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Trogocytosis of CAR molecule regulates CAR-T cell dysfunction and tumor antigen escape

Signal Transduction and Targeted Therapy 2024年第1期9卷 326-337页

作者： You Zhai Yicong Du Guanzhang Li mingchen Yu Huimin Hu Changqing Pan Di Wang Zhongfang Shi Xu Yan Xuesong Li Tao Jiang Wei Zhang Department of molecular Neuropathology Beijing Neurosurgical InstituteCapital Medical UniversityBeijingPR China Department of Neurosurgery Beijing Tiantan HospitalCapital Medical UniversityBeijingPR China Department of Urology Peking University First HospitalInstitute of UrologyPeking UniversityNational Urological Cancer CenterBeijingPR China Department of Pathophysiology Beijing Neurosurgical InstituteCapital Medical UniversityBeijingPR China China National Clinical research center for Neurological Diseases BeijingPR China center of brain Tumor Beijing Institute for Brain DisordersBeijingPR China research Unit of Accurate Diagnosis Treatmentand Translational Medicine of Brain TumorsChinese Academy of Medical SciencesBeijingPR China Chinese Glioma Genome Atlas Network(CGGA)and Asian Glioma Genome Atlas Network(AGGA) BeijingPR China

Chimeric antigen receptor(CAR)T-cell therapy has demonstrated clinical response in treating both hematologic malignancies and solid *** instances of rapid tumor remissions have been observed in animal models and clinical trials,tumor relapses occur with multiple therapeutic resistance ***,while the mechanisms underlying the long-term therapeutic resistance are well-known,short-term adaptation remains less ***,more views shed light on short-term adaptation and hold that it provides an opportunity window for long-term *** this study,we explore a previously unreported mechanism in which tumor cells employ trogocytosis to acquire CAR molecules from CAR-T cells,a reversal of previously documented *** mechanism results in the depletion of CAR molecules and subsequent CAR-T cell dysfunction,also leading to short-term antigen loss and antigen *** type of intercellular communication is independent of CAR downstream signaling,CAR-T cell condition,target antigen,and tumor cell ***,it is mainly dependent on antigen density and CAR sensitivity,and is associated with tumor cell cholesterol *** mitigation of this trogocytosis-induced CAR molecule transfer can be achieved by adaptively administering CAR-T cells with antigen density-individualized CAR ***,our study reveals a dynamic process of CAR molecule transfer and refining the framework of clinical CAR-T therapy for solid tumors.

关键词： Together instance depletion

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Three-phase Enriched Environment Improves Post-stroke Gait Dysfunction via facilitating Neuronal Plasticity in the Bilateral Sensorimotor Cortex:A multimodal mRI/PET Analysis in Rats

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Neuroscience Bulletin 2024年第6期40卷 719-731页

作者： Yun Lu Ziyue Lin mingcong Li Yuming Zhuang Binbin Nie Jianfeng Lei Yuanyuan Zhao Hui Zhao School of Traditional Chinese medicine Capital Medical UniversityBeijing100069China Beijing Key Lab of TCm Collateral Disease Theory research Beijing100069China Beijing Engineering research center of Radiographic Techniques and Equipment Institute of High Energy PhysicsChinese Academy of SciencesBeijing100049China medical imaging Laboratory of Core facility center Capital Medical UniversityBeijing100069China

The three-phase Enriched Environment(EE)paradigm has been shown to promote post-stroke functional improvement,but the neuronal mechanisms are still *** this study,we applied a multimodal neuroimaging protocol combining magnetic resonance imaging(mRI)and positron emission tomography(PET)to examine the effects of post-ischemic EE treatment on structural and functional neuroplasticity in the bilateral sensorimotor *** were subjected to permanent middle cerebral artery *** motor function of the rats was examined using the DigiGait *** was applied to investigate the EE-induced structural modifications of the bilateral sensorimotor cortex.[^(18)f]-fluorodeoxyglucose PET was used to detect glucose *** oxygen level-dependent(BOLD)-functional mRI(fmRI)was used to identify the regional brain activity and functional connectivity(fC).In addition,the expression of neuroplasticity-related signaling pathways including neurotrophic factors(BDNf/CREB),axonal guidance proteins(Robo1/Slit2),and axonal growth-inhibitory proteins(NogoA/NgR)as well as downstream proteins(RhoA/ROCK)in the bilateral sensorimotor cortex were measured by Western *** results showed the three-phase EE improved the walking *** T2 mapping imaging and diffusion tensor imaging demonstrated that EE benefited structure integrity in the bilateral sensorimotor ***-mRI fused images showed improved glucose metabolism in the corresponding regions after EE ***,the BOLD-based amplitude of low-frequency fluctuations showed that EE increased spontaneous activity in the bilateral motor cortex and ipsilateral sensory *** addition,fC results showed increased sensorimotor connectivity in the ipsilateral hemisphere and increased interhemispheric motor cortical connectivity and motor cortical-thalamic connectivity following EE *** addition,a strong correlation was found between increased functional connectivity and improv

