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| 1 | The gating charge pathway of an epilepsy-associated potassium channel accommodates chemical ligands显示文摘电压门钾(Kv ) 隧道在电压传感器领域(VSD ) 从 gating 费用的运动导出他们的电压敏感。gating 在 VSD 通过一条物理小径控告 translocate 打开或关门隧道。以前的研究证明 gating 控告 Shaker 的小径, Kv1.2-2.1 妄想的隧道被堵塞,形成集中的电场和 gating 费用转移中心的结构的基础。这里,我们证明 gating 控告电压门 KCNQ2 钾隧道的小径,哪个引起癫痫的活动减小,能提供各种各样的小分子 ligands。记录的联合 mutagenesis,分子的模拟和 electrophysiological,为探查使活跃之物的一个有约束力的模型, ztz240,在 gating 费用,小径被定义。这个信息被用来建立指向定义 ligand 有约束力的衣袋的基于船坞的虚拟屏蔽试金。有五新 chemotypes 的九使活跃之物被识别,并且在 vivo,实验显示出那三 ligands 绑定到 gating 费用小径展览重要反癫痫活动。由指向衣袋的虚拟屏蔽的各种各样的新奇使活跃之物的鉴定在 gating 费用小径支持一个 ligand 有约束力的地点的存在。gating 费用小径的能力提供新卓见提供小分子 ligands 进治疗学地相关的 KCNQ2 隧道的 gating 费用小径。 | Ping Li Zhuxi Chen Haiyan Xu Haifeng Sun Hao Li Hong Liu Huaiyu Yang Zhaobing Gao Hualiang Jiang Min Li | 2013 | Cell Research2013，23，9： | 8 |
| 2 | SARS-CoV-2 envelope protein causes acute respiratory distress syndrome (ARDS)-like pathological damages and constitutes an antiviral target显示文摘Cytokine storm and multi-organ failure are the main causes of SARS-CoV-2-related death.However,the origin of excessive damages caused by SARS-CoV-2 remains largely unknown.Here we show that the SARS-CoV-2 envelope(2-E)protein alone is able to cause acute respiratory distress syndrome(ARDS)-like damages in vitro and in vivo. | Bingqing Xia Xurui Shen Yang He Xiaoyan Pan Feng-Liang Liu Yi Wang Feipu Yang Sui Fang Yan Wu Zilei Duan Xiaoli Zuo Zhuqing Xie Xiangrui Jiang Ling Xu Hao Chi Shuangqu Li Qian Meng Hu Zhou Yubo Zhou Xi Cheng Xiaoming Xin Lin Jin Hai-Lin Zhang Dan-Dan Yu Ming-Hua Li Xiao-Li Feng Jiekai Chen Hualiang Jiang Gengfu Xiao Yong-Tang Zheng Lei-Ke Zhang Jingshan Shen Jia Li Zhaobing Gao | 2021 | Cell Research2021，31，8： | 7 |
| 3 | Velocity field of wave-induced local fluid flow in double-porosity media显示文摘Under the excitation of elastic waves,local fluid flow in a complex porous medium is a major cause for wave dispersion and attenuation.When the local fluid flow process is simulated with wave propagation equations in the double-porosity medium,two porous skeletons are usually assumed,namely,host and inclusions.Of them,the volume ratio of inclusion skeletons is low.All previous studies have ignored the consideration of local fluid flow velocity field in inclusions,and therefore they can not completely describe the physical process of local flow oscillation and should not be applied to the situation where the fluid kinetic energy in inclusions cannot be neglected.In this paper,we analyze the local fluid flow velocity fields inside and outside the inclusion,rewrite the kinetic energy function and dissipation function based on the double-porosity medium model containing spherical inclusions,and derive the reformulated Biot-Rayleigh(BR)equations of elastic wave propagation based on Hamilton’s principle.We present simulation examples with different rock and fluid types.Comparisons between BR equations and reformulated BR equations show that there are significant differences in wave response characteristics.Finally,we compare the reformulated BR equations with the previous theories and experimental data,and the results show that the theoretical results of this paper are correct and effective. | BA Jing ZHANG Lin SUN WeiTao HAO ZhaoBing | 2014 | Science China(Physics,Mechanics & Astronomy)2014，57，6： | 4 |
| 4 | Disruption of ER ion homeostasis maintained by an ER anion channel CLCC1 contributes to ALS-like pathologies显示文摘Although anion channel activities have been demonstrated in sarcoplasmic reticulum/endoplasmic reticulum(SR/ER),their molecular identities and functions remain unclear.Here,we link rare variants of Chloride Channel CLIC Like 1(CLCC1)to amyotrophic lateral sclerosis(ALS)-like pathologies.We demonstrate that CLCC1 is a pore-forming component of an ER anion channel and that ALS-associated mutations impair channel conductance.CLCC1 forms homomultimers and its channel activity is inhibited by luminal Ca^(2+)but facilitated by phosphatidylinositol 4,5-bisphosphate(PIP2).We identified conserved residues D25 and D181 in CLCC1 N-terminus responsible for Ca^(2+)binding and luminal Ca^(2+)-mediated inhibition on channel open probability and K298 in CLCC1 intraluminal loop as the critical PIP2-sensing residue.CLCC1 maintains steady-state[Cl^(–)]ER and[K+]ER and ER morphology and regulates ER Ca^(2+)homeostasis,including internal Ca^(2+)release and steady-state[Ca^(2+)]ER.ALS-associated mutant forms of CLCC1 increase steady-state[Cl^(–)]ER and impair ER Ca^(2+)homeostasis,and animals with the ALS-associated mutations are sensitized to stress challenge-induced protein misfolding.Phenotypic comparisons of multiple Clcc1 loss-of-function alleles,including ALS-associated mutations,reveal a CLCC1 dosage dependence in the severity of disease phenotypes in vivo.Similar to CLCC1 rare variations dominant in ALS,10%of K298A heterozygous mice developed ALS-like symptoms,pointing to a mechanism of channelopathy dominant-negatively induced by a loss-of-function mutation.Conditional knockout of Clcc1 cell-autonomously causes motor neuron loss and ER stress,misfolded protein accumulation,and characteristic ALS pathologies in the spinal cord.Thus,our findings support that disruption of ER ion homeostasis maintained by CLCC1 contributes to ALS-like pathologies. | Liang Guo Qionglei Mao Ji He Xiaoling Liu Xuejiao Piao Li Luo Xiaoxu Hao Hanzhi Yu Qiang Song Bailong Xiao Dongsheng Fan Zhaobing Gao Yichang Jia | 2023 | Cell Research2023，33，7： | 0 |
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