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The tumor-enriched small molecule gambogic amide suppresses glioma by targeting WDR1-dependent cytoskeleton remodeling

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Signal Transduction and Targeted Therapy 2023年第12期8卷 5904-5918页

作者： Jiaorong Qu Bojun Qiu Yuxin Zhang yan Hu Zhixing Wang Zhiang Guan Yiming Qin Tongtong Sui Fan Wu Boyang Li wei Han Xiaozhong Peng Department of Molecular Biology and Biochemistry Institute of Basic Medical SciencesMedical Primate Research CenterNeuroscience CenterChinese Academy of Medical SciencesSchool of Basic MedicinePeking Union Medical CollegeBeijing 100005China state key laboratory of Common Mechanism Research for Major Diseases BeijingChina Department of Molecular Neuropathology Beijing Neurosurgical InstituteCapital Medical UniversityBeijing 100070China Department of Neurosurgery Beijing Tiantan HospitalCapital Medical UniversityBeijingChina state key laboratory of Respiratory Health and Multimorbidity BeijingChina National Human Diseases Animal Model Resource Center Beijing Engineering Research Center for Experimental Animal Models of Human Critical DiseasesInstitute of Laboratory Animal ScienceChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100021China

Glioma is the most prevalent brain tumor,presenting with limited treatment options,while patients with malignant glioma and glioblastoma(GBM)have poor *** physical obstacle to drug delivery imposed by the blood‒brain barrier(BBB)and glioma stem cells(GSCs),which are widely recognized as crucial elements contributing to the unsatisfactory clinical *** this study,we found a small molecule,gambogic amide(GA-amide),exhibited the ability to effectively penetrate the blood-brain barrier(BBB)and displayed a notable enrichment within the tumor ***,GA-amide exhibited significant efficacy in inhibiting tumor growth across various in vivo glioma models,encompassing transgenic and primary patient-derived xenograft(PDX)*** further performed a genome-wide clustered regularly interspaced short palindromic repeats(CRISPR)knockout screen to determine the druggable target of *** the combination of the cellular thermal shift assay(CETSA),the drug affinity responsive target stability(DARTS)approach,molecular docking simulation and surface plasmon resonance(SPR)analysis,WD repeat domain 1(WDR1)was identified as the direct binding target of *** direct interaction with WDR1,GA-amide promoted the formation of a complex involving WDR1,MYH9 and Cofilin,which accelerate the depolymerization of F-actin to inhibit the invasion of patient-derived glioma cells(PDCs)and induce PDC apoptosis via the mitochondrial apoptotic *** conclusion,our study not only identified GA-amide as an effective and safe agent for treating glioma but also shed light on the underlying mechanisms of GA-amide from the perspective of cytoskeletal homeostasis.

关键词： glioma invasion homeostasis

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面向功能性用户体验质量评估的脑网络构建方法

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中国图象图形学报 2024年第9期29卷 2793-2805页

作者：牛一帆魏韬张远翟广涛邬霞北京师范大学人工智能学院北京100875 中国传媒大学媒体融合与传播国家重点实验室北京100024 上海交通大学电子信息与电气工程学院上海200240

目的新兴视频服务的功能参数设置将会直接影响到用户的认知状态,进一步影响用户体验质量,称为功能性用户体验质量(functional quality of experience,fQoE)。脑电信号蕴含丰富的大脑活动信息,能够揭示复杂脑活动中的脑网络模式,为fQoE... 详细信息

目的新兴视频服务的功能参数设置将会直接影响到用户的认知状态,进一步影响用户体验质量,称为功能性用户体验质量(functional quality of experience,fQoE)。脑电信号蕴含丰富的大脑活动信息,能够揭示复杂脑活动中的脑网络模式,为fQoE提供可靠的评估依据。为此,本文首次提出了一个基于脑电的脑网络构建方法以评估fQoE,并研究fQoE背后的神经机制。方法首先,通过改变功能参数诱发不同水平的fQoE,并同步收集脑电数据;然后,从脑电数据中提取单电极和多电极特征并以图结构进行融合,用以全面表征用户使用视频服务时的大脑状态;最后,使用基于自注意力图池化的脑网络构建模型来识别对fQoE敏感的脑网络,为fQoE提供可解释性,并进行分类以完成fQoE评估。结果本文以弹幕视频服务的弹幕覆盖率这一功能参数为例验证了方法的科学性和可行性。实验表明,提出的评估方法在多种视频类型的fQoE评估中均达到了满意的效果,最佳识别准确率分别为86%(鬼畜类)、81%(科技类)、80%(舞蹈类)、82%(影视类)和84%(音乐类)。结论来自fQoE相关的脑网络分析结果表明,额极、额中回、顶叶和颞叶的脑连接数量减少预示着观看弹幕视频的fQoE更高,即观看体验更好,同时也证明了功能参数通过影响人的脑状态进一步导致了fQoE的改变。本文的评估方法为fQoE的精确评估和视频服务功能参数的优化提供了来自神经生理学的定量工具和理论依据。

