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Broadening environmental research in the era of accurate protein structure determination and predictions

Frontiers of Environmental Science & Engineering 2024年第7期18卷 169-178页

作者： Mingda Zhou Tong Wang Ke Xu Han Wang Zibin Li Wei-xian Zhang Yayi Wang State Key laboratory of Pollution Control and Resources Reuse Shanghai Institute of Pollution Control and Ecological SecurityCollege of Environmental Science and EngineeringTongji UniversityShanghai 200092China Translational research Institute of brain and brain-Like Intelligence Shanghai Fourth People's HospitalSchool of MedicineTongji UniversityShanghai 200434China

The deep-learning protein structure prediction method AlphaFold2 has garnered enormous attention beyond the realm of structural biology,for its groundbreaking contribution to solving the"protein foiding problem"In this perspective,we explore the connection between protein structure studies and environmental research,delving into the potential for addressing specific environmental *** are promising for environmental applications because of the functional diversity endowed by their structural ***,structural studies on proteins with environmental significance remain ***,we present the opportunity to study proteins by advancing experimental determination and deep-learning prediction ***,the latest progress in environmental research via cryogenic electron microscopy is *** allows us to determine the structure of protein complexes in their native state within cells at molecular resolution,revealing environmentally-associated structural *** the remarkable advancements in computational power and experimental resolution,the study of protein structure and dynamics has reached unprecedented depth and *** advancements will undoubtedly accelerate the establishment of comprehensive environmental protein structural and functional *** opportunities for protein engineering exist to enable innovative solutions for environmental applications,such as the degradation of persistent contaminants,and the recovery of valuable metals as well as rare earth elements.

关键词： Environmental proteins Protein structure Cryogenic electron microscopy Protein structure prediction Protein engineering Artificial Intelligence

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Developmental Impairments of Synaptic Refinement in the Thalamus of a Mouse Model of Fragile X Syndrome

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Neuroscience Bulletin 2024年第4期40卷 439-450页

作者： Xiaotong Wu Yali Liu Xiaomeng Wang Lu Zheng Libiao Pan Hao Wang Department of Neurosurgery of Second Affiliated Hospital and School of brain Science and brain Medicine Key Laboratory for Biomedical Engineering of Education MinistryZhejiang University School of MedicineHangzhou310058China Nanhu brain-computer Interface Institute Hangzhou311100China NHC and CAMS Key laboratory of Medical Neurobiology MOE Frontier Science Center for Brain Research and Brain Machine IntegrationKey Laboratory of Precise Treatment and Clinical Translational Research of Neurological DiseasesSchool of Brain Science and Brain MedicineZhejiang UniversityHangzhou310058China Lingang laboratory Shanghai200031China

While somatosensory over-reactivity is a common feature of autism spectrum disorders such as fragile X syndrome(FXS),the thalamic mechanisms underlying this remain ***,we found that the developmental elimination of synapses formed between the principal nucleus of V(PrV)and the ventral posterior medial nucleus(VPm)of the somatosensory system was delayed in fragile X mental retardation 1 gene knockout(Fmr1 KO)mice,while the developmental strengthening of these synapses was *** showed excessive VGluT2 puncta in mutants at P12–13,but not at P7–8 or P15–16,confirming a delay in somatic pruning of PrV-VPm *** synaptic function was associated with a reduction in the frequency of quantal AMPA events,as well as developmental deficits in presynaptic vesicle size and *** results uncovered the developmental impairment of thalamic relay synapses in Fmr1 KO mice and suggest that a thalamic contribution to the somatosensory over-reactivity in FXS should be considered.

