoost also performed well for critical event prediction, with an AUC-ROC of 0.80 at 3 days, 0.79 at 5 days, 0.80 at 7 days, and 0.81 at 10 days. In external validation, XGBoost achieved an AUC-ROC of 0.88 at 3 days, 0.86 at 5 days, 0.86 at 7 days, and 0.84 at 10 days for mortality prediction. Similarly, the unimputed XGBoost model achieved an AUC-ROC of 0.78 at 3 days, 0.79 at 5 days, 0.80 at 7 days, and 0.81 at 10 days. Trends in performance on prospective validation sets were similar. At 7 days, acute kidney injury on admission, elevated LDH, tachypnea, and hyperglycemia were the strongest drivers of critical event prediction, while higher age, anion gap, and C-reactive protein were the strongest drivers of mortality prediction.
Conclusions:
We externally and prospectively trained and validated machine learning models for mortality and critical events for patients with COVID-19 at different time horizons. These models identified at-risk patients and uncovered underlying relationships that predicted outcomes.
River ecosystems receive and process vast quantities of terrestrial organic carbon, the fate of which depends strongly on microbial activity. Variation in and controls of processing rates, however, are poorly characterized at the global scale. In response, we used a peer-sourced research network and a highly standardized carbon processing assay to conduct a global-scale field experiment in greater than 1000 river and riparian sites. We found that Earth’s biomes have distinct carbon processing signatures. Slow processing is evident across latitudes, whereas rapid rates are restricted to lower latitudes. Both the mean rate and variability decline with latitude, suggesting temperature constraints toward the poles and greater roles for other environmental drivers (e.g., nutrient loading) toward the equator. These results and data set the stage for unprecedented “next-generation biomonitoring” by establishing baselines to help quantify environmental impacts to the functioning of ecosystems at a global scale.
We report the discovery of an unidentified, extended source of very-high-energy gamma-ray emission, VER J2019+407, within the radio shell of the supernova remnant SNR G78.2+2.1, using 21.4 hr of data taken by the VERITAS gamma-ray observatory in 2009. These data confirm the preliminary indications of gamma-ray emission previously seen in a two-year (2007-2009) blind survey of the Cygnus region by VERITAS. VER J2019+407, which is detected at a post-trials significance of 7.5 standard deviations in the 2009 data, is localized to the northwestern rim of the remnant in a region of enhanced radio and X-ray emission. It has an intrinsic extent of 0 degrees.23 +/- 0 degrees.03(stat-0 degrees.02sys)(+0 degrees.04) and its spectrum is well-characterized by a differential power law (dN/dE = N-0 x (E/TeV)-Gamma) with a photon index of Gamma = 2.37 +/- 0.14(stat) +/- 0.20(sys) and a flux normalization of N-0 = 1.5 +/- 0.2(stat) +/- 0.4(sys) x 10(-12) photon TeV-1 cm(-2) s(-1). This yields an integral flux of 5.2 +/- 0.8(stat) +/- 1.4(sys) x 10(-12) photon cm(-2) s(-1) above 320 GeV, corresponding to 3.7% of the Crab Nebula flux. We consider the relationship of the TeV gamma-ray emission with the GeV gamma-ray emission seen from SNR G78.2+2.1 as well as that seen from a nearby cocoon of freshly accelerated cosmic rays. Multiple scenarios are considered as possible origins for the TeV gamma-ray emission, including hadronic particle acceleration at the SNR shock.
Understanding the association between autonomic nervous system [ANS] function and brain morphology across the lifespan provides important insights into neurovisceral mechanisms underlying health and disease. Resting-state ANS activity, indexed by measures of heart rate [HR] and its variability [HRV] has been associated with brain morphology, particularly cortical thickness [CT]. While findings have been mixed regarding the anatomical distribution and direction of the associations, these inconsistencies may be due to sex and age differences in HR/HRV and CT. Previous studies have been limited by small sample sizes, which impede the assessment of sex differences and aging effects on the association between ANS function and CT. To overcome these limitations, 20 groups worldwide contributed data collected under similar protocols of CT assessment and HR/HRV recording to be pooled in a mega-analysis (N = 1,218 (50.5% female), mean age 36.7 years (range: 12-87)). Findings suggest a decline in HRV as well as CT with increasing age. CT, particularly in the orbitofrontal cortex, explained additional variance in HRV, beyond the effects of aging. This pattern of results may suggest that the decline in HRV with increasing age is related to a decline in orbitofrontal CT. These effects were independent of sex and specific to HRV; with no significant association between CT and HR. Greater CT across the adult lifespan may be vital for the maintenance of healthy cardiac regulation via the ANS-or greater cardiac vagal activity as indirectly reflected in HRV may slow brain atrophy. Findings reveal an important association between CT and cardiac parasympathetic activity with implications for healthy aging and longevity that should be studied further in longitudinal research.
