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High-resolution mapping of brain vasculature and its impairment in the hippocampus of Alzheimer's disease mice

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National Science Review 2019年第6期6卷 1223-1238页

作者： Xiaochuan Zhang Xianzhen Yin Jingjing Zhang Anan Li Hui Gong Qingming Luo Haiyan Zhang zhaobing gao Hualiang Jiang School of Pharmacy East China University of Science and Technology CAS Key Laboratory of Receptor Research Shanghai Institute of Materia MedicaChinese Academy of Sciences Britton Chance Center for Biomedical Photonics Wuhan National Laboratory for OptoelectronicsHuazhong University of Science and Technology MoE Key Laboratory for Biomedical Photonics School of Engineering Sciences Huazhong University of Science and Technology Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and TechnologyShanghai Tech University

Accumulating evidence indicates the critical importance of cerebrovascular dysfunction in the pathogenesis of Alzheimer’s disease(AD). However, systematic comparative studies on the precise brain vasculature of wild-type and AD model mice are still rare. Using an image-optimization method for analysing Micro-Optical Sectioning Tomography(MOST) data, we generated cross-scale whole-brain 3 D atlases that cover the entire vascular system from large vessels down to smallest capillaries at submicron resolution,for both wild-type mice and a transgenic(APP/PS1) mouse model of AD. In addition to distinct vascular patterns in different brain regions, we found that the main vessels of the molecular layer of the hippocampal dentate gyrus(DG-ml) undergo abrupt changes in both diameter and branch angle, spreading a unique comb-like pattern of capillaries. By using a quantitative analysis workflow, we identified in the hippocampus of AD mice an overall reduction of the mean vascular diameter, volume fraction and branch angle, with most significant impairment in the DG-ml. In addition, virtual endoscopy revealed irregular morphological features in the vessel lumen of the AD mice, potentially contributing to the impairment of blood flow. Our results demonstrate the capability of high-resolution cross-scale evaluation of brain vasculature and underscore the importance of studying hippocampal microcirculation for understanding AD pathogenesis.

关键词： Micro-Optical Sectioning Tomography image optimization Alzheimer’s disease impaired hippocampal vasculature virtual vascular endoscopy

Why is the SARS-CoV-2 Omicron variant milder?

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The Innovation 2022年第4期3卷 7-8页

作者： Bingqing Xia Yi Wang Xiaoyan Pan Xi Cheng Hongying Ji Xiaoli Zuo Hualiang Jiang Jia Li zhaobing gao CAS Key Laboratory of Receptor Research Stake Key Laboratory of Drug ResearchShanghai Institute of Materia MedicaChinese Academy of Sciences555 Zuchongzhi RoadShanghai 201203China University of Chinese Academy of Sciences 19A Yuquan RoadBeijing 100049China State Key Laboratory of Medical Neurobiology Institutes of Brain ScienceFudan UniversityShanghai 200032China State Key Laboratory of Virology Wuhan Institute of VirologyCenter for Biosafety Mega-ScienceChinese Academy of SciencesWuhan 430071China Lingang Laboratory Shanghai 201602China

In November 2021,a new SARS-CoV-2 variant emerged in South Africa and was designated the fifth variant of concern and named *** was detected in more than 26 countries worldwide,including *** Omicron variant is highly transmissible and has extensive morbidity,which has raised concerns related to antiviral *** reports have revealed that the Omicron variant exhibits a longer cycle of viral shedding and a decreased replication capacity and results in substantially attenuated lung pathology,indicating that the pathogenic ability of the Omicron variant is lower than that of previous variants.1Omicron has the largest number(>30)of substitutions,deletions,or insertions,with a mutation frequency of higher than 1%in the spike(S)*** studies of the spike protein receptor-binding domain have provided a plausible explanation for the increased transmissibility and antibody resistance of this ***,the molecular basis for its attenuated pathogenicity and replication capacity remains elusive.

关键词： insertion raised explanation

Two evaluation models of drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes(hiPSC-CMs)

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Two evaluation models of drug-induced cardiotoxicity using h...

