Osteoporosis is a known risk factor for rotator cuff tears(RCTs),but the causal correlation and underlying mechanisms remain unclear.This study aims to evaluate the impact of osteoporosis on RCT risk and investigate t...Osteoporosis is a known risk factor for rotator cuff tears(RCTs),but the causal correlation and underlying mechanisms remain unclear.This study aims to evaluate the impact of osteoporosis on RCT risk and investigate their genetic associations.Using data from the UK Biobank(n=457871),cross-sectional analyses demonstrated that osteoporosis was significantly associated with an increased risk of RCTs(adjusted OR[95%CI]=1.38[1.25–1.52]).A longitudinal analysis of a subset of patients(n=268117)over 11 years revealed that osteoporosis increased the risk of RCTs(adjusted HR[95%CI]=1.56[1.29–1.87]),which is notably varied between sexes in sex-stratified analysis.Causal inference methods,including propensity score matching,inverse probability weighting,causal random forest and survival random forest models further confirmed the causal effect,both from cross-sectional and longitudinal perspectives.展开更多
Background:Diabetic retinopathy(DR)urgently needs novel and effective therapeutic targets.Integrated analyses of plasma proteomic and genetic markers can clarify the causal relevance of proteins and discover novel tar...Background:Diabetic retinopathy(DR)urgently needs novel and effective therapeutic targets.Integrated analyses of plasma proteomic and genetic markers can clarify the causal relevance of proteins and discover novel targets for diseases,but no systematic screening for DR has been performed.Methods:Summary statistics of plasma protein quantitative trait loci(pQTL)were derived from two extensive genome-wide analysis study(GWAS)datasets and one systematic review,with over 100 thousand participants covering thousands of plasma proteins.DR data were sourced from the largest FinnGen study,comprising 10,413 DR cases and 308,633 European controls.Genetic instrumental variables were identified using multiple filters.In the two-sample MR analysis,Wald ratio and inverse variance-weighted(IVW)MR were utilized to investigate the causality of plasma proteins with DR.Bidirectional MR,Bayesian Co-localization,and phenotype scanning were employed to test for potential reverse causality and confounding factors in the main MR analyses.By systemically searching druggable gene lists,the ChEMBL database,DrugBank,and Gene Ontology database,the druggability and relevant functional pathways of the identified proteins were systematically evaluated.Results:Genetically predicted levels of 24 proteins were significantly associated with DR risk at a false discovery rate<0.05 including 11 with positive associations and 13 with negative associations.For each standard deviation increase in plasm protein levels,the odds ratios(ORs)for DR varied from 0.51(95%CI:0.36-0.73;P=2.22×10-5)for tubulin polymerization-promoting protein family member 3(TPPP3)to 2.02(95%CI:1.44-2.83;P=5.01×10-5)for olfactomedin like 3(OLFML3).Bidirectional MR indicated there was no reverse causality that interfered with the results of the main MR analyses.Four proteins exhibited strong co-localization evidence(PH4≥0.8):cytoplasmic tRNA synthetase(WARS),acrosin binding protein(ACRBP),and intercellular adhesion molecule 1(ICAM1)were negatively associated with DR risk,while neurogenic locus notch homolog protein 2(NOTCH2)showed a positive association.No confounding factors were detected between pQTLs and DR according to the phenotypic scan.Drugability assessments highlighted 6 proteins already in drug development endeavor and 18 novel drug targets,with metalloproteinase inhibitor 3(TIMP)currently in phase I clinical trials for DR.GO analysis identified 18 of 24 plasma proteins enriching 22 pathways related to cell differentiation and proliferation regulation.Conclusions:Twenty-four promising drug targets for DR were identified,including four plasma proteins with particular co-localization evidence.These findings offer new insights into DR's etiology and therapeutic targeting,exemplifying the value of genomic and proteomic data in drug target discovery.展开更多
Background Lung squamous cell carcinoma(LUSC)is a major subtype of non-small cell lung cancer with a high mortality rate.Identifying causal plasma proteins associated with LUSC could provide new insights into the path...Background Lung squamous cell carcinoma(LUSC)is a major subtype of non-small cell lung cancer with a high mortality rate.Identifying causal plasma proteins associated with LUSC could provide new insights into the pathophysiology of the disease and potential therapeutic targets.This study aimed to identify plasma proteins causally linked to LUSC risk using proteome-wide Mendelian randomization(MR)and colocalization analyses.Methods Proteome-wide MR analysis was conducted using data from the UK Biobank Pharma Proteomics Project and deCODE genetics.Summary-level data for LUSC were obtained from the ILCCO Consortium,the FinnGen study,and a separate GWAS study.A total of 1,046 shared protein quantitative trait loci(pQTLs)were analyzed.Sensitivity analyses included the HEIDI test for horizontal pleiotropy and colocalization analysis to validate the causal associations.Results MR analysis identified six plasma proteins associated with LUSC risk:HSPA1L,PCSK7,POLI,SPINK2,TCL1A,and