A disintegrin and metalloprotease 17(ADAM17)is a membrane-bound enzyme that cleaves cell-surface proteins.Here,we discovered that neuronal ADAM17-mediated signaling supports the reduction of inhibitory presynaptic inp...A disintegrin and metalloprotease 17(ADAM17)is a membrane-bound enzyme that cleaves cell-surface proteins.Here,we discovered that neuronal ADAM17-mediated signaling supports the reduction of inhibitory presynaptic inputs to the pre-sympathetic glutamatergic neural hub,located in the paraventricular nucleus of the hypothalamus(PVN),upon stimulation by angiotensin II(Ang-II).For Ang-II-induced disinhibition,targeting microglial migration had an effect similar to ADAM17 knockout in glutamatergic neurons.Ang-II promoted neuron-mediated chemotaxis of microglia via neuronal CX3CL1 and ADAM17.Inhibiting microglial chemotaxis by targeting CX3CR1 abolished the Ang-II-induced microglial displacement of GABAergic presynaptic terminals and significantly blunted Ang-II’s pressor response.Using conditional and targeted knockout models of ADAM17,an increase in the contact between pre-sympathetic neurons and reactive microglia in the PVN was demonstrated to be neuronal ADAM17-dependent during the developmental stage of salt-sensitive hypertension.Collectively,this study provides evidence that neuronal ADAM17-mediated microglial chemotaxis facilitates the disinhibition of pre-sympathetic glutamatergic tone upon hormonal stimulation.展开更多
Background:Prostate cancer(PCa)is the most prevalent malignancy in men and often correlates with distant metastasis in its advanced stages.The study aimed to investigate the effects of Ugonin J,a natural compound isol...Background:Prostate cancer(PCa)is the most prevalent malignancy in men and often correlates with distant metastasis in its advanced stages.The study aimed to investigate the effects of Ugonin J,a natural compound isolated from Helminthostachys zeylanica,on PCa metastasis.Methods:The effects of Ugonin J on cell motility were assessed using migration and invasion assays.Reverse Transcription Quantitative PCR(RT-qPCR)and Western blotting were used to evaluate the impact of Ugonin J on mRNA and protein expression.RNA sequencing(RNA-seq)analysis was performed to investigate candidate mechanisms.Differential gene expression analysis in PCa patients was conducted using multiple databases.Results:Here,we reveal that Ugonin J blocks migration and invasion in PCa cells without affecting cell viability.RNA-seq analysis suggests that epithelial-mesenchymal transition(EMT)is potentially involved in Ugonin J’s anti-motility effects.Ugonin J also suppresses the expression of mesenchymal markers N-cadherin,β-catenin,Snail,and Slug while upregulating the expression of the epithelial marker E-cadherin.Furthermore,among 13 A disintegrin and metalloproteinase(ADAM)proteins,A disintegrin and metalloproteinase domain-containing protein 9(ADAM9)is the most downregulated following Ugonin J treatment,according to our RNA-seq data.Importantly,clinical data revealed that ADAM9 expression are higher in PCa patients than in healthy controls and are associated with distant metastasis.Transfection with ADAM9 cDNA reverses Ugonin J-regulated downregulation of EMT,migration,and invasion in PCa cells.Ugonin J inhibits ADAM9-dependent motility by downregulating the phosphoinositide 3-kinase(PI3K),protein kinase B(Akt)and nuclear factor-κB(NF-κB)pathways.Conclusions:Our evidence suggests that Ugonin J is a novel therapeutic candidate for further development as a treatment for metastatic PCa.展开更多
【目的】针对现有桥梁施工线形预测方法的不足,提出一种基于自适应矩估计(adaptive moment estimation,Adam)优化反向传播(back propagation,BP)神经网络的连续刚构桥线形预测方法。【方法】以小乌江大桥为研究对象,通过正交试验确定了...【目的】针对现有桥梁施工线形预测方法的不足,提出一种基于自适应矩估计(adaptive moment estimation,Adam)优化反向传播(back propagation,BP)神经网络的连续刚构桥线形预测方法。【方法】以小乌江大桥为研究对象,通过正交试验确定了桥梁施工线形的敏感参数为混凝土容重、混凝土弹性模量、张拉控制应力和温度。以均方根误差、平均绝对误差、决定系数和运算耗时为评价指标,在初始学习率相同的条件下,对梯度下降、梯度下降最小化、均方根传播和Adam四种优化算法的性能进行对比。【结果】基于Adam优化算法的BP神经网络收敛时的运算耗时为0.518 s,相较于其他三种优化算法,Adam优化算法下BP神经网络具有更快的收敛速度和更高的拟合精度。【结论】所提方法可较准确地预测连续刚构桥施工过程的线形。展开更多
基金supported by the National Natural Science Foundation of China(82100454,32271016,82101586,and 81872563)the National Heart,Lung,Blood,and Sleep Institute(HL163588).
