Nucleotide binding domain,leucine-rich repeat,and pyrin domain-containing 3(NLRP3)is an NLR-protein family member that can be activated by diverse exogenous and endogenous stimuli but without direct binding of any of ...Nucleotide binding domain,leucine-rich repeat,and pyrin domain-containing 3(NLRP3)is an NLR-protein family member that can be activated by diverse exogenous and endogenous stimuli but without direct binding of any of these pathogen ligands.Biological studies show that inactive NLRP3 is usually in an as-sembly state and its activation requires a kinase protein,NEK7.However,our re-cent computational studies as well as other biological investigations have demonstrated that NEK7 does not play a significant role in the activation of NLRP3 assembly and activation.In-stead,biological studies suggest that NEK7 is essential in the dissociation of inactive NLRP3 assemblies.Despite extensive research,the dissociation mechanism of the inactive NLRP3 as-sembly remains largely elusive.In this work,an improved MM-PBSA method is applied to the protein-protein binding free energies in the inactive NLRP3 decamer.Combined with the po-tential mean force(PMF)computation for the 0°→5°conformational change,the standard free-energy change,ΔG^(0)is calculated for NEK7-driven association of the inactive NLRP3 de-camer.Our calculations show that in the absence of NEK7,the dissociation of the inactive NLRP3 decamer is an energetically unfavorable process(ΔG^(0)=99.69 kcal/mol),whereas upon NEK7 binding,the overall standard free energy differenceΔG^(0)=-24.21 kcal/mol is obtained for the inactive NLRP3 decamer dissociation.The free-energy difference calcula-tions in this work also disclose an energetically optimized dissociation pathway,along which the inactive NLRP3 decamer is disunited by a one-by-one dissociation mechanism.展开更多
目的探究妊娠期糖尿病(GDM)患者血清脂肪酸结合蛋白质4(FAP4)、25-羟维生素D[25(OH)D]水平与新生儿结局的关系。方法选取2018年3月至2020年4月本院收治的GDM患者102例(观察组),另选取同期在本院生产的健康孕妇83例(对照组),比较两组的...目的探究妊娠期糖尿病(GDM)患者血清脂肪酸结合蛋白质4(FAP4)、25-羟维生素D[25(OH)D]水平与新生儿结局的关系。方法选取2018年3月至2020年4月本院收治的GDM患者102例(观察组),另选取同期在本院生产的健康孕妇83例(对照组),比较两组的血脂相关指标、血糖相关指标、胰岛素抵抗指数(HOMA-IR)、血清FABP4、25(OH)D水平,采用受试者工作特征(ROC)曲线分析血清FABP4、25(OH)D水平预测新生儿结局的应用价值。结果观察组的总胆固醇(TC)、甘油三酯(TG)、空腹血糖(FPG)和餐后2 h血糖(2 h PG)水平均高于对照组,高密度脂蛋白胆固醇(HDL-C)和HOMA-IR水平均低于对照组,差异有统计学意义(P<0.05);两组的胎儿窘迫、胎儿生长受限、新生儿窒息和低体重出生发生率比较差异无统计学意义(P>0.05),观察组的新生儿不良结局总发生率高于对照组,差异有统计学意义(P<0.05);观察组的血清FABP4水平高于对照组,25(OH)D水平低于对照组,差异有统计学意义(P<0.05);观察组两亚组患者血清FABP4、25(OH)D水平比较,结局不良组患者的血清FABP4水平明显高于结局良好组,25(OH)D水平明显低于结局良好组,差异有统计学意义(P<0.05);ROC曲线分析结果显示,FABP4、25(OH)D的曲线下面积(AUC)分别为0.660和0.715,对新生儿结局均有一定的预测能力(P<0.05)。结论 GDM患者血清FABP4、25(OH)D水平与新生儿不良结局有关,二者对GDM患者新生儿不良结局具有一定的预测价值。展开更多
基金supported by Ministry of Science and Technology of China(2022YFA1303100)the National Natural Science Foundation of China(No.32090040)。
文摘Nucleotide binding domain,leucine-rich repeat,and pyrin domain-containing 3(NLRP3)is an NLR-protein family member that can be activated by diverse exogenous and endogenous stimuli but without direct binding of any of these pathogen ligands.Biological studies show that inactive NLRP3 is usually in an as-sembly state and its activation requires a kinase protein,NEK7.However,our re-cent computational studies as well as other biological investigations have demonstrated that NEK7 does not play a significant role in the activation of NLRP3 assembly and activation.In-stead,biological studies suggest that NEK7 is essential in the dissociation of inactive NLRP3 assemblies.Despite extensive research,the dissociation mechanism of the inactive NLRP3 as-sembly remains largely elusive.In this work,an improved MM-PBSA method is applied to the protein-protein binding free energies in the inactive NLRP3 decamer.Combined with the po-tential mean force(PMF)computation for the 0°→5°conformational change,the standard free-energy change,ΔG^(0)is calculated for NEK7-driven association of the inactive NLRP3 de-camer.Our calculations show that in the absence of NEK7,the dissociation of the inactive NLRP3 decamer is an energetically unfavorable process(ΔG^(0)=99.69 kcal/mol),whereas upon NEK7 binding,the overall standard free energy differenceΔG^(0)=-24.21 kcal/mol is obtained for the inactive NLRP3 decamer dissociation.The free-energy difference calcula-tions in this work also disclose an energetically optimized dissociation pathway,along which the inactive NLRP3 decamer is disunited by a one-by-one dissociation mechanism.
文摘目的探究妊娠期糖尿病(GDM)患者血清脂肪酸结合蛋白质4(FAP4)、25-羟维生素D[25(OH)D]水平与新生儿结局的关系。方法选取2018年3月至2020年4月本院收治的GDM患者102例(观察组),另选取同期在本院生产的健康孕妇83例(对照组),比较两组的血脂相关指标、血糖相关指标、胰岛素抵抗指数(HOMA-IR)、血清FABP4、25(OH)D水平,采用受试者工作特征(ROC)曲线分析血清FABP4、25(OH)D水平预测新生儿结局的应用价值。结果观察组的总胆固醇(TC)、甘油三酯(TG)、空腹血糖(FPG)和餐后2 h血糖(2 h PG)水平均高于对照组,高密度脂蛋白胆固醇(HDL-C)和HOMA-IR水平均低于对照组,差异有统计学意义(P<0.05);两组的胎儿窘迫、胎儿生长受限、新生儿窒息和低体重出生发生率比较差异无统计学意义(P>0.05),观察组的新生儿不良结局总发生率高于对照组,差异有统计学意义(P<0.05);观察组的血清FABP4水平高于对照组,25(OH)D水平低于对照组,差异有统计学意义(P<0.05);观察组两亚组患者血清FABP4、25(OH)D水平比较,结局不良组患者的血清FABP4水平明显高于结局良好组,25(OH)D水平明显低于结局良好组,差异有统计学意义(P<0.05);ROC曲线分析结果显示,FABP4、25(OH)D的曲线下面积(AUC)分别为0.660和0.715,对新生儿结局均有一定的预测能力(P<0.05)。结论 GDM患者血清FABP4、25(OH)D水平与新生儿不良结局有关,二者对GDM患者新生儿不良结局具有一定的预测价值。
