Multi-ancestry Mendelian randomization of omics traits revealing drug targets of COVID-19 severity

BACKGROUND: Recent omic studies prioritised several drug targets associated with coronavirus disease 2019 (COVID-19) severity. However, little evidence was provided to systematically estimate the effect of drug targets on COVID-19 severity in multiple ancestries. METHODS: In this study, we applied Mendelian randomization (MR) and colocalization approaches to understand the putative causal effects of 16,059 transcripts and 1608 proteins on COVID-19 severity in European and effects of 610 proteins on COVID-19 severity in African ancestry. We further integrated genetics, clinical and literature evidence to prioritise drug targets. Additional sensitivity analyses including multi-trait colocalization and phenome-wide MR were conducted to test for MR assumptions. FINDINGS: MR and colocalization prioritized four protein targets, FCRL3, ICAM5, ENTPD5 and OAS1 that showed effect on COVID-19 severity in European ancestry. One protein target, SERPINA1 showed a stronger effect in African ancestry but much weaker effect in European ancestry (odds ratio [OR] in Africans=0.369, 95%CI=0.203 to 0.668, P = 9.96 × 10(−4); OR in Europeans=1.021, 95%CI=0.901 to 1.157, P = 0.745), which suggested that increased level of SERPINA1 will reduce COVID-19 risk in African ancestry. One protein, ICAM1 showed suggestive effect on COVID-19 severity in both ancestries (OR in Europeans=1.152, 95%CI=1.063 to 1.249, P = 5.94 × 10(−4); OR in Africans=1.481, 95%CI=1.008 to 2.176; P = 0.045). The OAS1, SERPINA1 and ICAM1 effects were replicated using updated COVID-19 severity data in the two ancestries respectively, where alternative splicing events in OAS1 and ICAM1 also showed marginal effects on COVID-19 severity in Europeans. The phenome-wide MR of the prioritised targets on 622 complex traits provided information on potential beneficial effects on other diseases and suggested little evidence of adverse effects on major complications. INTERPRETATION: Our study identified six proteins as showing putative causal effects on COVID-19 severity. OAS1 and SERPINA1 were targets of existing drugs in trials as potential COVID-19 treatments. ICAM1, ICAM5 and FCRL3 are related to the immune system. Across the six targets, OAS1 has no reliable instrument in African ancestry; SERPINA1, FCRL3, ICAM5 and ENTPD5 showed a different level of putative causal evidence in European and African ancestries, which highlights the importance of more powerful ancestry-specific GWAS and value of multi-ancestry MR in informing the effects of drug targets on COVID-19 across different populations. This study provides a first step towards clinical investigation of beneficial and adverse effects of COVID-19 drug targets. FUNDING: No

Trans-ethnic Mendelian-randomization study reveals causal relationships between cardiometabolic factors and chronic kidney disease.