VARS.HSPA1L(OR=0.47;95%CI:0.34–0.65;P=4.89×10^(–6)),SPINK2(OR=0.68;95%CI:0.58–0.80;P=3.17×10^(–6)),and VARS(OR=0.44;95%CI:0.31–0.63;P=5.94×10^(–6))were associated with a decreased risk of LUSC.Conversely,PCSK7(OR=1.37;95%CI:1.21–1.56;P=1.40×10^(–6)),POLI(OR=4.50;95%CI:2.25–9.00;P=2.13×10–5),and TCL1A(OR=1.72;95%CI:1.34–2.21;P=1.89×10–5)were associated with an increased risk.The SMR analysis and HEIDI test confirmed the robustness of these associations.HSPA1L,SPINK2,and VARS showed significant inverse associations,with strong colocalization evidence for TCL1A(PPH4=0.817).Conclusions This study identified six plasma proteins potentially causal for LUSC risk.HSPA1L,SPINK2,and VARS are associated with decreased risk,while PCSK7,POLI,and TCL1A are linked to increased risk.These findings provide new insights into LUSC pathogenesis and highlight potential targets for therapeutic intervention.展开更多
Background A detailed understanding of genetic variants that affect beef merit helps maximize the efficiency of breeding for improved production merit in beef cattle.To prioritize the putative variants and genes,we ra...Background A detailed understanding of genetic variants that affect beef merit helps maximize the efficiency of breeding for improved production merit in beef cattle.To prioritize the putative variants and genes,we ran a com-prehensive genome-wide association studies(GWAS)analysis for 21 agronomic traits using imputed whole-genome variants in Simmental beef cattle.Then,we applied expression quantitative trait loci(eQTL)mapping between the genotype variants and transcriptome of three tissues(longissimus dorsi muscle,backfat,and liver)in 120 cattle.Results We identified 1,580 association signals for 21 beef agronomic traits using GWAS.We then illuminated 854,498 cis-eQTLs for 6,017 genes and 46,970 trans-eQTLs for 1,903 genes in three tissues and built a synergistic network by integrating transcriptomics with agronomic traits.These cis-eQTLs were preferentially close to the transcription start site and enriched in functional regulatory regions.We observed an average of 43.5%improvement in cis-eQTL discovery using multi-tissue eQTL mapping.Fine-mapping analysis revealed that 111,192,and 194 variants were most likely to be causative to regulate gene expression in backfat,liver,and muscle,respectively.The transcriptome-wide association studies identified 722 genes significantly associated with 11 agronomic traits.Via the colocalization and Mendelian randomization analyses,we found that eQTLs of several genes were associated with the GWAS signals of agronomic traits in three tissues,which included genes,such as NADSYN1,NDUFS3,LTF and KIFC2 in liver,GRAMD1C,TMTC2 and ZNF613 in backfat,as well as TIGAR,NDUFS3 and L3HYPDH in muscle that could serve as the candidate genes for economic traits.Conclusions The extensive atlas of GWAS,eQTL,fine-mapping,and transcriptome-wide association studies aid in the suggestion of potentially functional variants and genes in cattle agronomic traits and will be an invaluable source for genomics and breeding in beef cattle.展开更多
Based on the first-order upwind and second-order central type of finite volume (UFV and CFV) scheme, upwind and central type of perturbation finite volume (UPFV and CPFV) schemes of the Navier-Stokes equations were de...Based on the first-order upwind and second-order central type of finite volume (UFV and CFV) scheme, upwind and central type of perturbation finite volume (UPFV and CPFV) schemes of the Navier-Stokes equations were developed. In PFV method, the mass fluxes of across the cell faces of the control volume (CV) were expanded into power series of the grid spacing and the coefficients of the power series were determined by means of the conservation equation itself. The UPFV and CPFV scheme respectively uses the same nodes and expressions as those of the normal first-order upwind and second-order central scheme, which is apt to programming. The results of numerical experiments about the flow in a lid-driven cavity and the problem of transport of a scalar quantity in a known velocity field show that compared to the first-order UFV and second-order CFV schemes, upwind PFV scheme is higher accuracy and resolution, especially better robustness. The numerical computation to flow in a lid-driven cavity shows that the under-relaxation factor can be arbitrarily selected ranging from (0.3) to (0.8) and convergence perform excellent with Reynolds number variation from 10~2 to 10~4.展开更多
Objective: To investigate the colocalization of Somatostatin (SOM ) and NADPH--diaphorase (NADPHd ) of the neurons in raphe nuclei innervating pharyngeal muscles in the rats. Methods: After PRV was injected into the p...Objective: To investigate the colocalization of Somatostatin (SOM ) and NADPH--diaphorase (NADPHd ) of the neurons in raphe nuclei innervating pharyngeal muscles in the rats. Methods: After PRV was injected into the pharyngeal muscles. PRV and SOM immunofluorescence double labeling procedure was completed at first,then proceeded NADPH -d histochemistry. Results: PRV and SOM double--labled cells were present mainly in the nucleus raphe magnus. but some PRV and SOM double labled neurons were found in the other raphe nuclei as well, such as nucleus raphe pallidus. nucleus raphe obsurus, median raphe nucleus and dorsal raphe nucleus.NADPH -d positive neurons were also observed in the raphe nuclei. PRV. SOM and NADPH-d triple labeling neurons were found in the nucleus raphe magnus. Conclusion: It is suggested that the colocalization of SOM and NADPH--d of the neurons in the raphe nuclei innervating pharyngeal muscles may play an important role in the coordination of the pharyngeal motility.展开更多