关键词：新兴视频服务功能性用户体验质量(fQoE) 脑电信号(EEG) 脑网络构建

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Microvascular endothelial cells derived from spinal cord promote spinal cord injury repair

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Bioactive Materials 2023年第11期29卷 36-49页

作者： Zhifeng You Xu Gao Xinyi Kang Wen yang Tiandi Xiong Yue Li Feng wei yan Zhuang Ting Zhang Yifu Sun He Shen Jianwu Dai key laboratory for Nano-Bio Interface Research Division of NanobiomedicineSuzhou Institute of Nano-Tech and Nano-BionicsChinese Academy of SciencesSuzhou215123China Department of Orthopaedic Surgery China-Japan Union Hospital of Jilin UniversityChangchun130033China Department of Obstetrics and Gynecology The Second Affiliated Hospital of Soochow UniversitySuzhou215004China School of Nano-Tech and Nano-Bionics University of Science and Technology of ChinaHefei230026China i-Lab Key Laboratory of Multifunction Nanomaterials and Smart SystemsSuzhou Institute of Nano-Tech and Nano-BionicsChinese Academy of SciencesSuzhou215123China state key laboratory of Molecular Developmental Biology Institute of Genetics and Developmental BiologyChinese Academy of SciencesBeijing100101China

Neural regeneration after spinal cord injury (SCI) closely relates to the microvascular endothelial cell (MEC)- mediated neurovascular unit formation. However, the effects of central nerve system-derived MECs on neovascularization and neurogenesis, and potential signaling involved therein, are unclear. Here, we established a primary spinal cord-derived MECs (SCMECs) isolation with high cell yield and purity to describe the differences with brain-derived MECs (BMECs) and their therapeutic effects on SCI. Transcriptomics and proteomics revealed differentially expressed genes and proteins in SCMECs were involved in angiogenesis, immunity, metabolism, and cell adhesion molecular signaling was the only signaling pathway enriched of top 10 in differentially expressed genes and proteins KEGG analysis. SCMECs and BMECs could be induced angiogenesis by different stiffness stimulation of PEG hydrogels with elastic modulus 50-1650 Pa for SCMECs and 50-300 Pa for BMECs, respectively. Moreover, SCMECs and BMECs promoted spinal cord or brain-derived NSC (SNSC/BNSC) proliferation, migration, and differentiation at different levels. At certain dose, SCMECs in combination with the NeuroRegen scaffold, showed higher effectiveness in the promotion of vascular reconstruction. The potential underlying mechanism of this phenomenon may through VEGF/AKT/eNOS- signaling pathway, and consequently accelerated neuronal regeneration and functional recovery of SCI rats compared to BMECs. Our findings suggested a promising role of SCMECs in restoring vascularization and neural regeneration.

关键词： Microvascular endothelial cells Spinal cord injury NeuroRegen scaffold Neural regeneration

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Animal models of Alzheimer’s disease: Applications, evaluation, and perspectives

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Zoological Research 2022年第6期43卷 1026-1040页

作者： Zhi-Ya Chen yan Zhang state key laboratory of Membrane Biology College of Life SciencesPeking UniversityBeijing 100871China

Although great advances in elucidating the molecular basis and pathogenesis of Alzheimer’s disease(AD)have been made and multifarious novel therapeutic approaches have been developed,AD remains an incurable *** shows that AD neuropathology occurs decades before clinical *** is divided into three stages:preclinical stage,mild cognitive impairment(MCI),and AD *** the natural world,some animals,such as non-human primates(NHPs)and canines,can develop spontaneous AD-like ***,most animals do not develop *** the development of transgenic techniques,both invertebrate and vertebrate animals have been employed to uncover the mechanisms of AD and study treatment *** AD research focuses on early-onset familial AD(FAD)because FAD is associated with specific genetic ***,there are no well-established late-onset sporadic AD(SAD)animal models because SAD is not directly linked to any genetic mutation,and multiple environmental factors are ***,the widely used animal models are not able to sufficiently recapitulate the pathological events that occur in the MCI or preclinical *** review summarizes the common models used to study AD,from yeast to NHP models,and discusses the different applications,evaluation methods,and challenges related to AD animal models,as well as prospects for the evolution of future studies.

