Diabetic kidney disease(DKD)with increasing global prevalence lacks effective therapeutic targets to halt or reverse its progression.Therapeutic targets supported by causal genetic evidence are more likely to succeed ...Diabetic kidney disease(DKD)with increasing global prevalence lacks effective therapeutic targets to halt or reverse its progression.Therapeutic targets supported by causal genetic evidence are more likely to succeed in randomized clinical trials.In this study,we integrated large-scale plasma proteomics,genetic-driven causal inference,and experimental validation to identify prioritized targets for DKD using the UK Biobank(UKB)and FinnGen cohorts.Among 2844 diabetic patients(528 with DKD),we identified 37 targets significantly associated with incident DKD,supported by both observational and causal evidence.Of these,22%(8/37)of the potential targets are currently under investigation for DKD or other diseases.Our prospective study confirmed that higher levels of three prioritized targetsdinsulin-like growth factor binding protein 4(IGFBP4),family with sequence similarity 3 member C(FAM3C),and prostaglandin D2 synthase(PTGDS)dwere associated with a 4.35,3.51,and 3.57-fold increased likelihood of developing DKD,respectively.In addition,population-level protein-altering variants(PAVs)analysis and in vitro experiments cross-validated FAM3C and IGFBP4 as potential new target candidates for DKD,through the classic NLR family pyrin domain containing 3(NLRP3)-caspase-1-gasdermin D(GSDMD)apoptotic axis.Our results demonstrate that integrating omics data mining with causal inference may be a promising strategy for prioritizing therapeutic targets.展开更多
芝麻是八大类食物过敏原之一,快速准确识别芝麻过敏原对预防其过敏有重要意义。核酸适配体可以高效识别靶标过敏原,在过敏原检测中有良好的应用前景。为了获得芝麻主要过敏原Ses i 2的特异性核酸适体,本研究以Ses i 2为靶标,通过磁珠筛...芝麻是八大类食物过敏原之一,快速准确识别芝麻过敏原对预防其过敏有重要意义。核酸适配体可以高效识别靶标过敏原,在过敏原检测中有良好的应用前景。为了获得芝麻主要过敏原Ses i 2的特异性核酸适体,本研究以Ses i 2为靶标,通过磁珠筛选法(磁珠-SELEX)开展10轮筛选,经由高通量测序获得6条候补序列(S1~S6),并进行家族性、同源性分析及二级结构预测。结果表明,6条候选核酸适体的重复率可达46.38%,其自由能在-9.02到-2.47 kcal·moL^(-1)之间,根据自由能能量稳定原则,S1和S5吉布斯自由能最低最稳定,分别为-6.70和-9.02 kcal·moL^(-1)。利用ELISA试验进行亲和力测试,结果表明核酸适体S1和S2的亲和能力较强,S1:KD=67.02 nmol·L^(-1),R2=0.925 8,S2:KD=97.65 nmol·L^(-1),R2=0.795 1。核酸适体S1与过敏原Ses i 2的结合力和其他过敏原蛋白相比有显著差异,可视为具有特异性。本研究最终获得一条兼具良好亲和力和特异性的核酸适体S1,为芝麻过敏原快速检测提供了技术支撑。展开更多
掘进机回转台在截割煤岩时承受偏载荷及强冲击作用,其性能影响掘进机的工作效率及安全性。为探究掘进机回转台疲劳寿命的影响因素及最佳服役参数,提出了一种基于Kriging代理模型和DEM-MFBD(discrete element model-multi flexible body ...掘进机回转台在截割煤岩时承受偏载荷及强冲击作用,其性能影响掘进机的工作效率及安全性。为探究掘进机回转台疲劳寿命的影响因素及最佳服役参数,提出了一种基于Kriging代理模型和DEM-MFBD(discrete element model-multi flexible body dynamics,离散单元法-多柔性体动力学)双向耦合技术的回转台疲劳寿命预测方法。首先,建立了掘进机截割部与回转台的空间受力模型,明确了截割部与回转台的受力规律。然后,联合RecurDyn与EDEM软件对回转台进行双向刚柔耦合动力学仿真分析,获得了回转台在工作状态下的应力分布。最后,利用拉丁超立方抽样法选取15组掘进机服役参数作为输入,以回转台疲劳寿命为响应,建立了对应的Kriging代理模型,并利用粒子群优化算法对代理模型进行寻优,得到了回转台在最佳服役参数下的疲劳寿命。结果表明,当掘进机的截割头转速为54 r/min、回转台横摆速度为1.003 m/min、截割臂垂直摆角为7°时,回转台的疲劳寿命最长。结合DEM-MFBD双向耦合技术、Kriging代理模型与粒子群优化算法来探究掘进机的最佳服役参数,可为回转类部件的优化设计提供新思路。展开更多
基金supported by the National Natural Science Foundation of China(Grant Nos.:82204396,82304491,and 82400511).