Funder: Government Department of BusinessFunder: Energy and Industrial Strategy (BEIS)Funder: Vice-Chancellor Fellowship from the University of BristolFunder: Shanghai Thousand Talents ProgramFunder: Academy of Medical Sciences (AMS) Springboard AwardFunder: BBSRC Innovation fellowshipFunder: NIHR Biomedical Research Centre at University Hospitals Bristol NHS Foundation Trust and the University of BristolBACKGROUND: This study was to systematically test whether previously reported risk factors for chronic kidney disease (CKD) are causally related to CKD in European and East Asian ancestries using Mendelian randomization. METHODS: A total of 45 risk factors with genetic data in European ancestry and 17 risk factors in East Asian participants were identified as exposures from PubMed. We defined the CKD by clinical diagnosis or by estimated glomerular filtration rate of 25 kg/m2. CONCLUSIONS: Eight cardiometabolic risk factors showed causal effects on CKD in Europeans and three of them showed causality in East Asians, providing insights into the design of future interventions to reduce the burden of CKD.This research has been conducted using the UK Biobank resource under Application Numbers ‘40135’ and ‘15825’. J.Z. is funded by a Vice-Chancellor Fellowship from the University of Bristol. This research was also funded by the UK Medical Research Council Integrative Epidemiology Unit [MC_UU_00011/1, MC_UU_00011/4 and MC_UU_00011/7]. J.Z. is supported by the Academy of Medical Sciences (AMS) Springboard Award, the Wellcome Trust, the Government Department of Business, Energy and Industrial Strategy (BEIS), the British Heart Foundation and Diabetes UK [SBF006\1117]. This study was funded/supported by the NIHR Biomedical Research Centre at University Hospitals Bristol NHS Foundation Trust and the University of Bristol (G.D.S., T.R.G. and R.E.W.). This study received funding from the UK Medical Research Council [MR/R013942/1]. J.Z., Y.M.Z. and T.R.G are funded by a BBSRC Innovation fellowship. J.Z. is supported by the Shanghai Thousand Talents Program. Y.M.Z. is supported by the National Natural Science Foundation of China [81800636]. H.Z. is supported by the Training Program of the Major Research Plan of the National Natural Science Foundation of China [91642120], a grant from the Science and Technology Project of Beijing, China [D18110700010000] and the University of Michigan Health System–Peking University Health Science Center Joint Institute for Translational and Clinical Research [BMU2017JI007]. N.F. is supported by the National Institutes of Health awards R01-MD012765, R01-DK117445 and R21-HL140385. R.C. is funded by a Wellcome Trust GW4 Clinical Academic Training Fellowship [WT 212557/Z/18/Z]. The Trøndelag Health Study (the HUNT Study) is a collaboration between HUNT Research Centre (Faculty of Medicine and Health Sciences, NTNU, Norwegian University of Science and Technology), Trøndelag County Council, Central Norway Regional Health Authority and the Norwegian Institute of Public Health. M.C.B. is supported by the UK Medical Research Council (MRC) Skills Development Fellowship [MR/P014054/1]. S.F. is supported by a Wellcome Trust PhD studentship [WT108902/Z/15/Z]. Q.Y. is funded by a China Scholarship Council PhD scholarship [CSC201808060273]. Y.C. was supported by the National Key R&D Program of China [2016YFC0900500, 2016YFC0900501 and 2016YFC0900504]. The China Kadoorie Biobank baseline survey and the first resurvey were supported by a grant from the Kadoorie Charitable Foundation in Hong Kong. The long-term follow-up is supported by grants from the UK Wellcome Trust [202922/Z/16/Z, 088158/Z/09/Z and 104085/Z/14/Z]. Japan-Kidney-Biobank was supported by AMED under Grant Number 20km0405210. P.C.H. is supported by Cancer Research UK [grant number: C18281/A19169]. A.K. was supported by DFG KO 3598/5–1. N.F. is supported by NIH awards R01-DK117445, R01-MD012765 and R21-HL140385. The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health

Current perspectives and trends of the research on hypertensive nephropathy: a bibliometric analysis from 2000 to 2023

AbstractHypertensive nephropathy continues to be a major cause of end-stage renal disease and poses a significant global health burden. Despite the staggering development of research in hypertensive nephropathy, scientists and clinicians can only seek out useful information through articles and reviews, it remains a hurdle for them to quickly track the trend in this field. This study uses the bibliometric method to identify the evolutionary development and recent hotspots of hypertensive nephropathy. The Web of Science Core Collection database was used to extract publications on hypertensive nephropathy from January 2000 to November 2023. CiteSpace was used to capture the patterns and trends from multi-perspectives, including countries/regions, institutions, keywords, and references. In total, 557 publications on hypertensive nephropathy were eligible for inclusion. China (n = 208, 37.34%) was the most influential contributor among all the countries. Veterans Health Administration (n = 19, 3.41%) was found to be the most productive institution. Keyword bursting till now are renal fibrosis, outcomes, and mechanisms which are predicted to be the potential frontiers and hotspots in the future. The top seven references were listed, and their burst strength was shown. A comprehensive overview of the current status and research frontiers of hypertensive nephropathy has been provided through the bibliometric perspective. Recent advancements and challenges in hypertensive nephropathy have been discussed. These findings can offer informative instructions for researchers and scholars

Pretreatment with High-Dose Gamma Irradiation on Seeds Enhances the Tolerance of Sweet Osmanthus Seedlings to Salinity Stress