关键词： Fragile X syndrome Synaptic refinement VPm Sensory over-reactivity

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Advancing brain-inspired computing with hybrid neural networks

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National Science Review 2024年第5期11卷 56-71页

作者： Faqiang Liu Hao Zheng Songchen Ma Weihao Zhang Xue Liu Yansong Chua Luping Shi Rong Zhao Center for brain-Inspired Computing research Optical Memory National Engineering Research CenterTsinghua University-China Electronics Technology HIK Group Co.Joint Research Center for Brain-inspired ComputingIDGMc Govern Institute for Brain Research Department of Precision Instrument Tsinghua University Neuromorphic Computing laboratory China Nanhu Academy of Electronics and Information Technology

brain-inspired computing, drawing inspiration from the fundamental structure and information-processing mechanisms of the human brain, has gained significant momentum in recent years. It has emerged as a research paradigm centered on brain–computer dual-driven and multi-network integration. One noteworthy instance of this paradigm is the hybrid neural network(HNN), which integrates computer-science-oriented artificial neural networks(ANNs) with neuroscience-oriented spiking neural networks(SNNs). HNNs exhibit distinct advantages in various intelligent tasks, including perception, cognition and learning. This paper presents a comprehensive review of HNNs with an emphasis on their origin, concepts, biological perspective, construction framework and supporting systems. Furthermore, insights and suggestions for potential research directions are provided aiming to propel the advancement of the HNN paradigm.

关键词： brain-inspired computing hybrid neural network dual-brain driven multi-network integration neuromorphic system

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Transplantation of fibrin-thrombin encapsulated human induced neural stem cells promotes functional recovery of spinal cord injury rats through modulation of the microenvironment

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Neural Regeneration research 2024年第2期19卷 440-446页

作者： Sumei Liu Baoguo Liu Qian Li Tianqi Zheng Bochao Liu Mo Li Zhiguo Chen Cell Therapy Center Beijing Institute of GeriatricsXuanwu HospitalCapital Medical UniversityNational Clinical Research Center for Geriatric Diseasesand Key Laboratory of Neurodegenerative DiseasesMinistry of EducationBeijingChina Center of Neural injury and Repair Beijing Institute for Brain DisordersBeijingChina Center of Parkinson’s Disease Beijing Institute for Brain DisordersBeijingChina

Recent studies have mostly focused on engraftment of cells at the lesioned spinal cord,with the expectation that differentiated neurons facilitate *** a few studies have attempted to use transplanted cells and/or biomaterials as major modulators of the spinal cord injury ***,we aimed to investigate the role of microenvironment modulation by cell graft on functional recovery after spinal cord *** neural stem cells reprogrammed from human peripheral blood mononuclear cells,and/or thrombin plus fibrinogen,were transplanted into the lesion site of an immunosuppressed rat spinal cord injury ***,Beattie and Bresnahan score,electrophysiological function,and immunofluorescence/histological analyses showed that transplantation facilitates motor and electrophysiological function,reduces lesion volume,and promotes axonal neurofilament expression at the lesion *** of the graft and niche components revealed that although the graft only survived for a relatively short period(up to 15 days),it still had a crucial impact on the ***,induced neural stem cells and human fibrin reduced the number of infiltrated immune cells,biased microglia towards a regenerative M2 phenotype,and changed the cytokine expression profile at the lesion ***-induced changes of the microenvironment during the acute and subacute stages might have disrupted the inflammatory cascade chain reactions,which may have exerted a long-term impact on the functional recovery of spinal cord injury rats.

关键词： biomaterial fibrinogen functional recovery induced neural stem cell transplantation microenvironment microglia spinal cord injury thrombin

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Control of defensive behavior by the nucleus of Darkschewitsch GABAergic neurons

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National Science Review 2024年第4期11卷 70-83页

作者： Huiying Zhao Jinrong Liu Yujin Shao Xiang Feng Binhan Zhao Li Sun Yijun Liu Linghui Zeng Xiao-ming Li Hongbin Yang Shumin Duan Yan-qin Yu Department of Neurology of Second Affiliated Hospital and School of brain Science and brain Medicine Zhejiang University School of Medicine Nanhu brain-Computer Interface Institute Liangzhu laboratory MOE Frontier Science Center for Brain Science and Brain-Machine Integration State Key Laboratory of Brain-Machine Intelligence Zhejiang University NHC and CAMS Key laboratory of Medical Neurobiology Zhejiang University Key laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province School of Medicine Hangzhou City University