关键词： Enriched environment Gait function Neuronal plasticity Structural integrity Glucose metabolism functional connectivity microenvironmental molecules Axonogenesis

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Interplay between the glymphatic system and neurotoxic proteins in Parkinson’s disease and related disorders:current knowledge and future directions

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Neural Regeneration research 2024年第9期19卷 1973-1980页

作者： Yumei Yue Xiaodan Zhang Wen Lv Hsin-Yi Lai Ting Shen Department of Neurology of Sir Run Run Shaw Hospital Zhejiang University School of MedicineZhejiang UniversityHangzhouZhejiang ProvinceChina Department of Emergency medicine The University of Hong KongHong Kong Special Administrative RegionChina Department of Neurology of the Second Affiliated Hospital and School of brain Science and brain medicine Interdisciplinary Institute of Neuroscience and TechnologyKey Laboratory of Medical Neurobiology of Zhejiang ProvinceZhejiang University School of MedicineHangzhouZhejiang ProvinceChina College of Biomedical Engineering and Instrument Science Zhejiang UniversityHangzhouZhejiang ProvinceChina mOE frontier Science center for brain Science and brain-machine Integration State Key Laboratory of Brain-machine IntelligenceSchool of Brain Science and Brain MedicineZhejiang UniversityHangzhouZhejiang ProvinceChina

Parkinson’s disease is a common neurodegenerative disorder that is associated with abnormal aggregation and accumulation of neurotoxic proteins,includingα-synuclein,amyloid-β,and tau,in addition to the impaired elimination of these neurotoxic *** parkinsonism,which has the same clinical presentation and neuropathology as Parkinson’s disease,expands the disease landscape within the continuum of Parkinson’s disease and related *** glymphatic system is a waste clearance system in the brain,which is responsible for eliminating the neurotoxic proteins from the interstitial *** of the glymphatic system has been proposed as a significant contributor to the development and progression of neurodegenerative disease,as it exacerbates the aggregation of neurotoxic proteins and deteriorates neuronal ***,impairment of the glymphatic system could be considered as the final common pathway to *** evidence has provided initial insights into the potential effect of the impaired glymphatic system on Parkinson’s disease and related disorders;however,many unanswered questions *** review aims to provide a comprehensive summary of the growing literature on the glymphatic system in Parkinson’s disease and related *** focus of this review is on identifying the manifestations and mechanisms of interplay between the glymphatic system and neurotoxic proteins,including loss of polarization of aquaporin-4 in astrocytic endfeet,sleep and circadian rhythms,neuroinflammation,astrogliosis,and *** review further delves into the underlying pathophysiology of the glymphatic system in Parkinson’s disease and related disorders,and the potential implications of targeting the glymphatic system as a novel and promising therapeutic strategy.

关键词： atypical parkinsonism glymphatic system magnetic resonance imaging neurotoxic proteins Parkinson’s disease

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Variable frequency deep brain stimulation of subthalamic nucleus to improve freezing of gait in Parkinson's disease

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National Science Review 2024年第6期11卷 102-104页

作者： fumin Jia Aparna Wagle Shukla Wei Hu Yu ma Jianguo Zhang Leonardo Almeida Chris Kao Yi Guo Shizhong Zhang Yingqun Tao Zhipei Ling Xin Xu Zhiquan Yang fan-gang meng Xinhua Wan Hesheng Liu Peter E.Konard Luming Li National Engineering Laboratory for Neuromodulation Tsinghua University University of florida center for movement Disorders and Neurorestoration Tsinghua University Yuquan Hospital Beijing Tiantan Hospital Capital Medical University School of medicine Vanderbilt University Peking Union medical College Hospital ZhuJiang Hospital of Southern medical University The General Hospital of Shenyang military Chinese PLA General Hospital Xiangya Hospital Central South University Beijing Neurosurgical Institute Capital Medical University Athinoula A. martinos center for Biomedical imaging Harvard Medical School Precision medicine & Healthcare research center Tsinghua-Berkeley Shenzhen Institute man-machine-Environment Engineering Institute School of Aerospace EngineeringTsinghua University center of Epilepsy Beijing Institute for Brain Disorders