An effective method via tensor decomposition is proposed to deal with the joint direction-of-departure(DOD)and direction-of-arrival(DOA)estimation of noncircular sources in colocated coprime MIMO radar.By decomposing ...An effective method via tensor decomposition is proposed to deal with the joint direction-of-departure(DOD)and direction-of-arrival(DOA)estimation of noncircular sources in colocated coprime MIMO radar.By decomposing the transmitter and receiver into two sparse subarrays,noncircular property of source can be used to construct new extended received signal model for two sparse subarrays.The new received model can double the virtual array aperture due to the elliptic covariance of imping sources is nonzero.To further exploit the multidimensional structure of the noncircular received model,we stack the subarray output and its conjugation according to mode-1 unfolding and mode-2 unfolding of a third-order tensor,respectively.Thus,the corresponding extended tensor model consisted of noncircular information for DOA and DOD can be obtained.Then,the higher-order singular value decomposition technique is utilized to estimate the accurate signal subspace and angular parameter can be automatically paired via the rotational invariance relationship.Specifically,the ambiguous angle can be eliminated and the true targets can be achieved with the aid of the coprime property.Furthermore,a closed-form expression for the deterministic CRB under the NC sources scenario is also derived.Simulation results verify the superiority of the proposed estimator.展开更多
To the Editor:Atopic dermatitis(AD)is a chronic inflammatory skin condition marked by recurrent eczematous lesions and intense pruritus,affecting approximately 15–20%of children and up to 10%of adults worldwide.[1]Th...To the Editor:Atopic dermatitis(AD)is a chronic inflammatory skin condition marked by recurrent eczematous lesions and intense pruritus,affecting approximately 15–20%of children and up to 10%of adults worldwide.[1]The presence of AD significantly impairs patient quality of life and imposes substantial economic burdens on society.In recent years,the potential link between AD and lymphoma has attracted considerable attention from researchers and clinicians.Lymphoma,a malignancy of the lymphatic system,poses significant health risks due to its high mortality potential.[2]However,observational studies investigating the potential correlation between AD and lymphoma have yielded inconsistent results.Consequently,the association between AD and lymphoma remains controversial and warrants further investigation.展开更多
To enhance the tip positioning accuracy and robustness against disturbances of linear colocated motion systems,a novel composite feedforward(COMFF)control with Bi-Loop iterative feedforward tuning(IFFT)is proposed.The...To enhance the tip positioning accuracy and robustness against disturbances of linear colocated motion systems,a novel composite feedforward(COMFF)control with Bi-Loop iterative feedforward tuning(IFFT)is proposed.The tip positioning error consists of the coupled tip residual vibration and linear motor tracking error.Given the influence of nonlinear friction and load flexibility,the topology of COMFF is designed as decoupled structures so that COMFF can suppress the tip residual vibration and compensate for the linear motor tracking error compatibly.Furthermore,Bi-Loop IFFT is built to improve the robustness of COMFF in high-precision motor tracking performance.In the state space of the linear motor tracking error based on the projection theorem,two loops are performed in parallel along the iteration direction.One is the P-type iteration loop that drives linear motor tracking errors to converge to the zero state.The other is the observation loop constructed by the recursive least square with forgetting factors to accelerate the P-type iteration loop.Driven by the P-type iteration loop with the aid of the observation loop,the proposed COMFF is integrated with fast convergence and high robustness when confronted with model disturbances.The effectiveness of the proposed COMFF combined with Bi-Loop IFFT is validated by experiments.展开更多
Background Semen quality is one of the most important indicators of boar reproductive performance.In the past,boar breeding has mostly emphasized characteristics such as lean meat percentage,feed conversion efficiency...Background Semen quality is one of the most important indicators of boar reproductive performance.In the past,boar breeding has mostly emphasized characteristics such as lean meat percentage,feed conversion efficiency,and growth rate,while overlooking the genetic improvement of reproductive traits.This study employs advanced multi-omics approaches,such as transcriptome-wide association studies(TWAS)and colocalization between genome-wide association studies(GWAS)and expression quantitative trait loci(eQTLs),to provide a comprehensive understanding of the genetic mechanisms governing semen quality traits in boars.Results Here,we collected 190,000 ejaculate records across 11 semen