The landscape application of sweet osmanthus (Osmanthus fragrans) with flower fragrance and high ornamental value is severely limited by salinity stress. Gamma irradiation applied to seeds enhanced their tolerance to salinity stress as reported in other plants. In this study, O. fragrans ‘Huangchuang Jingui’ seeds were pretreated with different doses of gamma irradiation, and tolerance of the seedlings germinated from the irradiated seeds to salinity stress and the changes of reactive oxygen species (ROS) production and ROS scavenging systems induced by gamma irradiation were observed. The results showed that seed pretreatment with different doses of gamma irradiation enhanced the tolerance of sweet osmanthus seedlings to salinity stress, and the positive effect induced by gamma irradiation was more remarkable with the increase of radiation dose (50−150 Gy). The pretreatment with high-dose irradiation decreased O2− production under salinity stress and mitigated the oxidative damage marked by a lower malondialdehyde (MDA) level, which could be related to the significant increase of superoxide dismutase (SOD), peroxidase (POD) and catalase (CAT) activities in the seedlings germinated from the irradiated seeds compared to the corresponding control seedlings. In addition, the accumulation of proline in the irradiated seedlings may contribute to enhancing their tolerance to salt stress by the osmotic adjustment. The study demonstrated the importance of regulating plant ROS balance under salt stress and provided a potential approach to improve the tolerance of sweet osmanthus to salt stress

Current perspectives and trends of the research on hypertensive nephropathy: a bibliometric analysis from 2000 to 2023

Hypertensive nephropathy continues to be a major cause of end-stage renal disease and poses a significant global health burden. Despite the staggering development of research in hypertensive nephropathy, scientists and clinicians can only seek out useful information through articles and reviews, it remains a hurdle for them to quickly track the trend in this field. This study uses the bibliometric method to identify the evolutionary development and recent hotspots of hypertensive nephropathy. The Web of Science Core Collection database was used to extract publications on hypertensive nephropathy from January 2000 to November 2023. CiteSpace was used to capture the patterns and trends from multi-perspectives, including countries/regions, institutions, keywords, and references. In total, 557 publications on hypertensive nephropathy were eligible for inclusion. China (n = 208, 37.34%) was the most influential contributor among all the countries. Veterans Health Administration (n = 19, 3.41%) was found to be the most productive institution. Keyword bursting till now are renal fibrosis, outcomes, and mechanisms which are predicted to be the potential frontiers and hotspots in the future. The top seven references were listed, and their burst strength was shown. A comprehensive overview of the current status and research frontiers of hypertensive nephropathy has been provided through the bibliometric perspective. Recent advancements and challenges in hypertensive nephropathy have been discussed. These findings can offer informative instructions for researchers and scholars.</p

CO2-Driven Hydraulic Fracturing Trajectories across a Preexisting Fracture

Defining the trajectory of hydraulic fractures crossing bedding planes and other fractures is a significant issue in determining the effectiveness of the stimulation. In this work, a damage evolution law is used to describe the initiation and propagation of the fracture. The model couples rock deformation and gas seepage using the finite element method and is validated against classical theoretical analysis. The simulation results define four basic intersection scenarios between the fluid-driven and preexisting fractures: (a) inserting—the hydraulic fracture inserts into a bedding plane and continues to propagate along it; (b) L-shaped crossing—the hydraulic fracture approaches the fracture/bedding plane then branches into the plane without crossing it; (c) T-shaped crossing—the hydraulic fracture approaches the fracture/bedding plane, branches into it, and crosses through it; (d) direct crossing—the hydraulic fracture crosses one or more bedding planes without branching into them. The intersection scenario changes from (a) → (b) → (c) → (d) in specimens with horizontal bedding planes when the stress ratio β (β=σy/σx) increases from 0.2 to 5. Similarly, the intersection type changes from (d) → (c) → (a) with an increase in the bedding plane angle α (0° → 90°). Stiffness of the bedding planes also exerts a significant influence on the propagation of hydraulic fractures. As the stiffness ratio E1¯/E2¯ increases from 0.1 to 0.4 and 0.8, the seepage area decreases from 22.2% to 41.8%, and the intersection type changes from a T-shaped crossing to a direct crossing

Design and validation of the THMC China-Mock-Up test on buffer material for HLW disposal

According to the preliminary concept of the high-level radioactive waste (HLW) repository in China, a large-scale mock-up facility, named China-Mock-Up was constructed in the laboratory of Beijing Research Institute of Uranium Geology (BRIUG). A heater, which simulates a container of radioactive waste, is placed inside the compacted Gaomiaozi (GMZ)-Na-bentonite blocks and pellets. Water inflow through the barrier from its outer surface is used to simulate the intake of groundwater. The numbers of water injection pipes, injection pressure and the insulation layer were determined based on the numerical modeling simulations. The current experimental data of the facility are herein analyzed. The experiment is intended to evaluate the thermo-hydro-mechano-chemical (THMC) processes occurring in the compacted bentonite-buffer during the early stage of HLW disposal and to provide a reliable database for numerical modeling and further investigation of engineered barrier system (EBS), and the design of HLW repository