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a welle-stablished therapy for patients with Parkinson’s disease (PD) presenting with medication refractory tremors, motor fluctuations and dyskinesias induced by dopaminergic medications [1]. However,traditional high-frequency stimulation(HfS) does not effectively control axial symptoms such as gait dysfunction,postural instability and freezing of gait(fOG)[2,3].

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Nanoscale Reorganization of Glutamate Receptors Underlies Synaptic Plasticity and Pathology

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Neuroscience Bulletin 2024年第6期40卷 840-844页

作者： Jia-Hui Chen Ai-Hui Tang Hefei National Laboratory for Physical Sciences at the microscale CAS Key Laboratory of Brain Function and DiseaseNeurodegenerative Disorder Research Center and Biomedical Sciences and Health Laboratory of Anhui ProvinceUniversity of Science and Technology of ChinaHefei230027China Institute of Artificial Intelligence Hefei Comprehensive National Science CenterHefei230088China

Excitatory synapses serve as the primary sites for information transmission between neurons in the *** work over the past decades has identified and revealed multiple compositions and functions of the synaptic proteome in the postsynaptic density(PSD),including receptors,scaffold proteins,and signaling molecules,which work together to ensure stable and effective synaptic transmission.

关键词： Receptor scale Glutamate

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Comparative transcriptome analysis between rhesus macaques(macaca mulatta) and crab-eating macaques(m. fascicularis)

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Zoological research 2024年第2期45卷 299-310页

作者： Yu-Xiang mao Yamei Li Zikun Yang Ning Xu Shilong Zhang Xuankai Wang Xiangyu Yang Qiang Sun Yafei mao Institute of Neuroscience State Key Laboratory of NeuroscienceCenter for Excellence in Brain Science&Intelligence TechnologyChinese Academy of SciencesShanghai 200031China Shanghai center for brain Science and brain-Inspired Intelligence Technology Shanghai 201210China University of Chinese Academy of Sciences Beijing 100049China Key Laboratory of Genetic Evolution&Animal models Chinese Academy of SciencesKunmingYunnan 650201China Bio-X Institutes Key Laboratory for the Genetics of Developmental and Neuropsychiatric DisordersMinistry of EducationShanghai Jiao Tong UniversityShanghai 200030China Zhiyuan College Shanghai Jiao Tong UniversityShanghai 200240China center for Genomic research International Institutes of MedicineFourth Affiliated HospitalZhejiang UniversityYiwuZhejiang 322000China

Understanding gene expression variations between species is pivotal for deciphering the evolutionary diversity in phenotypes. Rhesus macaques(macaca mulatta, mmU)and crab-eating macaques(m. fascicularis, mfA) serve as crucial nonhuman primate biomedical models with different phenotypes. To date, however, large-scale comparative transcriptome research between these two species has not yet been fully explored. Here, we conducted systematic comparisons utilizing newly sequenced RNA-seq data from84 samples(41 mfA samples and 43 mmU samples)encompassing 14 common tissues. Our findings revealed a small fraction of genes(3.7%) with differential expression between the two species, as well as 36.5% of genes with tissue-specific expression in both macaques. Comparison of gene expression between macaques and humans indicated that 22.6% of orthologous genes displayed differential expression in at least two tissues. moreover,19.41% of genes that overlapped with macaque-specific structural variants showed differential expression between humans and macaques. Of these, the fAm220A gene exhibited elevated expression in humans compared to macaques due to lineage-specific duplication. In summary,this study presents a large-scale transcriptomic comparison between mmU and mfA and between macaques and humans. The discovery of gene expression variations not only enhances the biomedical utility of macaque models but also contributes to the wider field of primate genomics.