quality traits from 3,604 Duroc boars.The heritability of semen quality traits ranged from 0.095 to 0.343.Genetic correlations between semen quality traits varied from−0.802 to 0.661,and phenotypic correlations ranged from−0.833 to 0.776.Single-trait GWAS identified 19 independent variants,corresponding to 13 quantitative trait loci(QTLs).By integrating PigGTEx and FAANG resources,we combined TWAS and colocalization analyses to reveal genetic regulation of semen quality traits.Notably,both GWAS and colocalization analyses pinpointed the DCAF12 as a crucial gene associated with multiple semen quality traits.Additionally,the ZSCAN9 gene and the variant rs322211455 were found to significantly affect sperm motility(SPMOT),possibly through hypothalamic-pituitary-gonadal axis.PheWAS further highlighted an association between rs322211455 and sperm abnormality rate,demonstrating the crucial role of ZSCAN9 in male fertility.Conclusion This study reveals the genetic basis and regulatory mechanisms underlying semen quality traits in Duroc boars,identifying key candidate genes such as DCAF12 and ZSCAN9.These findings provide important insight into the genetic regulation of semen quality in boars.展开更多
Although the spatial characteristics within the tumor microenvironment of lung adenocarcinoma(LUAD)have been identified,the mechanisms by which these factors promote LUAD progression and immune evasion remain unclear....Although the spatial characteristics within the tumor microenvironment of lung adenocarcinoma(LUAD)have been identified,the mechanisms by which these factors promote LUAD progression and immune evasion remain unclear.Using spatial transcriptomics and single-cell RNA-sequencing data from multi-regional LUAD biopsies consisting of tumor core,tumor edge,and normal area,we sought to delineate the spatial heterogeneity and driving factors of cell colocalization.Two cancer cell sub-clusters(Cancer_c1 and Cancer_c2),associated with LUAD initiation and metastasis,respectively,exhibit distinct spatial distributions and immune cell colocalizations.In particular,Cancer_c1,enriched within the tumor core,could directly interact with B cells or indirectly recruit B cells through macrophages.Conversely,Cancer_c2 enriched within the tumor edge exhibits colocalization with CD8^(+)T cells.Collectively,our work elucidates the spatial distribution of cancer cell subtypes and their interaction with immune cells in the core and edge of LUAD,providing insights for developing therapeutic strategies for cancer intervention.展开更多
Most data centers currently tap into existing power grids to draw the immense amount of electricity they need to operate.But many of the data centers that Google(Mountain View,CA,USA)plans to open in the next few year...Most data centers currently tap into existing power grids to draw the immense amount of electricity they need to operate.But many of the data centers that Google(Mountain View,CA,USA)plans to open in the next few years will boast their own power plants,an arrangement known as colocation[1].Under an agreement announced in December 2024,the company will site data centers in industrial parks where its partner Intersect Power of Houston,TX,USA,has installed clean power facilities[1,2].The first of these complexes is scheduled to come online in 2026[1].展开更多
背景:骨关节炎是与代谢异常密切相关的复杂性疾病,然而以往研究仅涉及有限的血脂指标,未进行更全面的血脂谱分析。深入探讨血脂7项与骨关节炎之间的因果关系,不仅有助于理解骨关节炎的发病机制,还能为其预防和治疗提供新的研究方向和临...背景:骨关节炎是与代谢异常密切相关的复杂性疾病,然而以往研究仅涉及有限的血脂指标,未进行更全面的血脂谱分析。深入探讨血脂7项与骨关节炎之间的因果关系,不仅有助于理解骨关节炎的发病机制,还能为其预防和治疗提供新的研究方向和临床依据。目的:探讨血脂与骨关节炎的因果关系。方法:使用来自IEU OPEN GWAS数据库的血脂7项和骨关节炎的全基因组关联分析统计数据进行汇总,工具变量采用显著单核苷酸多态性,通过双样本孟德尔随机化分析得出血脂7项(血清总胆固醇、三酰甘油、低密度脂蛋白胆固醇、高密度脂蛋白胆固醇、载脂蛋白B、载脂蛋白AI和载脂蛋白A1)与骨关节炎(骨关节炎、膝或髋骨关节炎、膝骨关节炎和髋骨关节炎)的因果关系,以逆方差加权为主要效应,MR-Egger回归法和加权中位数法为补充效应。Bonferroni校正和反向孟德尔随机化分析保证有效性。采用多变量孟德尔随机化分析进一步破除混杂因素,得出血脂7项与骨关节炎的显著因果关系,保证分析的稳健性。采用共定位分析再次确保因果关系的稳健性,并得出显著影响作用的基因位点,使因果关系证据更充分。结果与结论:①双样本孟德尔随机化分析中逆方差加权结果显示,总胆固醇(OR=0.9372,95%CI=0.8856-0.9919,P=0.025)、低密度脂蛋白胆固醇(OR=0.9594,95%CI=0.9236-0.9966,P=0.033)、高密度脂蛋白胆固醇(OR=0.9112,95%CI=0.8335-0.9962,P=0.04)、载脂蛋白B(OR=0.926,95%CI=0.8877-0.9674,P=0.0005)和载脂蛋白AI(OR=0.9512,95%CI=0.9110-0.9931,P=0.023)与骨关节炎呈负相关,总胆固醇(OR=0.8923,95%CI=0.8431-0.9443,P=0.00008)、三酰甘油(OR=0.9385,95%CI=0.8847-0.9956,P=0.035)和载脂蛋白B(OR=0.9116,95%CI=0.8659-0.9597,P=0.0004)与膝或髋骨关节炎呈负相关,总胆固醇(OR=0.8983,95%CI=0.8412-0.9593,P=0.001)、高密度脂蛋白胆固醇(OR=0.8812,95%CI=0.7947-0.9770,P=0.016)和载脂蛋白B(OR=0.9190,95%CI=0.8698-0.9710,P=0.002)与膝骨关节炎呈负相关,总胆固醇(OR=0.8645,95%CI=0.7975-0.9373,P=0.0004)、低密度脂蛋白胆固醇(OR=0.9256,95%CI=0.8795-0.9741,P=0.003)和载脂蛋白B(OR=0.8888,95%CI=0.8176-0.9663,P=0.005)与髋骨关节炎呈负相关;在反向孟德尔随机化分析中结果无统计学差异。②多变量孟德尔随机化分析中逆方差加权结果显示,高密度脂蛋白胆固醇(OR=0.9427,95%CI=0.8961-0.9918,P=0.022)与骨关节炎呈负相关,总胆固醇(OR=0.799,95%CI=0.6478-0.987,P=0.037)和高密度脂蛋白胆固醇(OR=0.8651,95%CI=0.7781-0.9619,P=0.007)与膝骨关节炎呈负相关。③共定位分析结果显示,总胆固醇和低密度脂蛋白与骨关节炎的H4后验概率=99.9%,共同指向一个显著单核苷酸多态性,为rs13107325。④这些结果采用国际数据库、非亚洲人群,可为中国生物医学及中国人群骨关节炎的临床早期诊断、发病机制理解和预防与治疗提供有价值的借鉴意义和指导作用。展开更多
基金the Scientific Research Innovation Capability Support Project for Young Faculty(ZYGXQNJSKYCXNLZCXM-H8)Fundamental Research Funds for the Central Universities(2024ZYGXZR077)+3 种基金Guangdong Basic and Applied Basic Research Foundation(2023B1515120006)Guangzhou Basic and Applied Basic Research Foundation(2024A04J5776)the Research Fund(2023QN10Y421)Guangzhou Talent Recruitment Team Program(2024D03J0004),all related to this study.