关键词： Alzheimer’s disease Animal models Neuroinflammation Amyloid-β Tau protein

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Apolipoprotein E gene polymorphisms associated with processing speed and executive functions in healthy Han chinese

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Neuroscience Bulletin 2015年第3期31卷 368-370页

作者： Cheng-Cheng Zhang H ong-yan Ren Ming-LiLi Qiang Wang wei Deng Wan-Jun Guo wei Lei Bo Xiang Lian-Sheng Zhao Xiao-Hong Ma Yong-Gang Yao Tao Li The Mental Health Center West China Hospital Sichuan University The Psychiatric laboratory State Key Laboratory of Biotherapy West China Hospital Sichuan University key laboratory of Animal Models and Human Disease Mechanisms of the chinese academy of sciences a nd Yunnan Province Kunming Institute of Zoology

Dear Editor,A few studies have focused on exploring APOE gene- related effects on cognitive functions and brain activities in healthy populations. Bondi et aL found that ε4 carriers perform significantly worse on the California Verbal Learning Test than non-carriers in non-demented old subjects （mean age, 72 years）ε11. But the results are not entirely consistent. For example, Scarmeas et aL found no effect of the E4 allele on neuropsychological performance[2] in young adults, and Jochemsen et al. found that the ε4 allele is associated with age-related cognitive decline[3]. Furthermore, protective and negative effects of the E2 allele on cognition are inconsistent[4＇ s]. APOE E2 is thought to be a protective allele for AD in the elderly population due to its role in the superior cognitive performance of ε2 carriers compared to E3 or E4 carriers[5]. However, the ε2 allele has also been found to have a negative effect on AD pathology[4].

关键词： Apolipoprotein E gene polymorphisms associated with processing speed and executive functions in healthy Han chinese gene

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Efficient and Specific Modifications of the Drosophila Genome by Means of an Easy TALEN Strategy

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Journal of Genetics and Genomics 2012年第5期39卷 209-215页

作者： Jiyong Liu Changqing Li Zhongsheng Yu Peng Huang Honggang Wu Chuanxian wei Nannan Zhu yan Shen Yixu Chen Bo Zhang Wu-Min Deng Renjie Jiao state key laboratory of brain and cognitive Science Institute of Biophysics The Chinese Academy of Sciences Datun Road 15 Beijing 100101 China key laboratory of Cell Proliferation and Differentiation of Ministry of Education College of Life Sciences Peking University Beijing 100871 China Department of Biological Science Florida State University Tallahassee Florida 32304-4295 USA

Technology development has always been one of the forces driving breakthroughs in biomedical research. Since the time of Thomas Morgan, Drosophilists have, step by step, developed powerful genetic tools for manipulating and functionally dissecting the Drosophila genome, but room for improving these technologies and developing new techniques is still large, especially today as biologists start to study systematically the functional genomics of different model organisms, including humans, in a high-throughput manner. Here, we report, for the first time in Drosophila, a rapid, easy, and highly specific method for modifying the Drosophila genome at a very high efficiency by means of an improved transcription activator-like effector nuclease （TALEN） strategy. We took advantage of the very recently developed ＂unit assembly＂ strategy to assemble two pairs of specific TALENs designed to modify the yellow gene （on the sex chromosome） and a novel autosomal gene. The mRNAs of TALENs were subsequently injected into Drosophila embryos. From 31.2% of the injected Fo fertile flies, we detected inheritable modification involving the yellow gene. The entire process from construction of specific TALENs to detection of inheritable modifications can be accomplished within one month. The potential applications of this TALEN-mediated genome modification method in Drosophila are discussed.

关键词： TALEN Drosophila Genomic modification Unit assembly Reverse genetics

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Ribosylation induces cognitive impairment and neural cell death

Ribosylation induces cognitive impairment and neural cell de...

