近年来世界VLBI(Very Large Baseline Interferometry)终端技术发展迅速,主流的记录终端已发展到Mark5B记录系统,Mark5C也正在研制和测试阶段。为了适应未来高速率、海量数据以及数字基带转换器观测的要求,需要将现有的Mark5A升级到Mar...近年来世界VLBI(Very Large Baseline Interferometry)终端技术发展迅速,主流的记录终端已发展到Mark5B记录系统,Mark5C也正在研制和测试阶段。为了适应未来高速率、海量数据以及数字基带转换器观测的要求,需要将现有的Mark5A升级到Mark5B或Mark5B+,相应地需要将Mark4格式器升级为Mark5B采样器。主要描述了相关设备的原理以及Mark4格式器升级的步骤。展开更多
Gliomas are the most common primary intracranial neoplasms among all brain malignancies,and the microtubule affinity regulating kinases(MARKs)have become potential drug targets for glioma.Here,we report a novel dual s...Gliomas are the most common primary intracranial neoplasms among all brain malignancies,and the microtubule affinity regulating kinases(MARKs)have become potential drug targets for glioma.Here,we report a novel dual small-molecule inhibitor of MARK3 and MARK4,designated as PCC0208017.In vitro,PCC0208017 strongly inhibited kinase activity against MARK3 and MARK4,and strongly reduced proliferation in three glioma cell lines.This compound attenuated glioma cell migration,glioma cell invasion,and angiogenesis.Molecular mechanism studies revealed that PCC0208017 decreased the phosphorylation of Tau,disrupted microtubule dynamics,and induced a G2/M phase cell cycle arrest.In an in vivo glioma model,PCC0208017 showed robust anti-tumor activity,blood-brain barrier permeability,and a good oral pharmacokinetic profile.Molecular docking studies showed that PCC0208017 exhibited high binding affinity to MARK3 and MARK4.Taken together,our study describes for the first time that PCC0208017,a novel MARK3/MARK4 inhibitor,might be a promising lead compound for treatment of glioma.展开更多
Background Intraneuronal accumulation of hyperphosphorylated tau is a hallmark of Alzheimer’s disease(AD).Given the significant correlation between tau pathology and memory loss in AD patients,identifying vulnerable ...Background Intraneuronal accumulation of hyperphosphorylated tau is a hallmark of Alzheimer’s disease(AD).Given the significant correlation between tau pathology and memory loss in AD patients,identifying vulnerable brain regions,particularly susceptible neuron types in these regions,will advance our understanding of AD onset and shed light on therapeutic strategies to manage its progression.Methods Immunofluorescent staining was employed to identify the brain regions and neuron types vulnerable to tau pathology in AD.A combination of chemogenetics,electrophysiological recording,in vivo Ca2+recording,and a modified temporal-order discrimination behavior test was utilized to investigate the toxicity of tau accumulation to susceptible neurons in the dorsal part of the ventral hippocampus.Proteomics,phosphoproteomics,and molecular targeting were used to explore the underlying mechanisms of neuron susceptibility to tau accumulation in AD.The beneficial effects of microtubule affinity regulating kinase 4(MARK4)knockdown and administration of DEPhosphorylation TArgeting Chimera(DEPTAC)were evaluated in AD mice with tau pathology.Results In postmortem brains of AD patients,we observed robust accumulation of hyperphosphorylated tau in the anterior hippocampal CA1 region,particularly in its Calbindin1−(Calb1−)neurons,as opposed to the posterior hippocampal CA1 region and Calb1+neurons.The susceptibility of Calb1−neurons to phospho-tau accumulation was also observed in P301L mice,especially in the dorsal part of ventral(anterior in human)hippocampal CA1(dvCA1).In P301L mice,dvCA1 displayed distinct protein and phosphorylated protein networks compared with dorsal CA1,accompanied by overactivation of MARK4.Overexpressing human tau in Calb1−neurons in the dvCA1(dvCA1Calb1−neurons)specifically impairs the temporal-order discrimination of objects.Meanwhile,tau accumulation significantly inhibited the excitability and firing patterns of dvCA1Calb1−neurons associated with temporal-order discrimination.Knocking down MARK4 or reducing hyperphosporylated tau via DEPTAC in P301L mice significantly ameliorated AD-like tau pathology in dvCA1Calb1−neurons and improved temporal-order discrimination of objects.Conclusion These findings highlight the crucial role of dvCA1Calb1−neurons in the early stage of tau pathology and demonstrate the potential of targeting phosphorylated tau through MARK4 knockdown or DEPTAC administration to counter the vulnerability of dvCA1Calb1−neurons and,consequently,ameliorate episodic memory deficits in AD.展开更多
文摘近年来世界VLBI(Very Large Baseline Interferometry)终端技术发展迅速,主流的记录终端已发展到Mark5B记录系统,Mark5C也正在研制和测试阶段。为了适应未来高速率、海量数据以及数字基带转换器观测的要求,需要将现有的Mark5A升级到Mark5B或Mark5B+,相应地需要将Mark4格式器升级为Mark5B采样器。主要描述了相关设备的原理以及Mark4格式器升级的步骤。
基金partially supported by National Science Foundation of China(NSFC,81728020)Key Research Project of Shandong Province(2017GSF18177,China)+3 种基金Natural Science Foundation of Shandong Province(ZR2018LH025,China)The Science and Technology Support Program for Youth Innovation in Universities of Shandong(2019KJM009)Key Research Project of Yantai(2019XDHZ102,China)Taishan Scholar Project.