Molecular structural basis of TRPAl channel rectification A singe residue in the pore region determines the intrinsic rectification of TRPAl channel

中国毒理学会第九次全国青年科技大会暨第二届生物技术药物毒理与安全评价委员会学术会议

作者： Sui Fang Xueqin Chen Tong Zhou Yu Tang zhaobing gao Ion Channel Platform Shanghai Institute of Material MedicaChinese Academy of Sciences

Cardiovascular toxicity,a prominent reason for late-stage failures in drug development,has resulted in a demand for in vitro assays that can predict this liability in early drug *** the last 20 years,preclinical cardiovascular safety testing primarily focuses on hERG channel modulation in vitro,but single-target screening has some shortcomings.A comprehensive in vitro approach that stably recapitulates aspects of cardiovascular physiology is needed to be ***-CMs provide a human-relevant platform for cardiac function *** assays using hiPSC-CMs are increasingly being employed for regulatory ***,we aim to use hiPSC-CMs to develop a novel in vitro platform for pre-clinical cardiotoxicity and pro-arrhythmia screening for early drug ***,we obtained hiPSC-CMs with cardiomyocyte purity greater than 90% by chemical small molecule induced ***,two in vitro evaluation models of drug-induced cardiotoxicity were established in this *** the one hand,an action potential(AP) recording using hiPSC-CMs by manual patch clamp,and our results shown that both IKr/hERG specific blocking agents E4031 and specific ICaL inhibitor nifedipine were sensitive to ***,the candidate drug prolonged the APD90 duration in a concentration-dependent manner and therefore had a potential risk of *** the other hand,hiPSC-CMs-based multielectrode array(MEA) recording by xCELLigence RTCA CardioECR,which can simultaneously investigate the effects of drugs on cardiomyocyte viability,myocardial contraction,and field potential duration(FPD) from more physiological function level of *** candidate drugs have been tested using hiPSC-CMs/MEA assay in our ***,these two in vitro evaluation models of drug-induced cardiotoxicity can help detect the human cardiotoxic potential of candidates early in drug discovery.

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Molecular structural basis of TRPAl channel rectification A ...

基于[3.3.3]螺桨烷的电压门控钙离子通道α2δ亚基配体的合成和生物活性研究

第九届全国钙信号和细胞功能研讨会

作者： Xia Wan,Xueqin Chen,zhaobing gao State Key Laboratory of Drug Research,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,555 Zuchongzhi Road,Shanghai 201203,China

＜正＞The transient receptor potential ankyrin 1（TRPA 1）is an outward rectification channel in normal physiological ***,the molecular structure basis for the rectification is largely *** studies show that divalent cations, particularly calcium,interacting with acidic acids in the putative selectivity filter or C terminus,determines the *** we show both the divalent and monovalent cations contribute to the *** addition,we identified a conserved hvdrophobic amino residue in the S5-P-S6 region is involved in the rectitication *** of the residue to Cys converts the channel to

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有机化学 2023年第6期43卷 2226-2238页

作者：何金燕田富云吴青青郑月明陈玉婷许海燕金正盛詹丽程新强顾跃玲高召兵赵桂龙遵义医科大学药学院贵州遵义563003 中科中山药物创新研究院广东中山528400 中国科学院上海药物研究所上海201203

电压门控钙离子通道(VGCC)α2δ亚基配体类药物是目前治疗慢性神经疼痛最安全有效的药物之一.为了研究含有大位阻的、构象限制的烷基骨架对该类药物生物活性的影响,设计并合成了3个含有[3.3.3]螺桨烷结构和1个含二环[3.3.0]辛烷结构的γ... 详细信息