关键词： Crab-eating macaques Rhesus macaques Comparative transcriptomics Biomedical models Nonhuman primates RNA-seq Duplicated genes

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Hydrogen sulfide responsive nanoplatforms: Novel gas responsive drug delivery carriers for biomedical applications

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Asian Journal of Pharmaceutical Sciences 2024年第1期19卷 1-17页

作者： Jiafeng Zou Zeting Yuan Xiaojie Chen You Chen min Yao Yang Chen Xiang Li Yi Chen Wenxing Ding Chuanhe Xia Yuzheng Zhao feng Gao Shanghai frontier Science research Base of Optogenetic Techniques for Cell metabolism School of PharmacyEast China University of Science and TechnologyShanghai 200237China Key Laboratory of Neuropharmacology and Translational medicine of Zhejiang Province School of Pharmaceutical SciencesZhejiang Chinese Medical UniversityHangzhou 310053China Shanghai Key Laboratory of functional materials Chemistry East China University of Science and TechnologyShanghai 200237China Shanghai Key Laboratory of New Drug Design School of PharmacyEast China University of Science and TechnologyShanghai 200237China Optogenetics and Synthetic Biology Interdisciplinary research center State Key Laboratory of Bioreactor EngineeringEast China University of Science and TechnologyShanghai 200237China CAS center for Excellence in brain Science Shanghai Institutes for Biological SciencesChinese Academy of SciencesShanghai 200031China research Unit of New Techniques for Live-cell metabolic imaging Chinese Academy of Medical SciencesBeijing 100050China

Hydrogen sulfide(H_(2)S)is a toxic,essential gas used in various biological and physical processes and has been the subject of many targeted studies on its role as a new gas *** studies have mainly focused on the production and pharmacological side effects caused by H_(2)***,effective strategies to remove H_(2)S has become a key research ***,the development of novel nanoplatforms has provided new tools for the targeted removal of H_(2)*** paper was performed to review the association between H_(2)S anddisease,relatedH_(2)S inhibitory drugs,aswell as H_(2)S responsive nanoplatforms(HRNs).This review first analyzed the role of H_(2)S in multiple tissues and ***,common drugs used to eliminate H_(2)S,as well as their potential for combination with anticancer agents,were *** only the existing studies on HRNs,but also the inhibition H_(2)S combined with different therapeutic methods were both sorted out in this ***,this review provided in-depth analysis of the potential of HRNs about treatment or detection in ***,potential challenges of HRNs were *** study demonstrates the excellent potential of HRNs for biomedical applications.

关键词： Hydrogen sulfide Disease mechanisms Removal of hydrogen sulfide Responsive nanoplatforms Challenges Biomedical applications

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Sirolimus can promote the disappearance of renal angiomyolipoma associated with tuberous sclerosis complex:a prospective cohort study

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World Journal of Pediatrics 2024年第6期20卷 602-610页

作者： Shuo Dun Yang-Yang Wang Lin Wan Qiu-Hong Wang Qian Lu Xiao-Yan Yang Qi Zhang Hui-min Chen Lu-Peng Qiu Li-Ping Zou medical School of Chinese PLA Beijing 100853China Department of Pediatrics The First Medical CenterChinese PLA General HospitalBeijing 100853China center of Epilepsy Beijing Institute for Brain DisordersBeijing 100069China

Background Renal angiomyolipoma(RAmL)is the most common kidney lesion in patients with tuberous sclerosis complex(TSC),affecting about 80%of *** is a benign tumor that grows over time,usually bilaterally,and can easily lead to kidney complications such as acute ***,we investigated the efficacy and safety of sirolimus in children with TSC-associated RAmL and explored the factors affecting tumor disappearance under sirolimus treatment through subgroup *** A prospective cohort study was *** was initiated at 1 mg/(m^(2)×day),and dose adjustments were made by a 2-week titration period to attain a trough blood concentration of 5-10 ng/*** disappearance of RAmL in chil-dren after sirolimus treatment was observed,and Cox regression was used to screen the factors affecting tumor *** One hundred and twenty-six patients who met the criteria were *** 3 months,6 months,12 months,and 24 months of follow-up,tumors disappeared in 18(14.3%),30(23.8%),39(31.0%),and 42(33.3%)children,*** disappeared in 50(39.7%)children by the last visit of each individual,and 30(60%)of them occurred within 6 *** multivariate Cox regression analysis showed that patients with a smaller maximum tumor diameter at baseline had a higher tumor disappearance ***-six(29%)patients had stomatitis during the entire treatment period,and no serious *** Sirolimus could promote the disappearance of TSC-related *** disappearance rate was correlated with the maximum diameter at baseline,and the smaller the tumor was,the higher the disappearance *** is well tolerated in the treatment of RAmL associated with TSC.