文摘Diabetic kidney disease(DKD)with increasing global prevalence lacks effective therapeutic targets to halt or reverse its progression.Therapeutic targets supported by causal genetic evidence are more likely to succeed in randomized clinical trials.In this study,we integrated large-scale plasma proteomics,genetic-driven causal inference,and experimental validation to identify prioritized targets for DKD using the UK Biobank(UKB)and FinnGen cohorts.Among 2844 diabetic patients(528 with DKD),we identified 37 targets significantly associated with incident DKD,supported by both observational and causal evidence.Of these,22%(8/37)of the potential targets are currently under investigation for DKD or other diseases.Our prospective study confirmed that higher levels of three prioritized targetsdinsulin-like growth factor binding protein 4(IGFBP4),family with sequence similarity 3 member C(FAM3C),and prostaglandin D2 synthase(PTGDS)dwere associated with a 4.35,3.51,and 3.57-fold increased likelihood of developing DKD,respectively.In addition,population-level protein-altering variants(PAVs)analysis and in vitro experiments cross-validated FAM3C and IGFBP4 as potential new target candidates for DKD,through the classic NLR family pyrin domain containing 3(NLRP3)-caspase-1-gasdermin D(GSDMD)apoptotic axis.Our results demonstrate that integrating omics data mining with causal inference may be a promising strategy for prioritizing therapeutic targets.
文摘芝麻是八大类食物过敏原之一,快速准确识别芝麻过敏原对预防其过敏有重要意义。核酸适配体可以高效识别靶标过敏原,在过敏原检测中有良好的应用前景。为了获得芝麻主要过敏原Ses i 2的特异性核酸适体,本研究以Ses i 2为靶标,通过磁珠筛选法(磁珠-SELEX)开展10轮筛选,经由高通量测序获得6条候补序列(S1~S6),并进行家族性、同源性分析及二级结构预测。结果表明,6条候选核酸适体的重复率可达46.38%,其自由能在-9.02到-2.47 kcal·moL^(-1)之间,根据自由能能量稳定原则,S1和S5吉布斯自由能最低最稳定,分别为-6.70和-9.02 kcal·moL^(-1)。利用ELISA试验进行亲和力测试,结果表明核酸适体S1和S2的亲和能力较强,S1:KD=67.02 nmol·L^(-1),R2=0.925 8,S2:KD=97.65 nmol·L^(-1),R2=0.795 1。核酸适体S1与过敏原Ses i 2的结合力和其他过敏原蛋白相比有显著差异,可视为具有特异性。本研究最终获得一条兼具良好亲和力和特异性的核酸适体S1,为芝麻过敏原快速检测提供了技术支撑。
文摘掘进机回转台在截割煤岩时承受偏载荷及强冲击作用,其性能影响掘进机的工作效率及安全性。为探究掘进机回转台疲劳寿命的影响因素及最佳服役参数,提出了一种基于Kriging代理模型和DEM-MFBD(discrete element model-multi flexible body dynamics,离散单元法-多柔性体动力学)双向耦合技术的回转台疲劳寿命预测方法。首先,建立了掘进机截割部与回转台的空间受力模型,明确了截割部与回转台的受力规律。然后,联合RecurDyn与EDEM软件对回转台进行双向刚柔耦合动力学仿真分析,获得了回转台在工作状态下的应力分布。最后,利用拉丁超立方抽样法选取15组掘进机服役参数作为输入,以回转台疲劳寿命为响应,建立了对应的Kriging代理模型,并利用粒子群优化算法对代理模型进行寻优,得到了回转台在最佳服役参数下的疲劳寿命。结果表明,当掘进机的截割头转速为54 r/min、回转台横摆速度为1.003 m/min、截割臂垂直摆角为7°时,回转台的疲劳寿命最长。结合DEM-MFBD双向耦合技术、Kriging代理模型与粒子群优化算法来探究掘进机的最佳服役参数,可为回转类部件的优化设计提供新思路。