We present varve chronologies for sediments from two maar lakes in the Valle de Santiago region (Central Mexico): Hoya La Alberca (AD 1852-1973) and Hoya Rincn de Parangueo (AD 1839-1943). These are the first varve chronologies for Mexican lakes. The varved sections were anchored with tephras from Colima (1913) and Paricutin (1943/1944) and (210)Pb ages. We compare the sequences using the thickness of seasonal laminae and element counts (Al, Si, S, Cl, K, Ti, Mn, Fe, and Sr) determined by micro X-ray fluorescence spectrometry. The formation of the varve sublaminae is attributed to the strongly seasonal climate regime. Limited rainfall and high evaporation rates in winter and spring induce precipitation of carbonates (high Ca, Sr) enriched in (13)C and (18)O, whereas rainfall in summer increases organic and clastic input (plagioclase, quartz) with high counts of lithogenic elements (K, Al, Ti, and Si). Eolian input of Ti occurs also in the dry season. Moving correlations (5-yr windows) of the Ca and Ti counts show similar development in both sequences until the 1930s. Positive correlations indicate mixing of allochthonous Ti and autochthonous Ca, while negative correlations indicate their separation in sublaminae. Negative excursions in the correlations correspond with historic and reconstructed droughts, El Nio events, and positive SST anomalies. Based on our data, droughts (3-7 year duration) were severe and centred around the following years: the early 1850s, 1865, 1880, 1895, 1905, 1915 and the late 1920s with continuation into the 1930s. The latter dry period brought both lake systems into a critical state making them susceptible to further drying. Groundwater overexploitation due to the expansion of irrigation agriculture in the region after 1940 induced the transition from calcite to aragonite precipitation in Alberca and halite infiltration in Rincn. The proxy data indicate a faster response to increased evaporation for Rincn, the lake with the larger maar dimensions, solar radiation receipt and higher conductivity, whereas the smaller, steeper Alberca maar responded rapidly to increased precipitation.
We present varve chronologies for sediments from two maar lakes in the Valle de Santiago region (Central Mexico): Hoya La Alberca (AD 1852-1973) and Hoya Rincn de Parangueo (AD 1839-1943). These are the first varve chronologies for Mexican lakes. The varved sections were anchored with tephras from Colima (1913) and Paricutin (1943/ 1944) and Pb-210 ages. We compare the sequences using the thickness of seasonal laminae and element counts (Al, Si, S, Cl, K, Ti, Mn, Fe, and Sr) determined by micro X-ray fluorescence spectrometry. The formation of the varve sublaminae is attributed to the strongly seasonal climate regime. Limited rainfall and high evaporation rates in winter and spring induce precipitation of carbonates (high Ca, Sr) enriched in C-13 and O-18, whereas rainfall in summer increases organic and clastic input (plagioclase, quartz) with high counts of lithogenic elements (K, Al, Ti, and Si). Eolian input of Ti occurs also in the dry season. Moving correlations (5-yr windows) of the Ca and Ti counts show similar development in both sequences until the 1930s. Positive correlations indicate mixing of allochthonous Ti and autochthonous Ca, while negative correlations indicate their separation in sublaminae. Negative excursions in the correlations correspond with historic and reconstructed droughts, El Nio events, and positive SST anomalies. Based on our data, droughts (3-7 year duration) were severe and centred around the following years: the early 1850s, 1865, 1880, 1895, 1905, 1915 and the late 1920s with continuation into the 1930s. The latter dry period brought both lake systems into a critical state making them susceptible to further drying. Groundwater overexploitation due to the expansion of irrigation agriculture in the region after 1940 induced the transition from calcite to aragonite precipitation in Alberca and halite infiltration in Rincn. The proxy data indicate a faster response to increased evaporation for Rincn, the lake with the larger maar dimensions, solar radiation receipt and higher conductivity, whereas the smaller, steeper Alberca maar responded rapidly to increased precipitation.