文摘Osteoporosis is a known risk factor for rotator cuff tears(RCTs),but the causal correlation and underlying mechanisms remain unclear.This study aims to evaluate the impact of osteoporosis on RCT risk and investigate their genetic associations.Using data from the UK Biobank(n=457871),cross-sectional analyses demonstrated that osteoporosis was significantly associated with an increased risk of RCTs(adjusted OR[95%CI]=1.38[1.25–1.52]).A longitudinal analysis of a subset of patients(n=268117)over 11 years revealed that osteoporosis increased the risk of RCTs(adjusted HR[95%CI]=1.56[1.29–1.87]),which is notably varied between sexes in sex-stratified analysis.Causal inference methods,including propensity score matching,inverse probability weighting,causal random forest and survival random forest models further confirmed the causal effect,both from cross-sectional and longitudinal perspectives.
基金funded by the Hainan Province Clinical Medical Center(82171084)the National Natural Science Foundation of China(82371086).
文摘Background:Diabetic retinopathy(DR)urgently needs novel and effective therapeutic targets.Integrated analyses of plasma proteomic and genetic markers can clarify the causal relevance of proteins and discover novel targets for diseases,but no systematic screening for DR has been performed.Methods:Summary statistics of plasma protein quantitative trait loci(pQTL)were derived from two extensive genome-wide analysis study(GWAS)datasets and one systematic review,with over 100 thousand participants covering thousands of plasma proteins.DR data were sourced from the largest FinnGen study,comprising 10,413 DR cases and 308,633 European controls.Genetic instrumental variables were identified using multiple filters.In the two-sample MR analysis,Wald ratio and inverse variance-weighted(IVW)MR were utilized to investigate the causality of plasma proteins with DR.Bidirectional MR,Bayesian Co-localization,and phenotype scanning were employed to test for potential reverse causality and confounding factors in the main MR analyses.By systemically searching druggable gene lists,the ChEMBL database,DrugBank,and Gene Ontology database,the druggability and relevant functional pathways of the identified proteins were systematically evaluated.Results:Genetically predicted levels of 24 proteins were significantly associated with DR risk at a false discovery rate<0.05 including 11 with positive associations and 13 with negative associations.For each standard deviation increase in plasm protein levels,the odds ratios(ORs)for DR varied from 0.51(95%CI:0.36-0.73;P=2.22×10-5)for tubulin polymerization-promoting protein family member 3(TPPP3)to 2.02(95%CI:1.44-2.83;P=5.01×10-5)for olfactomedin like 3(OLFML3).Bidirectional MR indicated there was no reverse causality that interfered with the results of the main MR analyses.Four proteins exhibited strong co-localization evidence(PH4≥0.8):cytoplasmic tRNA synthetase(WARS),acrosin binding protein(ACRBP),and intercellular adhesion molecule 1(ICAM1)were negatively associated with DR risk,while neurogenic locus notch homolog protein 2(NOTCH2)showed a positive association.No confounding factors were detected between pQTLs and DR according to the phenotypic scan.Drugability assessments highlighted 6 proteins already in drug development endeavor and 18 novel drug targets,with metalloproteinase inhibitor 3(TIMP)currently in phase I clinical trials for DR.GO analysis identified 18 of 24 plasma proteins enriching 22 pathways related to cell differentiation and proliferation regulation.Conclusions:Twenty-four promising drug targets for DR were identified,including four plasma proteins with particular co-localization evidence.These findings offer new insights into DR's etiology and therapeutic targeting,exemplifying the value of genomic and proteomic data in drug target discovery.
基金supported by The Medical Engineering Cross Research Funding of Shanghai Jiaotong University"Star of Jiaotong University"Program(24X010301595).
