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A hnRNPA2B1 agonist effectively inhibits HBV and SARS-CoV-2 omicron in vivo 被引量:1
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作者 Daming Zuo Yu Chen +16 位作者 Jian-piaoCai hao-yang yuan Jun-Qi Wu Yue Yin Jing-Wen Xie Jing-Min Lin Jia Luo Yang Feng Long-Jiao Ge Jia Zhou Ronald JQuinn San-Jun Zhao Xing Tong Dong-Yan Jin Shuofeng yuan Shao-Xing Dai Min Xu 《Protein & Cell》 SCIE CSCD 2023年第1期37-50,共14页
The twenty-first century has already recorded more than ten major epidemics or pandemics of viral disease,including the devastating COVID-19.Novel effective antivirals with broad-spectrum coverage are urgently needed.... The twenty-first century has already recorded more than ten major epidemics or pandemics of viral disease,including the devastating COVID-19.Novel effective antivirals with broad-spectrum coverage are urgently needed.Herein,we reported a novel broad-spectrum antiviral compound PAC5.Oral administration of PAC5 eliminated HBV cccDNA and reduced the large antigen load in distinct mouse models of HBV infection.Strikingly,oral administration of PAC5 in a hamster model of SARS-CoV-2 omicron(BA.1)infection significantly decreases viral loads and attenuates lung inflammation.Mechanistically,PAC5 binds to a pocket near Asp49 in the RNA recognition motif of hnRNPA2B1.PAC5-bound hnRNPA2B1 is extensively activated and translocated to the cytoplasm where it initiates the TBK1-IRF3 pathway,leading to the production of type I IFNs with antiviral activity.Our results indicate that PAC5 is a novel small-molecule agonist of hnRNPA2B1,which may have a role in dealing with emerging infectious diseases now and in the future. 展开更多
关键词 hnRNPA2B1 PAC5 HBV SARS-CoV-2 omicron TBK1-IRF3 pathway type I IFNs
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Striatal CDK5 Regulates Cholinergic Neuron Activation and Dyskinesia-like Behaviors through BK Channels
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作者 Chu Tong Peng-Xiang Min +13 位作者 Qian Zhang Ru-Xin Gu Yao-Hai Wen Yi Shi Yu-Huan Bao Xiang Chen Yi-Xuan Zhang Xing-Feng Mao hao-yang yuan Xiu-Xiu Liu Takuya Sasaki Li Zhang Feng Han Ying-Mei Lu 《Research》 SCIE EI CSCD 2023年第4期739-753,共15页
Disturbance of the cholinergic system plays a crucial role in the pathological progression of neurological diseases that cause dyskinesia-like behaviors.However,the molecular mechanisms underlying this disturbance rem... Disturbance of the cholinergic system plays a crucial role in the pathological progression of neurological diseases that cause dyskinesia-like behaviors.However,the molecular mechanisms underlying this disturbance remain elusive.Here,we showed that cyclin-dependent kinase 5(Cdk5)was reduced in cholinergic neurons of midbrain according to the single-nucleus RNA sequencing analysis.Serum levels of CDK5 also decreased in patients with Parkinson’s disease accompanied by motor symptoms.Moreover,Cdk5 deficiency in cholinergic neurons triggered paw tremors,abnormal motor coordination,and motor balance deficits in mice.These symptoms occurred along with cholinergic neuron hyperexcitability and increases in the current density of large-conductance Ca2+-activated K+channels(BK channels).Pharmacological inhibition of BK channels restrained the excessive intrinsic excitability of striatal cholinergic neurons in Cdk5-deficient mice.Furthermore,CDK5 interacted with BK channels and negatively regulated BK channel activity via phosphorylation of threonine-908.Restoration of CDK5 expression in striatal cholinergic neurons reduced dyskinesia-like behaviors in ChAT-Cre;Cdk5f/f mice.Together,these findings indicate that CDK5-induced phosphorylation of BK channels involves in cholinergic-neuronmediated motor function,providing a potential new therapeutic target for treating dyskinesia-like behaviors arising from neurological diseases. 展开更多
关键词 CDK5 NEURON CDK5
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BOD1 regulates the cerebellar IV/V lobe-fastigial nucleus circuit associated with motor coordination 被引量:2
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作者 Xiu-Xiu Liu Xing-Hui Chen +14 位作者 Zhi-Wei Zheng Qin Jiang Chen Li Lin Yang Xiang Chen Xing-Feng Mao hao-yang yuan Li-Li Feng Quan Jiang Wei-Xing Shi Takuya Sasaki Kohji Fukunaga Zhong Chen Feng Han Ying-Mei Lu 《Signal Transduction and Targeted Therapy》 SCIE CSCD 2022年第7期2490-2503,共14页
Cerebellar ataxias are characterized by a progressive decline in motor coordination,but the specific output circuits and underlying pathological mechanism remain poorly understood.Through cell-type-specific manipulati... Cerebellar ataxias are characterized by a progressive decline in motor coordination,but the specific output circuits and underlying pathological mechanism remain poorly understood.Through cell-type-specific manipulations,we discovered a novel GABAergic Purkinje cell(PC)circuit in the cerebellar IV/V lobe that projected to CaMKIIα+neurons in the fastigial nucleus(FN),which regulated sensorimotor coordination.Furthermore,transcriptomics profiling analysis revealed various cerebellar neuronal identities,and we validated that biorientation defective 1(BOD1)played an important role in the circuit of IV/V lobe to FN.BOD1 deficit in PCs of IV/V lobe attenuated the excitability and spine density of PCs,accompany with ataxia behaviors.Instead,BOD1 enrichment in PCs of IV/V lobe reversed the hyperexcitability of CaMKIIα+neurons in the FN and ameliorated ataxia behaviors in L7-Cre;BOD1f/f mice.Together,these findings further suggest that specific regulation of the cerebellar IV/V lobePCs→FNCaMKIIα+circuit might provide neuromodulatory targets for the treatment of ataxia behaviors. 展开更多
关键词 fastigial reversed TOGETHER
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