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中国生物化学与分子生物学会第十二届全国会员代表大会暨2018年全国学术会议

作者： yan wei Rongqiao HE state key laboratory of brain and cognitive Science Institute of BiophysicsChinese Academy of Sciences

D-ribose in cells and human serum participates in the glycation of proteins resulting in advanced glycation end products(AGEs) that affect cell metabolism and induce cell *** have been shown to be implicated in the senile plaques and neurofibrillary tangles in the brain of Alzheimer’s *** high levels of ribose,along with glucose were found in the urine of patients with type 2 diabetic ***,the effects of D-ribose and ribosylation on protein,cell and animal were investigated by biochemical,cellular and animal *** with D-ribose induced protein to misfold rapidly and form globular amyloid-like aggregations which play an important role in cytotoxicity to neural cells.D-ribose also decreased cell viability and induced more AGE accumulation in *** injection,oral administration and tail intravenous injection of D-ribose caused impairment of spatial learning and memory ability in animals,along with A deposition,tau hyperphosphorylation and glia activation,which were the key pathological features in Alzheimer’s *** may be some mechanistic link between ribosylation and cognitive *** ribosylation could be a promising therapeutic strategy to prevent Alzheimer’s disease and diabetic encephalopathies.

关键词： ribosylation Alzheimer’s disease tau hyperphosphorylation cognitive impairment

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Testing the role of genetic variation of the MC4R gene in chinese population in antipsychotic-induced metabolic disturbance

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Science china(Life sciences) 2019年第4期62卷 535-543页

作者： Yamin Zhang Hongyan Ren Qiang Wang wei Deng weihua Yue Hao yan Liwen Tan Qi Chen Guigang yang Tianlan Lu Lifang Wang Fuquan Zhang Jianli yang Keqing Li Luxian Lv Qingrong Tan Hongyan Zhang Xin Ma Fude yang Lingjiang Li Chuanyue Wang Dai Zhang Liansheng Zhao Huiyao Wang Xiaojing Li Wanjun Guo Xun Hu yang Tian Xiaohong Ma Tao Li chinese Antipsychotics Pharmacogenomics Consortium Mental Health Center and Psychiatric laboratory the State Key Laboratory of BiotherapyWest China Hospital of Sichuan UniversityChengdu 610041China Tianjin Medical University General Hospital Tianjin Medical UniversityTianjin 300070China Hebei Mental Health Center Baoding 71000China Second Affiliated Hospital of Xinxiang Medical University Xinxiang 453002China Department of Psychiatry Xijing HospitalFourth Military Medical UniversityXi'an 710032China Huaxi Biobank West China Hospital of Sichuan UniversityChengdu 610041China West china brain Research Center West China Hospital of Sichuan UniversityChengdu 610041China Peking University Sixth Hospital(institute of Mental Health) Beijing 100191China National Clinical Research Center for Mental Disorders & key laboratory of Mental Health Ministry of Health(Peking University)Beijing 100191China 5Second Xiangya Hospital Central South UniversityChangsha 410011China beijing Andi ng Hospital Beijing Institute for Brain DisordersCapital Medical UniversityBeijing 100088China beijing HuiLongGuan Hospital Beijing 100096China Wuxi Mental Health Center Nanjing Medical UniversityWuxi 214151China institute of Mental Health Tianjin Anding HospitalTianjin 300070China 不详

Antipsychotic-induced metabolic disturbance(AIMD) is a common adverse effect of antipsychotics with genetics partly underpinning variation in susceptibility among schizophrenia patients. Melanocortin4 receptor(MC4 R) gene, one of the candidate genes for AIMD, has been under-studied in the chinese patients. We conducted a pharmacogenetic study in a large cohort of chinese patients with schizophrenia. In this study, we investigated the genetic variation of MC4 R in chinese population by genotyping two SNPs(rs489693 and rs17782313) in 1,991 chinese patients and examined association of these variants with the metabolic effects that were often observed to be related to AIMD. Metabolic measures, including body mass index(BMI), waist circumference(WC), glucose, triglyceride, high-density lipoprotein(HDL), and low-density lipoprotein(LDL) levels were assessed at baseline and after 6-week antipsychotic treatment. We found that interaction of SNP×medication status(drug-na?ve/medicated) was significantly associated with BMI, WC, and HDL change %, respectively. Both SNPs were significantly associated with baseline BMI and WC in the medicated group. Moderate association of rs489693 with WC, Triglyceride, and HDL change % were observed in the whole sample. In the drug-na?ve group, we found recessive effects of rs489693 on BMI gain more than 7%, WC and Triglyceride change %, with AA incurring more metabolic adverse effects. In conclusion, the association between rs489693 and the metabolic measures is ubiquitous but moderate. Rs17782313 is less involved in AIMD. Two SNPs confer risk of AIMD to patients treated with different antipsychotics in a similar way.