文摘Background Lung squamous cell carcinoma(LUSC)is a major subtype of non-small cell lung cancer with a high mortality rate.Identifying causal plasma proteins associated with LUSC could provide new insights into the pathophysiology of the disease and potential therapeutic targets.This study aimed to identify plasma proteins causally linked to LUSC risk using proteome-wide Mendelian randomization(MR)and colocalization analyses.Methods Proteome-wide MR analysis was conducted using data from the UK Biobank Pharma Proteomics Project and deCODE genetics.Summary-level data for LUSC were obtained from the ILCCO Consortium,the FinnGen study,and a separate GWAS study.A total of 1,046 shared protein quantitative trait loci(pQTLs)were analyzed.Sensitivity analyses included the HEIDI test for horizontal pleiotropy and colocalization analysis to validate the causal associations.Results MR analysis identified six plasma proteins associated with LUSC risk:HSPA1L,PCSK7,POLI,SPINK2,TCL1A,and VARS.HSPA1L(OR=0.47;95%CI:0.34–0.65;P=4.89×10^(–6)),SPINK2(OR=0.68;95%CI:0.58–0.80;P=3.17×10^(–6)),and VARS(OR=0.44;95%CI:0.31–0.63;P=5.94×10^(–6))were associated with a decreased risk of LUSC.Conversely,PCSK7(OR=1.37;95%CI:1.21–1.56;P=1.40×10^(–6)),POLI(OR=4.50;95%CI:2.25–9.00;P=2.13×10–5),and TCL1A(OR=1.72;95%CI:1.34–2.21;P=1.89×10–5)were associated with an increased risk.The SMR analysis and HEIDI test confirmed the robustness of these associations.HSPA1L,SPINK2,and VARS showed significant inverse associations,with strong colocalization evidence for TCL1A(PPH4=0.817).Conclusions This study identified six plasma proteins potentially causal for LUSC risk.HSPA1L,SPINK2,and VARS are associated with decreased risk,while PCSK7,POLI,and TCL1A are linked to increased risk.These findings provide new insights into LUSC pathogenesis and highlight potential targets for therapeutic intervention.
基金supported by grants from the Central Public-interest Scientific Institution Basal Research Fund(2020-YWF-YB-02)the Young Scientists Fund of the National Natural Science Foundation of China(32202652)+1 种基金China Agriculture Research System of MOF and MARA(CARS-37)the Science and Technology Project of Inner Mongolia Autonomous Region(2020GG0210).
文摘Background A detailed understanding of genetic variants that affect beef merit helps maximize the efficiency of breeding for improved production merit in beef cattle.To prioritize the putative variants and genes,we ran a com-prehensive genome-wide association studies(GWAS)analysis for 21 agronomic traits using imputed whole-genome variants in Simmental beef cattle.Then,we applied expression quantitative trait loci(eQTL)mapping between the genotype variants and transcriptome of three tissues(longissimus dorsi muscle,backfat,and liver)in 120 cattle.Results We identified 1,580 association signals for 21 beef agronomic traits using GWAS.We then illuminated 854,498 cis-eQTLs for 6,017 genes and 46,970 trans-eQTLs for 1,903 genes in three tissues and built a synergistic network by integrating transcriptomics with agronomic traits.These cis-eQTLs were preferentially close to the transcription start site and enriched in functional regulatory regions.We observed an average of 43.5%improvement in cis-eQTL discovery using multi-tissue eQTL mapping.Fine-mapping analysis revealed that 111,192,and 194 variants were most likely to be causative to regulate gene expression in backfat,liver,and muscle,respectively.The transcriptome-wide association studies identified 722 genes significantly associated with 11 agronomic traits.Via the colocalization and Mendelian randomization analyses,we found that eQTLs of several genes were associated with the GWAS signals of agronomic traits in three tissues,which included genes,such as NADSYN1,NDUFS3,LTF and KIFC2 in liver,GRAMD1C,TMTC2 and ZNF613 in backfat,as well as TIGAR,NDUFS3 and L3HYPDH in muscle that could serve as the candidate genes for economic traits.Conclusions The extensive atlas of GWAS,eQTL,fine-mapping,and transcriptome-wide association studies aid in the suggestion of potentially functional variants and genes in cattle agronomic traits and will be an invaluable source for genomics and breeding in beef cattle.
文摘Based on the first-order upwind and second-order central type of finite volume (UFV and CFV) scheme, upwind and central type of perturbation finite volume (UPFV and CPFV) schemes of the Navier-Stokes equations were developed. In PFV method, the mass fluxes of across the cell faces of the control volume (CV) were expanded into power series of the grid spacing and the coefficients of the power series were determined by means of the conservation equation itself. The UPFV and CPFV scheme respectively uses the same nodes and expressions as those of the normal first-order upwind and second-order central scheme, which is apt to programming. The results of numerical experiments about the flow in a lid-driven cavity and the problem of transport of a scalar quantity in a known velocity field show that compared to the first-order UFV and second-order CFV schemes, upwind PFV scheme is higher accuracy and resolution, especially better robustness. The numerical computation to flow in a lid-driven cavity shows that the under-relaxation factor can be arbitrarily selected ranging from (0.3) to (0.8) and convergence perform excellent with Reynolds number variation from 10~2 to 10~4.
文摘Objective: To investigate the colocalization of Somatostatin (SOM ) and NADPH--diaphorase (NADPHd ) of the neurons in raphe nuclei innervating pharyngeal muscles in the rats. Methods: After PRV was injected into the pharyngeal muscles. PRV and SOM immunofluorescence double labeling procedure was completed at first,then proceeded NADPH -d histochemistry. Results: PRV and SOM double--labled cells were present mainly in the nucleus raphe magnus. but some PRV and SOM double labled neurons were found in the other raphe nuclei as well, such as nucleus raphe pallidus. nucleus raphe obsurus, median raphe nucleus and dorsal raphe nucleus.NADPH -d positive neurons were also observed in the raphe nuclei. PRV. SOM and NADPH-d triple labeling neurons were found in the nucleus raphe magnus. Conclusion: It is suggested that the colocalization of SOM and NADPH--d of the neurons in the raphe nuclei innervating pharyngeal muscles may play an important role in the coordination of the pharyngeal motility.
基金Project supported by the National Natural Science Foundation of China(Grant Nos.61701507,61890542,and 61890540).
