Tutin,an established toxic natural product that causes epilepsy in rodents,is often used as a tool to develop animal model of acute epileptic seizures.However,the molecular target and toxic mechanism of tutin were unc...Tutin,an established toxic natural product that causes epilepsy in rodents,is often used as a tool to develop animal model of acute epileptic seizures.However,the molecular target and toxic mechanism of tutin were unclear.In this study,for the first time,we conducted experiments to clarify the targets in tutin-induced epilepsy using thermal proteome profiling.Our studies showed that calcineurin(CN)was a target of tutin,and that tutin activated CN,leading to seizures.Binding site studies further established that tutin bound within the active site of CN catalytic subunit.CN inhibitor and calcineurin A(CNA)knockdown experiments in vivo proved that tutin induced epilepsy by activating CN,and produced obvious nerve damage.Together,these findings revealed that tutin caused epileptic seizures by activating CN.Moreover,further mechanism studies found that N-methyl-D-aspartate(NMDA)receptors,gammaaminobutyric acid(GABA)receptors and voltage-and Ca2+-activated K+(BK)channels might be involved in related signaling pathways.Our study fully explains the convulsive mechanism of tutin,which provides new ideas for epilepsy treatment and drug development.展开更多
本文基于观测数据和模式产品,探讨了南海西边界流(South China Sea western boundary current,SCSwbc)区域海洋涡旋的统计特征、涡致热输运并重点探讨了两类冬季环流形态及其风场分布对它们的影响。结果表明研究区域的涡旋气候态上存在...本文基于观测数据和模式产品,探讨了南海西边界流(South China Sea western boundary current,SCSwbc)区域海洋涡旋的统计特征、涡致热输运并重点探讨了两类冬季环流形态及其风场分布对它们的影响。结果表明研究区域的涡旋气候态上存在旋转速度很强,半径较大,振幅略高于平均值的涡旋统计特征,其中气旋式涡旋(cyclonic eddy,CE)的占比约为56.8%。并且涡旋的生成和消亡主要发生在冬/春季,而涡旋的振幅、半径和旋转速度在夏/秋季发展到顶峰。年际时间尺度上,年平均经向风应力与反气旋式涡旋(anticyclonic eddy,AE)的振幅、半径、旋转速度和消亡均有较好的相关性,但与CE特征的相关性并不好。“O”型冬季环流模态下,风场和南海西边界流显著减弱,冬季环流在越南沿岸发生向东分支。涡旋在“O”模态下吸收平均流能量迅速发展,在越南沿岸东部地区产生了强的涡致热输运(eddy-induced heat transport,EHT)。同时,涡旋内部旋转速度减小且反气旋式涡旋个数减少;“U”型冬季环流模态下,情况则相反。展开更多
基金the Natural Science Foundation of China(No.21732008)CAMS Innovation Fund for Medical Sciences(No.CIFMS-2021-I2M-1-027,CIFMS-2021-I2M-1-028,CIFMS-2022-I2M-JB-009).
文摘Tutin,an established toxic natural product that causes epilepsy in rodents,is often used as a tool to develop animal model of acute epileptic seizures.However,the molecular target and toxic mechanism of tutin were unclear.In this study,for the first time,we conducted experiments to clarify the targets in tutin-induced epilepsy using thermal proteome profiling.Our studies showed that calcineurin(CN)was a target of tutin,and that tutin activated CN,leading to seizures.Binding site studies further established that tutin bound within the active site of CN catalytic subunit.CN inhibitor and calcineurin A(CNA)knockdown experiments in vivo proved that tutin induced epilepsy by activating CN,and produced obvious nerve damage.Together,these findings revealed that tutin caused epileptic seizures by activating CN.Moreover,further mechanism studies found that N-methyl-D-aspartate(NMDA)receptors,gammaaminobutyric acid(GABA)receptors and voltage-and Ca2+-activated K+(BK)channels might be involved in related signaling pathways.Our study fully explains the convulsive mechanism of tutin,which provides new ideas for epilepsy treatment and drug development.
文摘本文基于观测数据和模式产品,探讨了南海西边界流(South China Sea western boundary current,SCSwbc)区域海洋涡旋的统计特征、涡致热输运并重点探讨了两类冬季环流形态及其风场分布对它们的影响。结果表明研究区域的涡旋气候态上存在旋转速度很强,半径较大,振幅略高于平均值的涡旋统计特征,其中气旋式涡旋(cyclonic eddy,CE)的占比约为56.8%。并且涡旋的生成和消亡主要发生在冬/春季,而涡旋的振幅、半径和旋转速度在夏/秋季发展到顶峰。年际时间尺度上,年平均经向风应力与反气旋式涡旋(anticyclonic eddy,AE)的振幅、半径、旋转速度和消亡均有较好的相关性,但与CE特征的相关性并不好。“O”型冬季环流模态下,风场和南海西边界流显著减弱,冬季环流在越南沿岸发生向东分支。涡旋在“O”模态下吸收平均流能量迅速发展,在越南沿岸东部地区产生了强的涡致热输运(eddy-induced heat transport,EHT)。同时,涡旋内部旋转速度减小且反气旋式涡旋个数减少;“U”型冬季环流模态下,情况则相反。