The nucleus of Darkschewitsch(ND), mainly composed of GABAergic neurons, is widely recognized as a component of the eye-movement controlling system. However, the functional contribution of ND GABAergic neurons(NDGABA) in animal behavior is largely unknown. Here, we show that NDGABA neurons were selectively activated by different types of fear stimuli, such as predator odor and foot *** and chemogenetic manipulations revealed that NDGABA neurons mediate freezing ***, using circuit-based optogenetic and neuroanatomical tracing methods, we identified an excitatory pathway from the lateral periaqueductal gray(l PAG) to the ND that induces freezing by exciting ND inhibitory outputs to the motor-related gigantocellular reticular nucleus, ventral part(Gi V). Together,these findings indicate the NDGABA population as a novel hub for controlling defensive response by relaying fearful information from the l PAG to Gi V, a mechanism critical for understanding how the freezing behavior is encoded in the mammalian brain.

关键词： nucleus of Darkschewitsch GABAergic population defensive behavior freezing neural circuitry

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Pathological and physiological functional cross-talks ofα-synuclein and tau in the central nervous system

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Neural Regeneration research 2024年第4期19卷 855-862页

作者： Mingyue Jin Shengming Wang Xiaodie Gao Zhenyou Zou Shinji Hirotsune Liyuan Sun Guangxi Key laboratory of brain and Cognitive Neuroscience Guilin Medical University Department of Genetic Disease research Osaka Metropolitan University Graduate School of Medicine Department of Scientific research Brain Hospital of Guangxi Zhuang Autonomous Region

α-Synuclein and tau are abundant multifunctional brain proteins that are mainly expressed in the presynaptic and axonal compartments of neurons,*** works have revealed that intracellular deposition ofα-synuclein and/or tau causes many neurodegenerative disorders,including Alzheimer’s disease and Parkinson’s *** intense investigation,the normal physiological functions and roles ofα-synuclein and tau are still unclear,owing to the fact that mice with knockout of either of these proteins do not present apparent ***,the co-occurrence ofα-synuclein and tau aggregates was found in post-mortem brains with synucleinopathies and tauopathies,some of which share similarities in clinical ***,the direct interaction ofα-synuclein with tau is considered to promote the fibrillization of each of the proteins in vitro and in *** the other hand,our recent findings have revealed thatα-synuclein and tau are cooperatively involved in brain development in a stage-dependent *** findings indicate strong cross-talk between the two proteins in physiology and *** this review,we provide a summary of the recent findings on the functional roles ofα-synuclein and tau in the physiological conditions and pathogenesis of neurodegenerative diseases.A deep understanding of the interplay betweenα-synuclein and tau in physiological and pathological conditions might provide novel targets for clinical diagnosis and therapeutic strategies to treat neurodegenerative diseases.

关键词： alpha-synuclein microtubule-associated protein neurodegenerative disease tau

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Unresolved Excess Accumulation of Myelin-Derived Cholesterol Contributes to Scar Formation after Spinal Cord injury

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research 2024年第1期2023卷 17-32页

作者： Bolin Zheng Yijing He Shuai Yin Xu Zhu Qing Zhao Huiyi Yang Zhaojie wang Rongrong Zhu Liming Cheng Key laboratory of Spine and Spinal Cord injury Repair and Regeneration Ministry of EducationDepartment of OrthopedicsTongji HospitalSchool of MedicineTongji UniversityShanghai 200092China Frontier Science Center for Stem Cell research School of Life Science and TechnologyTongji UniversityShanghai 200092China Clinical Center for brain and Spinal Cord research Tongji UniversityShanghai 200092China

Spinal cord injury triggers complex pathological cascades,resulting in destructive tissue damage and incomplete tissue *** formation is generally considered a barrier for regeneration in the central nervous ***,the intrinsic mechanism of scar formation after spinal cord injury has not been fully ***,we report that excess cholesterol accumulates in phagocytes and is inefficiently removed from spinal cord lesions in young adult ***,we observed that excessive cholesterol also accumulates in injured peripheral nerves but is subsequently removed by reverse ***,preventing reverse cholesterol transport leads to macrophage accumulation and fibrosis in injured peripheral ***,the neonatal mouse spinal cord lesions are devoid of myelin-derived lipids and can heal without excess cholesterol *** found that transplantation of myelin into neonatal lesions disrupts healing with excessive cholesterol accumulation,persistent macrophage activation,and *** internalization suppresses macrophage apoptosis mediated by CD5L expression,indicating that myelin-derived cholesterol plays a critical role in impaired wound *** together,our data suggest that the central nervous system lacks an efficient approach for cholesterol clearance,resulting in excessive accumulation of myelin-derived cholesterol,thereby inducing scar formation after injury.