电压门控钙离子通道(VGCC)α2δ亚基配体类药物是目前治疗慢性神经疼痛最安全有效的药物之一.为了研究含有大位阻的、构象限制的烷基骨架对该类药物生物活性的影响,设计并合成了3个含有[3.3.3]螺桨烷结构和1个含二环[3.3.0]辛烷结构的γ-氨基丁酸(GABA)衍生物.所合成的化合物使用了~1H NMR,^(13)C NMR和高分辨质谱(HRMS)进行了结构表征,并测试了它们对人源化电压门控钙离子通道α2δ亚基的亲和力(IC_(50)).研究结果发现:[3.3.3]螺桨烷在VGCCα2δ配体类药物结构中具有一定的兼容性,但是其体积已经超过了脂肪族取代结构的最佳体积;VGCCα2δ配体类药物分子中的GABA链上的氨基不能有任何取代或者衍生,否则活性降低甚至完全丧失.本研究的结论对于未来设计新颖的VGCCα2δ配体类药物具有重要的指导作用.

关键词：螺桨烷电压门控钙离子通道 α2δ亚基合成生物活性构效关系

Activation of KCNQ potassium channels by small chemical moleculars

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Activation of KCNQ potassium channels by small chemical mole...

融合BDS-3新信号的GNSS动态PPP模糊度固定

中国神经科学学会第九届全国学术会议暨第五次会员代表大会

作者： zhaobing gao~1,Min LI~(1,2) 1 State Key Laboratory of Drug Research,Shanghai Institute of Materia Medica,Shanghai Institutes for Biological Sciences,Chinese Academy of Sciences,555 Zu Chong Zhi Road,Zhangjiang Hi-Tech Park,Shanghai 201203,China 2 Department of Neuroscience,High Throughput Biology Center and Johns Hopkins Ion Channel Center,School of Medicine,Johns Hopkins University,Baltimore,Maryland 21205

＜正＞KCNQ potassium channels play a critical role in controlling membrane *** a typical voltagegated ion channels（Kv）,KCNQ channels undergo closed to open transitions by sensing transmembrane potential changes and mediate inhibitory potassium *** of KCNQ channel activity as results of genetic mutation is causal to a variety of human diseases including epilepsy,arrhythmia and ***,discovery of small compounds to activate voltage-gated ion channels is an important strategy for clinical intervention in human diseases caused by membrane hyperexcitability,including anxiety,epilepsy,arrhythmia and neuropathic *** the binding of these molecules induces a conformational change leading to the opening of these channels,there is also a considerable conceptual interest in understanding the molecular basis of these "gain of a function" *** molecule activators of cation channels are rare;however,several novel compounds have been identified for KCNQ potassium ***,we reported two new molecules which potentiate either cardical or neuronal KCNQ channels and identified molecular determinants for their activity,which provide exciting insights into activation of voltage-gated channels by small molecuars.

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中国矿业大学学报 2022年第6期51卷 1222-1231页

作者：李增科陈昭冰刘赞高井祥赵龙徐磊中国矿业大学环境与测绘学院江苏徐州221116

为探索北斗三号全球卫星导航系统(BDS-3)新信号对于全球导航卫星系统(GNSS)多系统定位的作用以及动态环境下BDS-3新信号的性能,通过多路径和信噪比参数对比分析BDS-3新旧信号在静态开阔环境和动态复杂环境的差异性,从定位精度、固定率... 详细信息

为探索北斗三号全球卫星导航系统(BDS-3)新信号对于全球导航卫星系统(GNSS)多系统定位的作用以及动态环境下BDS-3新信号的性能,通过多路径和信噪比参数对比分析BDS-3新旧信号在静态开阔环境和动态复杂环境的差异性,从定位精度、固定率、首次固定时间以及平均卫星数4个方面综合评估融合BDS-3新信号的多系统精密单点定位(PPP)模糊度固定性能.结果表明:动态环境下,BDS-3新信号在抗多路径等噪声方面更有优势,多路径等伪距观测噪声仅为旧信号的1/2,载波信噪比在动态模式下更稳定且信号强度更高;融合BDS-3新信号后,多系统PPP固定解的定位性能得到提升,相比于融合BDS-3旧信号,东方向定位精度提升10%~20%,模糊度固定率提升至90%以上.

