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101.
Chao Zhang Anurag Verma Yuanqing Feng Marcelo C. R. Melo Michael McQuillan Matthew Hansen Anastasia Lucas Joseph Park Alessia Ranciaro Simon Thompson Meagan A. Rubel Michael C. Campbell William Beggs Jibril Hirbo Sununguko Wata Mpoloka Gaonyadiwe George Mokone Regeneron Genetic Center Thomas Nyambo Dawit Wolde Meskel Gurja Belay Charles Fokunang Alfred K. Njamnshi Sabah A. Omar Scott M. Williams Daniel J. Rader Marylyn D. Ritchie Cesar de la Fuente-Nunez Giorgio Sirugo Sarah A. Tishkoff 《Proceedings of the National Academy of Sciences of the United States of America》2022,119(21)
Human genomic diversity has been shaped by both ancient and ongoing challenges from viruses. The current coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has had a devastating impact on population health. However, genetic diversity and evolutionary forces impacting host genes related to SARS-CoV-2 infection are not well understood. We investigated global patterns of genetic variation and signatures of natural selection at host genes relevant to SARS-CoV-2 infection (angiotensin converting enzyme 2 [ACE2], transmembrane protease serine 2 [TMPRSS2], dipeptidyl peptidase 4 [DPP4], and lymphocyte antigen 6 complex locus E [LY6E]). We analyzed data from 2,012 ethnically diverse Africans and 15,977 individuals of European and African ancestry with electronic health records and integrated with global data from the 1000 Genomes Project. At ACE2, we identified 41 nonsynonymous variants that were rare in most populations, several of which impact protein function. However, three nonsynonymous variants (rs138390800, rs147311723, and rs145437639) were common among central African hunter-gatherers from Cameroon (minor allele frequency 0.083 to 0.164) and are on haplotypes that exhibit signatures of positive selection. We identify signatures of selection impacting variation at regulatory regions influencing ACE2 expression in multiple African populations. At TMPRSS2, we identified 13 amino acid changes that are adaptive and specific to the human lineage compared with the chimpanzee genome. Genetic variants that are targets of natural selection are associated with clinical phenotypes common in patients with COVID-19. Our study provides insights into global variation at host genes related to SARS-CoV-2 infection, which have been shaped by natural selection in some populations, possibly due to prior viral infections.Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Coronaviruses are enveloped, positive-sense, and single-stranded RNA viruses, many of which are zoonotic pathogens that crossed over into humans. Seven coronavirus species, including SARS-CoV-2, have been discovered that, depending on the virus and host physiological condition, may cause mild or lethal respiratory disease. There is considerable variation in disease prevalence and severity across populations and communities. Importantly, minority populations in the United States appear to have been disproportionally affected by COVID-19 (1, 2). For example, in Chicago, more than 50% of COVID-19 cases and nearly 70% of COVID-19 deaths are in African Americans (who make up 30% of the population of Chicago) (1). While social and economic factors are largely responsible for driving COVID-19 health disparities, investigating genetic diversity at host genes related to SARS-CoV-2 infection could help identify functionally important variation, which may play a role in individual risk for severe COVID-19 infection.In this study, we focused on four key genes playing a role in SARS-CoV-2 infection (3). The ACE2 gene, encoding the angiotensin-converting enzyme-2 protein, was reported to be a main binding site for severe acute respiratory syndrome coronavirus (SARS-CoV) during an outbreak in 2003, and evidence showed stronger binding affinity to SARS-CoV-2, which enters the target cells via ACE2 receptors (3, 4). The ACE2 gene is located on the X chromosome (chrX); its expression level varies among populations (5); and it is ubiquitously expressed in the lung, blood vessels, gut, kidney, testis, and brain, all organs that appear