关键词： healing Spinal impaired

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Pericytes protect rats and mice from sepsis-induced injuries by maintaining vascular reactivity and barrier function:implication of miRNAs and microvesicles

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Military Medical research 2024年第1期11卷 1-18页

作者： Zi-Sen Zhang Yi-Yan Liu Shuang-Shuang He Dai-Qin Bao Hong-Chen Wang Jie Zhang Xiao-Yong Peng Jia-Tao Zang Yu Zhu Yue Wu Qing-Hui Li Tao Li Liang-Ming Liu State Key laboratory of Trauma Burns and Combined InjuryDepartment of Shock and TransfusionResearch Institute of SurgeryDaping HospitalArmy Medical UniversityChongqing 400042China

Background Vascular hyporeactivity and leakage are key pathophysiologic features that produce multi-organ damage upon *** hypothesized that pericytes,a group of pluripotent cells that maintain vascular integrity and tension,are protective against sepsis via regulating vascular reactivity and *** We conducted a series of in vivo experiments using wild-type(WT),platelet-derived growth factor receptor-β(PDGFR-β)-Cre+mT/mG transgenic mice and Tie2-Cre+Cx43^(flox/flox)mice to examine the relative contribution of pericytes in sepsis,either induced by cecal ligation and puncture(CLP)or lipopolysaccharide(LPS)*** a separate set of experiments with Sprague-Dawley(SD)rats,pericytes were depleted using CP-673451,a selective PDGFR-βinhibitor,at a dosage of 40 mg/(kg·d)for 7 consecutive *** pericytes,vascular endothelial cells(VECs)and vascular smooth muscle cells(VSMCs)were used for mechanistic *** effects of pericytes and pericyte-derived microvesicles(PCMVs)and candidate miRNAs on vascular reactivity and barrier function were also *** CLP and LPS induced severe injury/loss of pericytes,vascular hyporeactivity and leakage(P<0.05).Transplantation with exogenous pericytes protected vascular reactivity and barrier function via microvessel colonization(P<0.05).Cx43 knockout in either pericytes or VECs reduced pericyte colonization in microvessels(P<0.05).Additionally,PCMVs transferred miR-145 and miR-132 to VSMCs and VECs,respectively,exerting a protective effect on vascular reactivity and barrier function after sepsis(P<0.05).miR-145 primarily improved the contractile response of VSMCs by activating the sphingosine kinase 2(Sphk2)/sphingosine-1-phosphate receptor(S1PR)1/phosphorylation of myosin light chain 20 pathway,whereas miR-132 effectively improved the barrier function of VECs by activating the Sphk2/S1PR2/zonula occludens-1 and vascular endothelial-cadherin *** Pericytes are protective a

关键词： Pericyte Vascular reactivity Vascular permeability Cx43 Microvesicle

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Potential role of hippocampal neurogenesis in spinal cord injury induced post-trauma depression

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Neural Regeneration research 2024年第10期19卷 2144-2156页

作者： Ying Ma Yue Qiao Xiang Gao Spinal Cord and brain injury research Group Stark Neuroscience Research InstituteIndianapolisINUSA Department of Neurological Surgery Indiana University School of MedicineIndianapolisINUSA Department of Neurology Shengjing Hospital of China Medical UniversityShenyangLiaoning ProvinceChina

It has been reported both in clinic and rodent models that beyond spinal cord injury directly induced symptoms, such as paralysis, neuropathic pain, bladder/bowel dysfunction, and loss of sexual function, there are a variety of secondary complications, including memory loss, cognitive decline, depression, and Alzheimer's disease. The largescale longitudinal population-based studies indicate that post-trauma depression is highly prevalent in spinal cord injury patients. Yet, few basic studies have been conducted to address the potential molecular mechanisms. One of possible factors underlying the depression is the reduction of adult hippocampal neurogenesis which may come from less physical activity, social isolation, chronic pain, and elevated neuroinflammation after spinal cord injury. However, there is no clear consensus yet. In this review, we will first summarize the alteration of hippocampal neurogenesis post-spinal cord injury. Then, we will discuss possible mechanisms underlie this important spinal cord injury consequence. Finally, we will outline the potential therapeutic options aimed at enhancing hippocampal neurogenesis to ameliorate depression.