关键词： BDS-3新信号精密单点定位模糊度固定动态

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舍温对母猪行为与仔猪保温箱利用率的影响

农业工程学报 2011年第12期27卷 191-194页

作者：高娅俊李保明李明丽林保忠顾招兵重庆市畜牧科学院重庆402460 中国农业大学农业部设施农业工程重点开放实验室北京100083 云南农业大学动物科技学院昆明650201

为分析分娩猪舍温度与保温箱温度对母猪行为和哺乳仔猪保温箱利用率的影响,设置了高温(30.4℃)和低温(15.3℃)2个组,选取12头约克夏母猪(每组6头)进行了现场试验。结果表明,低温组的仔猪保温箱利用率(62.4%)较高,而高温组的仔猪保温箱... 详细信息

为分析分娩猪舍温度与保温箱温度对母猪行为和哺乳仔猪保温箱利用率的影响,设置了高温(30.4℃)和低温(15.3℃)2个组,选取12头约克夏母猪(每组6头)进行了现场试验。结果表明,低温组的仔猪保温箱利用率(62.4%)较高,而高温组的仔猪保温箱利用率仅为1%;低温与高温组母猪从站立到躺卧的行为转换时间分别为4.0和3.4s(P<0.05)。低温组母猪坐立-腹卧或腹卧-坐立的行为转换频次比高温组母猪的低(P<0.01)。低温组未有仔猪被压死,而高温组的仔猪压死率达15.2%(P<0.001)。低温组的仔猪增重也相对较快。维持保温箱与分娩舍间适宜温差有利于提高仔猪的保温箱利用率,实现降低仔猪压死率的目的。

关键词：温度压死率行为保温箱利用率母猪仔猪

鄂尔多斯盆地华庆地区延长组6段深水致密砂岩填隙物特征及对储层发育的影响

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石油与天然气地质 2021年第5期42卷 1098-1111页

作者：陈朝兵赵振宇付玲高建荣宋微陈新晶西安石油大学地球科学与工程学院陕西西安710065 陕西省油气成藏地质学重点实验室陕西西安710065 中国石油勘探开发研究院北京100083 中国石油天然气股份有限公司长庆油田分公司第六采油厂陕西西安710200

深水重力流成因的致密砂岩油藏是目前非常规油气勘探开发的新热点。深水环境水动力复杂,填隙物类型及含量变化大,储层微观非均质性强,严重制约了深水沉积储层油气资源的勘探开发进程。通过铸体薄片、扫描电镜、矿物自动识别与分析系统(Q... 详细信息

深水重力流成因的致密砂岩油藏是目前非常规油气勘探开发的新热点。深水环境水动力复杂,填隙物类型及含量变化大,储层微观非均质性强,严重制约了深水沉积储层油气资源的勘探开发进程。通过铸体薄片、扫描电镜、矿物自动识别与分析系统(QEMSCAN)、电子探针和纳米CT等实验分析手段,对鄂尔多斯盆地华庆地区延长组6段(长6段)深水致密砂岩不同填隙物的微观特征进行了精细表征,探讨了不同填隙物对储层孔隙结构及物性的影响。结果表明:杂基并非完全致密,经过成岩改造后的杂基能够产生一定数量的杂基晶间孔和杂基溶孔,孔径介于20~1000 nm,构成了复杂的杂基次生孔隙网络。当杂基含量≤7%时,杂基次生孔隙发育,对储层产生积极影响。当杂基含量>7%时,杂基次生孔隙发育程度降低,加剧了储层的致密。粘土矿物胶结物的晶间孔在一定程度上缓解了孔隙度的降低,但不同粘土矿物的形态、产状及对储层造成的敏感性又加剧了粘土矿物与渗透率关系的复杂性。伊利石、伊/蒙混层和绿泥石含量的高值区,储层物性通常较差,优质储层多分布在高岭石的发育区;碳酸盐和硅质胶结物是深水致密砂岩储层物性降低的主要因素。综合分析认为,杂基含量≤7%,且高岭石胶结物相对发育的地区是深水致密砂岩油藏勘探开发的重点区域。

关键词：杂基粘土矿物填隙物深水重力流深水致密砂岩优质储层华庆地区鄂尔多斯盆地