As the oldest known magnetic material, magnetite (Fe3O4) has fascinated mankind for millennia. As the first oxide in which a relationship between electrical conductivity and fluctuating/localized electronic order was shown(1), magnetite represents a model system for understanding correlated oxides in general. Nevertheless, the exact mechanism of the insulator-metal, or Verwey, transition has long remained inaccessible(2-8). Recently, three- Fe- site lattice distortions called trimeronswere identified as the characteristic building blocks of the low-temperature insulating electronically ordered phase(9). Here we investigate the Verwey transition with pump- probe X- ray diffraction and optical reflectivity techniques, and show how trimerons become mobile across the insulator-metal transition. We find this to be a two- step process. After an initial 300 fs destruction of individual trimerons, phase separation occurs on a 1.5 +/- 0.2 ps timescale to yield residual insulating and metallic regions. This work establishes the speed limit for switching in future oxide electronics(10).
Myriapods (e. g., centipedes and millipedes) display a simple homonomous body plan relative to other arthropods. All members of the class are terrestrial, but they attained terrestriality independently of insects. Myriapoda is the only arthropod class not represented by a sequenced genome. We present an analysis of the genome of the centipede Strigamia maritima. It retains a compact genome that has undergone less gene loss and shuffling than previously sequenced arthropods, and many orthologues of genes conserved from the bilaterian ancestor that have been lost in insects. Our analysis locates many genes in conserved macro-synteny contexts, and many small-scale examples of gene clustering. We describe several examples where S. maritima shows different solutions from insects to similar problems. The insect olfactory receptor gene family is absent from S. maritima, and olfaction in air is likely effected by expansion of other receptor gene families. For some genes S. maritima has evolved paralogues to generate coding sequence diversity, where insects use alternate splicing. This is most striking for the Dscam gene, which in Drosophila generates more than 100,000 alternate splice forms, but in S. maritima is encoded by over 100 paralogues. We see an intriguing linkage between the absence of any known photosensory proteins in a blind organism and the additional absence of canonical circadian clock genes. The phylogenetic position of myriapods allows us to identify where in arthropod phylogeny several particular molecular mechanisms and traits emerged. For example, we conclude that juvenile hormone signalling evolved with the emergence of the exoskeleton in the arthropods and that RR-1 containing cuticle proteins evolved in the lineage leading to Mandibulata. We also identify when various gene expansions and losses occurred. The genome of S. maritima offers us a unique glimpse into the ancestral arthropod genome, while also displaying many adaptations to its specific life history.
Observations of radio halos and relics in galaxy clusters indicate efficient electron acceleration. Protons should likewise be accelerated and, on account of weak energy losses, can accumulate, suggesting that clusters may also be sources of very high energy (VHE; E > 100 GeV) gamma-ray emission. We report here on VHE gamma-ray observations of the Coma galaxy cluster with the VERITAS array of imaging Cerenkov telescopes, with complementing Fermi Large Area Telescope observations at GeV energies. No significant gamma-ray emission from the Coma Cluster was detected. Integral flux upper limits at the 99% confidence level were measured to be on the order of (2-5) x 10(-8) photonsm(-2) s(-1) (VERITAS, >220 GeV) and similar to 2 x 10(-6) photonsm(-2) s(-1) (Fermi, 1-3GeV), respectively. We use the gamma-ray upper limits to constrain cosmic rays (CRs) and magnetic fields in Coma. Using an analytical approach, the CR-to-thermal pressure ratio is constrained to be < 16% from VERITAS data and <1.7% from Fermi data (averaged within the virial radius). These upper limits are starting to constrain the CR physics in self-consistent cosmological cluster simulations and cap the maximum CR acceleration efficiency at structure formation shocks to be <50%. Alternatively, this may argue for non-negligible CR transport processes such as CR streaming and diffusion into the outer cluster regions. Assuming that the radio-emitting electrons of the Coma halo result from hadronic CR interactions, the observations imply a lower limit on the central magnetic field in Coma of similar to(2-5.5) mu G, depending on the radial magnetic field profile and on the gamma-ray spectral index. Since these values are below those inferred by Faraday rotation measurements in Coma (for most of the parameter space), this renders the hadronic model a very plausible explanation of the Coma radio halo. Finally, since galaxy clusters are dark matter (DM) dominated, the VERITAS upper limits have been used to place constraints on the thermally averaged product of the total self-annihilation cross section and the relative velocity of the DM particles, <sigma nu >.