文摘An effective method via tensor decomposition is proposed to deal with the joint direction-of-departure(DOD)and direction-of-arrival(DOA)estimation of noncircular sources in colocated coprime MIMO radar.By decomposing the transmitter and receiver into two sparse subarrays,noncircular property of source can be used to construct new extended received signal model for two sparse subarrays.The new received model can double the virtual array aperture due to the elliptic covariance of imping sources is nonzero.To further exploit the multidimensional structure of the noncircular received model,we stack the subarray output and its conjugation according to mode-1 unfolding and mode-2 unfolding of a third-order tensor,respectively.Thus,the corresponding extended tensor model consisted of noncircular information for DOA and DOD can be obtained.Then,the higher-order singular value decomposition technique is utilized to estimate the accurate signal subspace and angular parameter can be automatically paired via the rotational invariance relationship.Specifically,the ambiguous angle can be eliminated and the true targets can be achieved with the aid of the coprime property.Furthermore,a closed-form expression for the deterministic CRB under the NC sources scenario is also derived.Simulation results verify the superiority of the proposed estimator.
基金supported by grants from the National Key R&D Program of China(Nos.2022YFC3602002 and 2024YFF0507404)National High Level Hospital Clinical Research Funding(Nos.2022-NHLHCRF-LX-02-03 and 2023-NHLHCRF-YXHZ-ZRZD-06).
文摘To the Editor:Atopic dermatitis(AD)is a chronic inflammatory skin condition marked by recurrent eczematous lesions and intense pruritus,affecting approximately 15–20%of children and up to 10%of adults worldwide.[1]The presence of AD significantly impairs patient quality of life and imposes substantial economic burdens on society.In recent years,the potential link between AD and lymphoma has attracted considerable attention from researchers and clinicians.Lymphoma,a malignancy of the lymphatic system,poses significant health risks due to its high mortality potential.[2]However,observational studies investigating the potential correlation between AD and lymphoma have yielded inconsistent results.Consequently,the association between AD and lymphoma remains controversial and warrants further investigation.
基金supported by the National Natural Science Foundation Regional Innovation and Development Joint Fund Integrated Project(Grant No.U23A6017)the Central Guidance on Local Science and Technology Development Fund of Hebei Province(Grant No.226Z1805G).
文摘To enhance the tip positioning accuracy and robustness against disturbances of linear colocated motion systems,a novel composite feedforward(COMFF)control with Bi-Loop iterative feedforward tuning(IFFT)is proposed.The tip positioning error consists of the coupled tip residual vibration and linear motor tracking error.Given the influence of nonlinear friction and load flexibility,the topology of COMFF is designed as decoupled structures so that COMFF can suppress the tip residual vibration and compensate for the linear motor tracking error compatibly.Furthermore,Bi-Loop IFFT is built to improve the robustness of COMFF in high-precision motor tracking performance.In the state space of the linear motor tracking error based on the projection theorem,two loops are performed in parallel along the iteration direction.One is the P-type iteration loop that drives linear motor tracking errors to converge to the zero state.The other is the observation loop constructed by the recursive least square with forgetting factors to accelerate the P-type iteration loop.Driven by the P-type iteration loop with the aid of the observation loop,the proposed COMFF is integrated with fast convergence and high robustness when confronted with model disturbances.The effectiveness of the proposed COMFF combined with Bi-Loop IFFT is validated by experiments.
基金supported by grants from The Sci-Tech Innovation 2030 Agenda(2023ZD04045)Guangxi Key Research and Development Program(AB241484033).
文摘Background Semen quality is one of the most important indicators of boar reproductive performance.In the past,boar breeding has mostly emphasized characteristics such as lean meat percentage,feed conversion efficiency,and growth rate,while overlooking the genetic improvement of reproductive traits.This study employs advanced multi-omics approaches,such as transcriptome-wide association studies(TWAS)and colocalization between genome-wide association studies(GWAS)and expression quantitative trait loci(eQTLs),to provide a comprehensive understanding of the genetic mechanisms governing semen quality traits in boars.Results Here,we collected 190,000 ejaculate records across 11 semen quality traits from 3,604 Duroc boars.The heritability of semen quality traits ranged from 0.095 to 0.343.Genetic correlations between semen quality traits varied from−0.802 to 0.661,and phenotypic correlations ranged from−0.833 to 0.776.Single-trait GWAS identified 19 independent variants,corresponding to 13 quantitative trait loci(QTLs).By integrating PigGTEx and FAANG resources,we combined TWAS and colocalization analyses to reveal genetic regulation of semen quality traits.Notably,both GWAS and colocalization analyses pinpointed the DCAF12 as a crucial gene associated with multiple semen quality traits.Additionally,the ZSCAN9 gene and the variant rs322211455 were found to significantly affect sperm motility(SPMOT),possibly through hypothalamic-pituitary-gonadal axis.PheWAS further highlighted an association between rs322211455 and sperm abnormality rate,demonstrating the crucial role of ZSCAN9 in male fertility.Conclusion This study reveals the genetic basis and regulatory mechanisms underlying semen quality traits in Duroc boars,identifying key candidate genes such as DCAF12 and ZSCAN9.These findings provide important insight into the genetic regulation of semen quality in boars.