to be affected as part of the COVID-19 clinical spectrum (6). SARS-CoV-2 infects cells through a membrane fusion mechanism, which in the case of SARS-CoV, is known to induce down-regulation of ACE2 (7). Such down-regulation has been shown to cause inefficient counteraction of angiotensin II effects, leading to enhanced pulmonary inflammation and intravascular coagulation (7). Additionally, altered expression of ACE2 has been associated with cardiovascular and cerebrovascular disease, which is highly relevant to COVID-19 as several cardiovascular conditions are associated with severe disease. TMPRSS2, located on the outer membrane of host target cells, binds to and cleaves ACE2, resulting in activation of spike proteins on the viral envelope and facilitating membrane fusion and endocytosis (8). Two additional genes, DPP4 and LY6E, have been shown to play an important role in the entry of SARS-CoV-2 virus into host cells. DPP4 is a known functional receptor for the Middle East respiratory syndrome coronavirus (MERS-CoV), causing a severe respiratory illness with high mortality (9, 10). LY6E encodes a glycosylphosphatidylinositol-anchored cell surface protein, which is a critical antiviral immune effector that controls coronavirus infection and pathogenesis (11). Mice lacking LY6E in hematopoietic cells were susceptible to murine coronavirus infection (11).Previous studies of genetic diversity at ACE2 and TMPRSS2 in global human populations did not include an extensive set of African populations (5, 12–14). No common coding variants (defined here as minor allele frequency [MAF] > 0.05) at ACE2 were identified in any prior population studies. However, few studies included diverse indigenous African populations whose genomes harbor the greatest diversity among humans. This leads to a substantial disparity in the representation of African ancestries in human genetic studies of COVID-19, impeding health equity as the transferability of findings based on non-African ancestries to African populations can be low (15). Including more African populations in studying the genetic diversity of genes involved in SARS-CoV-2 infection is extremely necessary. Additionally, the evolutionary forces underlying global patterns of genetic diversity at host genes related to SARS-CoV-2 infection are not well understood. Using methods to detect natural selection signatures at host genes related to viral infections helps identify putatively functional variants that could play a role in disease risk.We characterized genetic variation and studied natural selection signatures at ACE2, TMPRSS2, DPP4, and LY6E in ethnically diverse human populations by analyzing 2,012 genomes from ethnically diverse Africans (referred to as the “African diversity” dataset), 2,504 genomes from the 1000 Genomes Project (1KG), and whole-exome sequencing of 15,977 individuals of European ancestry (EA) and African ancestry from the Penn Medicine BioBank (PMBB) dataset (SI Appendix, Fig. S1). The African diversity dataset includes populations with diverse subsistence patterns (hunter-gatherers, pastoralists, agriculturalists) and speaking languages belonging to the four major language families in Africa (Khoesan; Niger–Congo, of which Bantu is the largest subfamily; Afroasiatic; and Nilo-Saharan). We identify functionally relevant variation, compare the patterns of variation across global populations, and provide insight into the evolutionary forces underlying these patterns of genetic variation. In addition, we perform an association study using the variants identified from whole-exome sequencing at the four genes and clinical traits derived from electronic health record (EHR) data linked to the subjects enrolled in the PMBB. The EHR data include diseases related to organ dysfunctions associated with severe COVID-19, such as respiratory, cardiovascular, liver, and renal complications. Our study of genetic variation in genes involved in SARS-CoV-2 infection provides data to investigate infection susceptibility within and between populations and indicates that variants in these genes may play a role in comorbidities relevant to COVID-19 severity. 相似文献
102.