文摘A disintegrin and metalloprotease 17(ADAM17)is a membrane-bound enzyme that cleaves cell-surface proteins.Here,we discovered that neuronal ADAM17-mediated signaling supports the reduction of inhibitory presynaptic inputs to the pre-sympathetic glutamatergic neural hub,located in the paraventricular nucleus of the hypothalamus(PVN),upon stimulation by angiotensin II(Ang-II).For Ang-II-induced disinhibition,targeting microglial migration had an effect similar to ADAM17 knockout in glutamatergic neurons.Ang-II promoted neuron-mediated chemotaxis of microglia via neuronal CX3CL1 and ADAM17.Inhibiting microglial chemotaxis by targeting CX3CR1 abolished the Ang-II-induced microglial displacement of GABAergic presynaptic terminals and significantly blunted Ang-II’s pressor response.Using conditional and targeted knockout models of ADAM17,an increase in the contact between pre-sympathetic neurons and reactive microglia in the PVN was demonstrated to be neuronal ADAM17-dependent during the developmental stage of salt-sensitive hypertension.Collectively,this study provides evidence that neuronal ADAM17-mediated microglial chemotaxis facilitates the disinhibition of pre-sympathetic glutamatergic tone upon hormonal stimulation.
基金supported by the National Science and Technology Council(NSTC 113-2320-B-039-049-MY3 and NSTC 114-2314-B-039-051-MY3)China Medical University(CMU113-ASIA-05,CMU-114-ASIA-01).
文摘Background:Prostate cancer(PCa)is the most prevalent malignancy in men and often correlates with distant metastasis in its advanced stages.The study aimed to investigate the effects of Ugonin J,a natural compound isolated from Helminthostachys zeylanica,on PCa metastasis.Methods:The effects of Ugonin J on cell motility were assessed using migration and invasion assays.Reverse Transcription Quantitative PCR(RT-qPCR)and Western blotting were used to evaluate the impact of Ugonin J on mRNA and protein expression.RNA sequencing(RNA-seq)analysis was performed to investigate candidate mechanisms.Differential gene expression analysis in PCa patients was conducted using multiple databases.Results:Here,we reveal that Ugonin J blocks migration and invasion in PCa cells without affecting cell viability.RNA-seq analysis suggests that epithelial-mesenchymal transition(EMT)is potentially involved in Ugonin J’s anti-motility effects.Ugonin J also suppresses the expression of mesenchymal markers N-cadherin,β-catenin,Snail,and Slug while upregulating the expression of the epithelial marker E-cadherin.Furthermore,among 13 A disintegrin and metalloproteinase(ADAM)proteins,A disintegrin and metalloproteinase domain-containing protein 9(ADAM9)is the most downregulated following Ugonin J treatment,according to our RNA-seq data.Importantly,clinical data revealed that ADAM9 expression are higher in PCa patients than in healthy controls and are associated with distant metastasis.Transfection with ADAM9 cDNA reverses Ugonin J-regulated downregulation of EMT,migration,and invasion in PCa cells.Ugonin J inhibits ADAM9-dependent motility by downregulating the phosphoinositide 3-kinase(PI3K),protein kinase B(Akt)and nuclear factor-κB(NF-κB)pathways.Conclusions:Our evidence suggests that Ugonin J is a novel therapeutic candidate for further development as a treatment for metastatic PCa.
文摘【目的】针对现有桥梁施工线形预测方法的不足,提出一种基于自适应矩估计(adaptive moment estimation,Adam)优化反向传播(back propagation,BP)神经网络的连续刚构桥线形预测方法。【方法】以小乌江大桥为研究对象,通过正交试验确定了桥梁施工线形的敏感参数为混凝土容重、混凝土弹性模量、张拉控制应力和温度。以均方根误差、平均绝对误差、决定系数和运算耗时为评价指标,在初始学习率相同的条件下,对梯度下降、梯度下降最小化、均方根传播和Adam四种优化算法的性能进行对比。【结果】基于Adam优化算法的BP神经网络收敛时的运算耗时为0.518 s,相较于其他三种优化算法,Adam优化算法下BP神经网络具有更快的收敛速度和更高的拟合精度。【结论】所提方法可较准确地预测连续刚构桥施工过程的线形。