基金supported by the National Natural Science Foundation of China(82002432 to J.W.,82302068 to M.Z.,and 32300568 to T.W.)the Natural Science Foundation of Shandong Province(ZR2024MH159 to Y.Z.,ZR2020QH179 to J.W.,ZR2022QH057 to M.Z.,and ZR2021QH005 to T.W.)the China Postdoctoral Science Foundation(2024M752006 to S.M.)。
文摘Although the spatial characteristics within the tumor microenvironment of lung adenocarcinoma(LUAD)have been identified,the mechanisms by which these factors promote LUAD progression and immune evasion remain unclear.Using spatial transcriptomics and single-cell RNA-sequencing data from multi-regional LUAD biopsies consisting of tumor core,tumor edge,and normal area,we sought to delineate the spatial heterogeneity and driving factors of cell colocalization.Two cancer cell sub-clusters(Cancer_c1 and Cancer_c2),associated with LUAD initiation and metastasis,respectively,exhibit distinct spatial distributions and immune cell colocalizations.In particular,Cancer_c1,enriched within the tumor core,could directly interact with B cells or indirectly recruit B cells through macrophages.Conversely,Cancer_c2 enriched within the tumor edge exhibits colocalization with CD8^(+)T cells.Collectively,our work elucidates the spatial distribution of cancer cell subtypes and their interaction with immune cells in the core and edge of LUAD,providing insights for developing therapeutic strategies for cancer intervention.
文摘Most data centers currently tap into existing power grids to draw the immense amount of electricity they need to operate.But many of the data centers that Google(Mountain View,CA,USA)plans to open in the next few years will boast their own power plants,an arrangement known as colocation[1].Under an agreement announced in December 2024,the company will site data centers in industrial parks where its partner Intersect Power of Houston,TX,USA,has installed clean power facilities[1,2].The first of these complexes is scheduled to come online in 2026[1].
文摘背景:骨关节炎是与代谢异常密切相关的复杂性疾病,然而以往研究仅涉及有限的血脂指标,未进行更全面的血脂谱分析。深入探讨血脂7项与骨关节炎之间的因果关系,不仅有助于理解骨关节炎的发病机制,还能为其预防和治疗提供新的研究方向和临床依据。目的:探讨血脂与骨关节炎的因果关系。方法:使用来自IEU OPEN GWAS数据库的血脂7项和骨关节炎的全基因组关联分析统计数据进行汇总,工具变量采用显著单核苷酸多态性,通过双样本孟德尔随机化分析得出血脂7项(血清总胆固醇、三酰甘油、低密度脂蛋白胆固醇、高密度脂蛋白胆固醇、载脂蛋白B、载脂蛋白AI和载脂蛋白A1)与骨关节炎(骨关节炎、膝或髋骨关节炎、膝骨关节炎和髋骨关节炎)的因果关系,以逆方差加权为主要效应,MR-Egger回归法和加权中位数法为补充效应。Bonferroni校正和反向孟德尔随机化分析保证有效性。采用多变量孟德尔随机化分析进一步破除混杂因素,得出血脂7项与骨关节炎的显著因果关系,保证分析的稳健性。采用共定位分析再次确保因果关系的稳健性,并得出显著影响作用的基因位点,使因果关系证据更充分。结果与结论:①双样本孟德尔随机化分析中逆方差加权结果显示,总胆固醇(OR=0.9372,95%CI=0.8856-0.9919,P=0.025)、低密度脂蛋白胆固醇(OR=0.9594,95%CI=0.9236-0.9966,P=0.033)、高密度脂蛋白胆固醇(OR=0.9112,95%CI=0.8335-0.9962,P=0.04)、载脂蛋白B(OR=0.926,95%CI=0.8877-0.9674,P=0.0005)和载脂蛋白AI(OR=0.9512,95%CI=0.9110-0.9931,P=0.023)与骨关节炎呈负相关,总胆固醇(OR=0.8923,95%CI=0.8431-0.9443,P=0.00008)、三酰甘油(OR=0.9385,95%CI=0.8847-0.9956,P=0.035)和载脂蛋白B(OR=0.9116,95%CI=0.8659-0.9597,P=0.0004)与膝或髋骨关节炎呈负相关,总胆固醇(OR=0.8983,95%CI=0.8412-0.9593,P=0.001)、高密度脂蛋白胆固醇(OR=0.8812,95%CI=0.7947-0.9770,P=0.016)和载脂蛋白B(OR=0.9190,95%CI=0.8698-0.9710,P=0.002)与膝骨关节炎呈负相关,总胆固醇(OR=0.8645,95%CI=0.7975-0.9373,P=0.0004)、低密度脂蛋白胆固醇(OR=0.9256,95%CI=0.8795-0.9741,P=0.003)和载脂蛋白B(OR=0.8888,95%CI=0.8176-0.9663,P=0.005)与髋骨关节炎呈负相关;在反向孟德尔随机化分析中结果无统计学差异。②多变量孟德尔随机化分析中逆方差加权结果显示,高密度脂蛋白胆固醇(OR=0.9427,95%CI=0.8961-0.9918,P=0.022)与骨关节炎呈负相关,总胆固醇(OR=0.799,95%CI=0.6478-0.987,P=0.037)和高密度脂蛋白胆固醇(OR=0.8651,95%CI=0.7781-0.9619,P=0.007)与膝骨关节炎呈负相关。③共定位分析结果显示,总胆固醇和低密度脂蛋白与骨关节炎的H4后验概率=99.9%,共同指向一个显著单核苷酸多态性,为rs13107325。④这些结果采用国际数据库、非亚洲人群,可为中国生物医学及中国人群骨关节炎的临床早期诊断、发病机制理解和预防与治疗提供有价值的借鉴意义和指导作用。