Nickel-based alloys, referred to as the most difficult-to-cut materials, pose a great challenge to cutting tool materials due to their excellent high-temperature properties. Ceramic tools have the potential to improve the machinability of these alloys with the advance of toughening mechanisms. In this work, the wear mechanisms of SiC whisker-reinforced alumina and Sialon when high-speed turning Inconel 718 alloy under dry cutting condition were investigated. The results showed that the wear process of Al2O3-SiCw WG300 was dominated by the notch wear, while the flank wear characterized by ridges and grooves perpendicular to the cutting edge was the main wear mode for Sialon SX9. A Ti−enriched belt was found at the boundary of the wear band for both ceramic tools. The SEM inspection and EDS analysis for this belt suggested the trace of diffusion between the workpiece material and tool matrix. As for the notch formation, the periodically adhesive action of the workpiece material at the depth-of-cut line combined with the thermal shock resistance of ceramic tools were considered to account for its formation. In addition, the oxidation of the workpiece material at the depth-of-cut line played a positive role in reducing the adhesive affinity and consequent notch wear. 相似文献
103.
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105.
目的 探讨关节镜下关节腔清理术治疗痛风性膝关节炎中的临床治疗效果。方法 选取2019年5月—2020年5月在医院收治的痛风性膝关节炎患者80例作为研究对象,按照治疗方式不同分为两组,各40例,其中,对照组患者接受保守治疗措施,观察组患者接受关节镜下关节腔清理术治疗措施,对两组患者的治疗情况进行观察并对比。结果 (1)观察组优16例,良20例,治疗优良率90.0%,对照组优6例,良22例,治疗优良率70.0%,差异有统计学意义(P <0.05)。(2)治疗后观察组膝关节疼痛情况(1.0±0.3)分、关节活动度(104.3±1.0)分、膝关节功能(48.4±1.2)分均显著优于对照组,差异有统计学意义(P <0.05);(3)治疗后,观察组生理功能(91.4±3.1)分、社会功能(91.3±4.3)分、躯体疼痛(92.0±3.2)分、精神健康(91.2±2.5)分均显著高于对照组水平,差异有统计学意义(P <0.05)。结论 关节镜下关节腔清理术治疗痛风性膝关节炎中的临床效果显著,能够快速改善患者的膝关节疼痛情况,并且提高患者的生活质量,值得肯定,能够在临床上推广应用。 相似文献
106.
In this paper, we investigate the spin–orbit torque and transport property in a 2D Rashba ferromagnetic electron gas. The longitudinal conductivity can be divided into two parts: the first term is determined by the charge density and is independent of the spin degrees of freedom. The second term depends on the two bands that spin in the opposite directions, and it is directly proportional to spin–orbit torque regardless of the band structure and temperature. This is a general and underlying relation between the transport property and spin–orbit torque. Moreover, we show the impacts of the spin–orbit coupling constant and Fermi energy on transverse conductivity and spin–orbit torque, which is helpful for relevant experiments. 相似文献
107.
Xiao-Yu Liu Bin Zhang Yu-Xi Cheng Wei Tao Chao Yuan Zheng-Qiang Wei Dong Peng 《World journal of gastrointestinal oncology》2022,14(6):1199-1209
BACKGROUNDThe effect of chronic kidney disease (CKD) on the outcomes of colorectal cancer (CRC) patients after primary CRC surgery is controversial.AIMTo analyze whether CKD had specific effect on the outcomes after CRC surgery.METHODSWe searched the PubMed, Embase, Cochrane Library databases and CNKI, from inception to March 14, 2022. Newcastle-Ottawa Scale was used for the quality assessment in this meta-analysis, and we used RevMan 5.3 was used for data analysis.RESULTSA total of nine studies including 47771 patients were eligible for this meta-analysis. No significant difference was found in terms of overall postoperative complications [odds ratio (OR) = 1.78, 95%CI: 0.64-4.94, P = 0.27]. We analyzed the specific complications and found that the CKD group had higher rates of pulmonary infection (OR = 2.70, 95%CI: 1.82-4.00, P < 0.01), cardiovascular complications (OR = 3.39, 95%CI: 2.34-4.91, P < 0.01) and short-term death (OR = 3.01, 95%CI: 2.20-4.11, P < 0.01). After pooling the hazard ratio (HR), the CKD group had worse overall survival (OS) (HR = 1.51, 95%CI: 1.04-2.20, P = 0.03). We performed subgroup analyses of the dialysis and non-dialysis groups, and no significant difference was found in the non-dialysis group (HR = 1.20, 95%CI: 0.98-1.47, P = 0.08). The dialysis group had worse OS (HR = 3.36, 95%CI: 1.92-5.50, P < 0.01) than the non-dialysis group. The CKD group had worse disease-free survival (DFS) (HR = 1.41, 95%CI: 1.12-1.78, P < 0.01), and in the subgroup analysis of the dialysis and non-dialysis groups, no significant difference was found in the non-dialysis group (HR = 1.27, 95%CI: 0.97-1.66, P = 0.08). The dialysis group had worse OS (HR = 1.95, 95%CI: 1.23-3.10, P < 0.01) than the non-dialysis group.CONCLUSIONPreexisting CKD was associated with higher rates of pulmonary infection, higher rates of short-term death, and worse OS and poorer DFS following CRC surgery. 相似文献
108.