关键词： Angiomyolipoma mTOR inhibitor Sirolimus Tuberous sclerosis

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Probiotics administration alleviates cognitive impairment and circadian rhythm disturbance induced by sleep deprivation

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food Science and Human Wellness 2024年第4期13卷 1951-1961页

作者： Peijun Tian Yunfei Hou Zheng Wang Jiaona Jiang Xin Qian Zhihao Qu Jianxin Zhao Gang Wang Wei Chen State Key Laboratory of food Science and Resources Jiangnan UniversityWuxi 214122China School of food Science and Technology Jiangnan UniversityWuxi 214122China National Engineering research center for functional food Jiangnan UniversityWuxi 214122China Institute of food Biotechnology(Yangzhou) Jiangnan UniversityYangzhou 225004China

Gut microbiome is indispensable for maintaining normal brain ***,gut microbiota plays a causal role in sleep deprivation(SD)-induced cognitive *** this study,neurobehavioral effects of the Bifidobacterium breve strain(CCfm1025)were assessed in sleep-deprived ***1025 improved the body weight and food and water intake of the *** also alleviated SD-induced cognitive behavioural abnormalities(in the novel object recognition test),but did not show beneficial effects on mood-and spatial memory-related ***1025 significantly altered the gut microbial composition and genome *** microbial metabolites that may regulate sleep function were also identified,such as isovaleric acid andγ-aminobutyric acid in the gut and purine metabolites in the *** metabolites may participate in gutbrain communication by acting on the striatal melatonin system,for example to increase melatonin levels,and by regulating the expression of circadian clock genes such as those encoding the adenosine A2A receptor and period circadian regulator ***,administration of probiotics alleviated cognitive impairment and circadian rhythm disturbance induced by SD via modulation of gut microbiome and its *** findings may help guide the treatment of insomnia or other sleep disorders via dietary strategies.

关键词： Bifidobacterium Sleep Circadian rhythm Purine Gut microbiome

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A novel dual serotonin transporter and m-channel inhibitor D01 for antidepression and cognitive improvement

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Acta Pharmaceutica Sinica B 2024年第3期14卷 1457-1466页

作者： Yaqin Wei Xiangqing Xu Qiang Guo Song Zhao Yinli Qiu Dongli Wang Wenwen Yu Yani Liu KeWei Wang School of Pharmacy Xuzhou Medical UniversityXuzhou 221004China Institute of Pharmaceutical research Jiangsu Nhwa Pharmaceutical Co.Ltd.&Jiangsu Key Laboratory of Central Nervous System Drug Research and DevelopmentXuzhou 221116China Department of Pharmacology School of PharmacyQingdao University Medical CollegeQingdao 266073China Institute of Innovative Drug Qingdao UniversityQingdao 266021China center for brain Science and brain-Inspired Intelligence Guangdong-Hong Kong-Macao Greater Bay AreaGuangzhou 510515China

Cognitive dysfunction is a core symptom common in psychiatric disorders including depression that is primarily managed by antidepressants lacking efficacy in improving *** this study,we report a novel dual serotonin transporter and voltage-gated potassium Kv7/KCNQ/m-channel inhibitor D01(a 2-methyl-3-aryloxy-3-heteroarylpropylamines derivative)that exhibits both anti-depression effects and improvements in cognition.D01 inhibits serotonin transporters(K_(i)=30.1±6.9 nmol/L)and m channels(IC_(50)=10.1±2.4μmol/L).D01 also reduces the immobility duration in the mouse fST and TST assays in a dose-dependent manner without a stimulatory effect on *** administrations of D01(20 and 40 mg/kg)can significantly shorten the immobility time in a mouse model of chronic restraint stress(CRS)-induced depression-like ***,D01 dose-dependently improves the cognitive deficit induced by CRS in morris water maze test and increases the exploration time with novel objects in normal or scopolamine-induced cognitive deficits in mice,but not ***,D01 reverses the long-term potentiation(LTP)inhibition induced by *** together,our findings demonstrate that D01,a dual-target serotonin reuptake and m channel inhibitor,is highly effective in the treatment-resistant depression and cognitive deficits,thus holding potential for development as therapy of depression with cognitive deficits.

关键词： SERT 5-HT Kv7/KCNQ/m current D01 Depression Cognition

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