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- acute kidney injury (2)
- end-stage kidney disease (2)
- genome-wide association (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.
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.
Multiple P-T-d-t paths reveal the evolution of the final Nuna assembly in northeast Australia
(2020)
The final assembly of the Mesoproterozoic supercontinent Nuna was marked by the collision of Laurentia and Australia at 1.60 Ga, which is recorded in the Georgetown Inlier of NE Australia. Here, we decipher the metamorphic evolution of this final Nuna collisional event using petrostructural analysis, major and trace element compositions of key minerals, thermodynamic modelling, and multi-method geochronology. The Georgetown Inlier is characterised by deformed and metamorphosed 1.70-1.62 Ga sedimentary and mafic rocks, which were intruded byc. 1.56 Ga old S-type granites. Garnet Lu-Hf and monazite U-Pb isotopic analyses distinguish two major metamorphic events (M1 atc. 1.60 Ga and M2 atc. 1.55 Ga), which allows at least two composite fabrics to be identified at the regional scale-c. 1.60 Ga S1 (consisting in fabrics S1a and S1b) andc. 1.55 Ga S2 (including fabrics S2a and S2b). Also, three tectono-metamorphic domains are distinguished: (a) the western domain, with S1 defined by low-P(LP) greenschist facies assemblages; (b) the central domain, where S1 fabric is preserved as medium-P(MP) amphibolite facies relicts, and locally as inclusion trails in garnet wrapped by the regionally dominant low-Pamphibolite facies S2 fabric; and (c) the eastern domain dominated by upper amphibolite to granulite facies S2 foliation. In the central domain, 1.60 GaMP-medium-T(MT) metamorphism (M1) developed within the staurolite-garnet stability field, with conditions ranging from 530-550 degrees C at 6-7 kbar (garnet cores) to 620-650 degrees C at 8-9 kbar (garnet rims), and it is associated with S1 fabric. The onset of 1.55 GaLP-high-T(HT) metamorphism (M2) is marked by replacement of staurolite by andalusite (M2a/D2a), which was subsequently pseudomorphed by sillimanite (M2b/D2b) where granite and migmatite are abundant.P-Tconditions ranged from 600 to 680 degrees C and 4-6 kbar for the M2b sillimanite stage. 1.60 Ga garnet relicts within the S2 foliation highlight the progressive obliteration of the S1 fabric by regional S2 in the central zone during peak M2 metamorphism. In the eastern migmatitic complex, partial melting of paragneiss and amphibolite occurred syn- to post-S2, at 730-770 degrees C and 6-8 kbar, and at 750-790 degrees C and 6 kbar, respectively. The pressure-temperature-deformation-time paths reconstructed for the Georgetown Inlier suggest ac. 1.60 Ga M1/D1 event recorded under greenschist facies conditions in the western domain and under medium-Pand medium-Tconditions in the central domain. This event was followed by the regional 1.56-1.54 Ga low-Pand high-Tphase (M2/D2), extensively recorded in the central and eastern domains. Decompression between these two metamorphic events is ascribed to an episode of exhumation. The two-stage evolution supports the previous hypothesis that the Georgetown Inlier preserves continental collisional and subsequent thermal perturbation associated with granite emplacement.
High-resolution surface velocities and strain for Anatolia from Sentinel-1 InSAR and GNSS data
(2020)
Measurements of present-day surface deformation are essential for the assessment of long-term seismic hazard. The European Space Agency's Sentinel-1 satellites enable global, high-resolution observation of crustal motion from Interferometric Synthetic Aperture Radar (InSAR). We have developed automated InSAR processing systems that exploit the first similar to 5 years of Sentinel-1 data to measure surface motions for the similar to 800,000-km(2) Anatolian region. Our new 3-D velocity and strain rate fields illuminate deformation patterns dominated by westward motion of Anatolia relative to Eurasia, localized strain accumulation along the North and East Anatolian Faults, and rapid vertical signals associated with anthropogenic activities and to a lesser extent extension across the grabens of western Anatolia. We show that automatically processed Sentinel-1 InSAR data can characterize details of the velocity and strain rate fields with high resolution and accuracy over large regions. These results are important for assessing the relationship between strain accumulation and release in earthquakes. <br /> Plain Language Summary Satellite-based measurements of small rates of motion of the Earth's surface made at high spatial resolutions and over large areas are important for many geophysical applications including improving earthquake hazard models. We take advantage of recent advances in geodetic techniques in order to measure surface velocities and tectonic strain accumulation across the Anatolia region, including the highly seismogenic and often deadly North Anatolian Fault. We show that by combining Sentinel-1 Interferometric Synthetic Aperture Radar (InSAR) data with Global Navigation Satellite System (GNSS) measurements we can enhance our view of surface deformation associated with active tectonics, the earthquake cycle, and anthropogenic processes.
The UK Biobank is a prospective study of 502,543 individuals, combining extensive phenotypic and genotypic data with streamlined access for researchers around the world(1). Here we describe the release of exome-sequence data for the first 49,960 study participants, revealing approximately 4 million coding variants (of which around 98.6% have a frequency of less than 1%). The data include 198,269 autosomal predicted loss-of-function (LOF) variants, a more than 14-fold increase compared to the imputed sequence. Nearly all genes (more than 97%) had at least one carrier with a LOF variant, and most genes (more than 69%) had at least ten carriers with a LOF variant. We illustrate the power of characterizing LOF variants in this population through association analyses across 1,730 phenotypes. In addition to replicating established associations, we found novel LOF variants with large effects on disease traits, includingPIEZO1on varicose veins,COL6A1on corneal resistance,MEPEon bone density, andIQGAP2andGMPRon blood cell traits. We further demonstrate the value of exome sequencing by surveying the prevalence of pathogenic variants of clinical importance, and show that 2% of this population has a medically actionable variant. Furthermore, we characterize the penetrance of cancer in carriers of pathogenicBRCA1andBRCA2variants. Exome sequences from the first 49,960 participants highlight the promise of genome sequencing in large population-based studies and are now accessible to the scientific community. <br /> Exome sequences from the first 49,960 participants in the UK Biobank highlight the promise of genome sequencing in large population-based studies and are now accessible to the scientific community.
Renormalisation and locality
(2020)
Five known compounds (1-5) were isolated from the extract of Mundulea sericea leaves. Similar investigation of the roots of this plant afforded an additional three known compounds (6-8). The structures were elucidated using NMR spectroscopic and mass spectrometric analyses. The absolute configuration of 1 was established using ECD spectroscopy. In an antiplasmodial activity assay, compound 1 showed good activity with an IC50 of 2.0 mu M against chloroquine-resistant W2, and 6.6 mu M against the chloroquine-sensitive 3D7 strains of Plasmodium falciparum. Some of the compounds were also tested for antileishmanial activity. Dehydrolupinifolinol (2) and sericetin (5) were active against drug-sensitive Leishmania donovani (MHOM/IN/83/AG83) with IC50 values of 9.0 and 5.0 mu M, respectively. In a cytotoxicity assay, lupinifolin (3) showed significant activity on BEAS-2B (IC50 4.9 mu M) and HePG2 (IC50 10.8 mu M) human cell lines. All the other compounds showed low cytotoxicity (IC50 > 30 mu M) against human lung adenocarcinoma cells (A549), human liver cancer cells (HepG2), lung/bronchus cells (epithelial virus transformed) (BEAS-2B) and immortal human hepatocytes (LO2)