109.
Xiaobei Cheng Pei Yu Xiang Zhou Jiale Zhu Yubao Han Chao Zhang Lingyi Kong 《药学学报(英文版)》2022,12(2):924-938
Although multifarious tumor-targeting modifications of nanoparticulate systems have been attempted in joint efforts by our predecessors, it remains challenging for nanomedicine to traverse physiological barriers involving blood vessels, tissues, and cell barriers to thereafter demonstrate excellent antitumor effects. To further overcome these inherent obstacles, we designed and prepared mycoplasma membrane (MM)-fused liposomes (LPs) with the goal of employing circulating neutrophils with the advantage of inflammatory cytokine-guided autonomous tumor localization to transport nanoparticles. We also utilized in vivo neutrophil activation induced by the liposomal form of the immune activator resiquimod (LPs-R848). Fused LPs preparations retained mycoplasma pathogen characteristics and achieved rapid recognition and endocytosis by activated neutrophils stimulated by LPs-R848. The enhanced neutrophil infiltration in homing of the inflammatory tumor microenvironment allowed more nanoparticles to be delivered into solid tumors. Facilitated by the formation of neutrophil extracellular traps (NETs), podophyllotoxin (POD)-loaded MM-fused LPs (MM-LPs-POD) were concomitantly released from neutrophils and subsequently engulfed by tumor cells during inflammation. MM-LPs-POD displayed superior suppression efficacy of tumor growth and lung metastasis in a 4T1 breast tumor model. Overall, such a strategy of pathogen-mimicking nanoparticles hijacking neutrophils in situ combined with enhanced neutrophil infiltration indeed elevates the potential of chemotherapeutics for tumor targeting therapy. 相似文献
110.
目的 对饮用水硝酸盐进行健康风险评估,为水质干预决策提供技术依据。 方法 对2016~2020年淄博市2 575份城乡饮用水样品检测硝酸盐含量,采用我国《化学物质环境健康风险评估技术指南》(WS/T 777-2021)的环境健康风险评价模型,分析不同年度、不同监测点类型、不同水源、不同处理方式的硝酸盐含量和非致癌健康风险的时空分布特征。 结果 2016~2020年共检测水样2 575份,硝酸盐超标率为10.76%。饮用水硝酸盐含量具有空间聚集性,高值主要集中在沂源县中部和东部、博山区西南部,低值集中在高青县和桓台县。饮用水硝酸盐含量和非致癌健康风险总体呈现逐年升高趋势,农村水高于城区水、地下水高于地表水、未处理水高于处理水。5年总体平均非致癌风险为0.21,对人体产生的非致癌风险较低;最高非致癌风险为1.99,主要集中在沂源县,对人体存在长期暴露的非致癌健康风险。 结论 淄博市局部区域饮用水硝酸盐污染较严重,存在非致癌健康风险,应引起关注并采取水质干预措施。 相似文献