关键词： antidepressants chronic pain depression exercise hippocampal neurogenesis inflammation inhibition neuroinflammation physical activity deficits social isolation spinal cord injury

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SH2B1 Tunes Hippocampal ERK Signaling to Influence Fluid Intelligence in Humans and Mice

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research 2024年第3期2023卷 369-389页

作者： Xiujuan Du Yuhua Yan Juehua Yu Tailin Zhu Chu-Chung Huang Lingli Zhang Xingyue Shan Ren Li Yuan Dai Hui LV Xiao-Yong Zhang Jianfeng Feng Wei-Guang Li Qiang Luo Fei Li Developmental and Behavioral Pediatric Department Brain and Behavioral Research Unit of Shanghai Institute for Pediatric Research and Ministry of Education-Shanghai Key Laboratory for Children's Environmental HealthXinhua Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai 200092China Developmental and Behavioral Pediatric Department Shanghai Xinhua Children's HospitalShanghai 200092China National Clinical research Center for Aging and Medicine at Huashan Hospital Institute of Science and Technology for Brain-lnspired IntelligenceMinistry of Education-Key Laboratory of Computational Neuroscience and Brain-lnspired IntelligenceFudan UniversityShanghai 200433China State Key laboratory of Medical Neurobiology and Ministry of Education Frontiers Center for brain Science Institutes of Brain Science and Human Phenom InstituteFudan UniversityShanghai 200032China Shanghai Key laboratory of brain Functional Genomics(Ministry of Education) School of Life SciencesEast China Normal UniversityShanghai 200062China Department of Rehabilitation Medicine Huashan HospitalInstitute for Translational Brain ResearchState Key Laboratory of Medical Neurobiology and Ministry of Education Frontiers Center for Brain ScienceFudan UniversityShanghai 200032China Center for Experimental Studies and research The First Affliated Hospital of Kunming Medical UniversityKunming 650032China Shanghai research Center for brain Science and brain-lnspired Intelligence Shanghai201210China Institute of Cognitive Neuroscience School of Psychology and Cognitive ScienceEast China Normal UniversityShanghai 200062China.

Fluid intelligence is a cognitive domain that encompasses general reasoning, pattern recognition, and problem-solving abilities independent of task-specific experience. Understanding its genetic and neural underpinnings is critical yet challenging for predicting human development, lifelong health, and well-being. One approach to address this challenge is to map the network of correlations between intelligence and other constructs. In the current study, we performed a genome-wide association study using fluid intelligence quotient scores from the UK Biobank to explore the genetic architecture of the associations between obesity risk and fluid intelligence. Our results revealed novel common genetic loci (SH2B1, TUFM, ATP2A1, and FOXO3) underlying the association between fluid intelligence and body metabolism. Surprisingly, we demonstrated that SH2B1 variation influenced fluid intelligence independently of its effects on metabolism but partially mediated its association with bilateral hippocampal volume. Consistently, selective genetic ablation of Sh2b1 in the mouse hippocampus, particularly in inhibitory neurons, but not in excitatory neurons, significantly impaired working memory, short-term novel object recognition memory, and behavioral flexibility, but not spatial learning and memory, mirroring the human intellectual performance. Single-cell genetic profiling of Sh2B1-regulated molecular pathways revealed that Sh2b1 deletion resulted in aberrantly enhanced extracellular signal-regulated kinase (ERK) signaling, whereas pharmacological inhibition of ERK signaling reversed the associated behavioral impairment. Our cross-species study thus provides unprecedented insight into the role of SH2B1 in fluid intelligence and has implications for understanding the genetic and neural underpinnings of lifelong mental health and well-being.

关键词： metabolism impaired reversed

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