关键词： MC4R antipsychotics metabolic disturbance

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L-theanine inhibits nicotine-induced dependence via regulation of the nicotine acetylcholine receptor-dopamine reward pathway

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Science china(Life sciences) 2012年第12期55卷 1064-1074页

作者： DI XiaoJing yan JingQi ZHAO yan CHANG yanZhong ZHAO BaoLu state key laboratory of brain and cognitive Science Institute of Biophysics Chinese Academy of Sciences Beijing 100101 China Department of Food sciences and Technology Harbin Institute of Technology at Weihai Weihai 264209 China institute of Molecular Neurobiology Hebei Normal University Shijiazhuang 050016 China

In this study, the inhibitory effect of L-theanine, an amino acid derivative of tea, on the rewarding effects of nicotine and its underlying mechanisms of action were studied. We found that L-theanine inhibited the rewarding effects of nicotine in a con- ditioned place preference （CPP） model of the mouse and reduced the excitatory status induced by nicotine in SH-SY5Y cells to the same extent as the nicotine receptor inhibitor dihydro-beta-erythroidine （DHI3E）. Further studies using high performance liquid chromatography, western blotting and immunofluorescence staining analyses showed that L-theanine significantly in- hibited nicotine-induced tyrosine hydroxylase （TH） expression and dopamine production in the midbrain of mice. L-theanine treatment also reduced the upregulation of the ~4,132 and c^7 nicotine acetylcholine receptor （nAChR） subunits induced by nico- tine in mouse brain regions that related to the dopamine reward pathway, thus decreasing the number of cells that could react to nicotine. In addition, L-theanine treatment inhibited nicotine-induced c-Fos expression in the reward circuit related areas of the mouse brain. Knockdown of c-Fos by siRNA inhibited the excitatory status of cells but not the upregulation of TH induced by nicotine in SH-SY5Y cells. Overall, the present study showed that L-theanine reduced the nicotine-induced reward effects via inhibition of the nAChR-dopamine reward pathway. These results may offer new therapeutic strategies for treatment of to- bacco addiction.

关键词： nicotine addiction L-theanine nicotine acetylcholine receptor (nAChR) dopamine conditioned place preference (CPP)

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Ultrathin SrTiO_(3)-based oxide memristor with both drift and diffusive dynamics as versatile synaptic emulators for neuromorphic computing

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Materials Futures 2023年第3期2卷 156-163页

作者： Fang Nie Jie Wang Hong Fang Shuanger Ma Feiyang Wu Wenbo Zhao Shizhan wei Yuling Wang Le Zhao Shishen yan Chen Ge Limei Zheng School of Physics State Key Laboratory of Crystal MaterialsShandong UniversityJinan 250100People’s Republic of China School of Information and Automation Engineering Qilu University of Technology(Shandong Academy of Science)Jinan 250353People’s Republic of China Functional Materials and Acousto-Optic Instruments institute School of Instrumentation Science and EngineeringHarbin Institute of TechnologyHarbin 150080People’s Republic of China Spintronics institute School of Physics and TechnologyUniversity of JinanJinan 250022People’s Republic of China Heilongjiang Provincial key laboratory of Oilfield Applied Chemistry and Technology School of Mechatronic EngineeringDaqing Normal UniversityDaqing 163712People’s Republic of China beijing National laboratory for Condensed Matter Physics Institute of PhysicsChinese Academy of SciencesBeijing 100190People’s Republic of China

Artificial synapses are electronic devices that simulate important functions of biological synapses,and therefore are the basic components of artificial neural morphological networks for brain-like *** of the most important objectives for developing artificial synapses is to simulate the characteristics of biological synapses as much as possible,especially their self-adaptive ability to external ***,we have successfully developed an artificial synapse with multiple synaptic functions and highly adaptive characteristics based on a simple SrTiO_(3)/Nb:SrTiO_(3)heterojunction type *** functions of synaptic learning,such as short-term/long-term plasticity(STP/LTP),transition from STP to LTP,learning–forgetting–relearning behaviors,associative learning and dynamic filtering,are all bio-realistically implemented in a single *** remarkable synaptic performance is attributed to the fascinating inherent dynamics of oxygen vacancy drift and diffusion,which give rise to the coexistence of volatile-and nonvolatile-type resistive *** work reports a multi-functional synaptic emulator with advanced computing capability based on a simple heterostructure,showing great application potential for a compact and low-power neuromorphic computing system.

关键词： memristor artificial synapse synaptic plasticity associative learning learning-experience

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