文摘Gliomas are the most common primary intracranial neoplasms among all brain malignancies,and the microtubule affinity regulating kinases(MARKs)have become potential drug targets for glioma.Here,we report a novel dual small-molecule inhibitor of MARK3 and MARK4,designated as PCC0208017.In vitro,PCC0208017 strongly inhibited kinase activity against MARK3 and MARK4,and strongly reduced proliferation in three glioma cell lines.This compound attenuated glioma cell migration,glioma cell invasion,and angiogenesis.Molecular mechanism studies revealed that PCC0208017 decreased the phosphorylation of Tau,disrupted microtubule dynamics,and induced a G2/M phase cell cycle arrest.In an in vivo glioma model,PCC0208017 showed robust anti-tumor activity,blood-brain barrier permeability,and a good oral pharmacokinetic profile.Molecular docking studies showed that PCC0208017 exhibited high binding affinity to MARK3 and MARK4.Taken together,our study describes for the first time that PCC0208017,a novel MARK3/MARK4 inhibitor,might be a promising lead compound for treatment of glioma.
基金supported in part by grants from the Natural Science Foundation of China(82071219,82371436,82230041,91949205)the Sanming Project of Medicine in Shenzhen(SZSM202211010)+1 种基金the Special Project of Technological Innovation of Hubei Province(2018ACA142)Guangdong Provincial Key S&T Program(018B030336001).
文摘Background Intraneuronal accumulation of hyperphosphorylated tau is a hallmark of Alzheimer’s disease(AD).Given the significant correlation between tau pathology and memory loss in AD patients,identifying vulnerable brain regions,particularly susceptible neuron types in these regions,will advance our understanding of AD onset and shed light on therapeutic strategies to manage its progression.Methods Immunofluorescent staining was employed to identify the brain regions and neuron types vulnerable to tau pathology in AD.A combination of chemogenetics,electrophysiological recording,in vivo Ca2+recording,and a modified temporal-order discrimination behavior test was utilized to investigate the toxicity of tau accumulation to susceptible neurons in the dorsal part of the ventral hippocampus.Proteomics,phosphoproteomics,and molecular targeting were used to explore the underlying mechanisms of neuron susceptibility to tau accumulation in AD.The beneficial effects of microtubule affinity regulating kinase 4(MARK4)knockdown and administration of DEPhosphorylation TArgeting Chimera(DEPTAC)were evaluated in AD mice with tau pathology.Results In postmortem brains of AD patients,we observed robust accumulation of hyperphosphorylated tau in the anterior hippocampal CA1 region,particularly in its Calbindin1−(Calb1−)neurons,as opposed to the posterior hippocampal CA1 region and Calb1+neurons.The susceptibility of Calb1−neurons to phospho-tau accumulation was also observed in P301L mice,especially in the dorsal part of ventral(anterior in human)hippocampal CA1(dvCA1).In P301L mice,dvCA1 displayed distinct protein and phosphorylated protein networks compared with dorsal CA1,accompanied by overactivation of MARK4.Overexpressing human tau in Calb1−neurons in the dvCA1(dvCA1Calb1−neurons)specifically impairs the temporal-order discrimination of objects.Meanwhile,tau accumulation significantly inhibited the excitability and firing patterns of dvCA1Calb1−neurons associated with temporal-order discrimination.Knocking down MARK4 or reducing hyperphosporylated tau via DEPTAC in P301L mice significantly ameliorated AD-like tau pathology in dvCA1Calb1−neurons and improved temporal-order discrimination of objects.Conclusion These findings highlight the crucial role of dvCA1Calb1−neurons in the early stage of tau pathology and demonstrate the potential of targeting phosphorylated tau through MARK4 knockdown or DEPTAC administration to counter the vulnerability of dvCA1Calb1−neurons and,consequently,ameliorate episodic memory deficits in AD.
