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Graph based recurrent network for context specific synthetic lethality prediction

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Science China(Life Sciences) 2025年第2期68卷 527-540页

作者： Yuyang Jiang Jing Wang Yixin Zhang ZhiWei Cao Qinglong Zhang Jinsong Su Song He Xiaochen Bo Academy of Medical Engineering and Translational medicine Tianjin UniversityTianjin 300072China department of bioinformatics Institute of Health Service and Transfusion MedicineBeijing 100850China School of medicine Tsinghua UniversityBeijing 100084China School of Informatics Xiamen UniversityXiamen 361005China

The concept of synthetic lethality(SL)has been successfully used for targeted *** further explore SL for cancer therapy,identifying more SL interactions with therapeutic potential are ***,graph neural network-based deep learning methods have been proposed for SL prediction,which reduce the SL search space of wet-lab based ***,these methods ignore that most SL interactions depend strongly on genetic context,which limits the application of the predicted *** this study,we proposed a graph recurrent network-based model for specific context-dependent SL prediction(SLGRN).In particular,we introduced a Graph Recurrent Network-based encoder to acquire a context-specific,low-dimensional feature representation for each node,facilitating the prediction of novel *** leveraged gate recurrent unit(GRU)and it incorporated a context-dependent-level state to effectively integrate information from all *** a result,SLGRN outperforms the state-of-the-arts models for SL *** subsequently validate novel SL interactions under different contexts based on combination therapy or patient survival *** in vitro experiments and retrospective clinical analysis,we emphasize the potential clinical significance of this context-specific SL prediction model.

关键词： synthetic lethality graph recurrent network context-specific graph combination therapy

Emerging structures and dynamic mechanisms ofγ-secretase for Alzheimer’s disease

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Neural Regeneration Research 2025年第1期20卷 174-180页

作者： Yinglong Miao Michael S.Wolfe computational medicine Program and department of Pharmacology University of North Carolina–Chapel HillChapel HillNCUSA department of Medicinal Chemistry University of KansasLawrenceKSUSA

γ-Secretase,called“the proteasome of the membrane,”is a membrane-embedded protease complex that cleaves 150+peptide substrates with central roles in biology and medicine,including amyloid precursor protein and the Notch family of cell-surface *** inγ-secretase and amyloid precursor protein lead to early-onset familial Alzheimer’s disease.γ-Secretase has thus served as a critical drug target for treating familial Alzheimer’s disease and the more common late-onset Alzheimer’s disease as ***,critical gaps remain in understanding the mechanisms of processive proteolysis of substrates,the effects of familial Alzheimer’s disease mutations,and allosteric modulation of substrate cleavage byγ-*** this review,we focus on recent studies of structural dynamic mechanisms ofγ-*** mechanisms,including the“Fit-Stay-Trim,”“Sliding-Unwinding,”and“Tilting-Unwinding,”have been proposed for substrate proteolysis of amyloid precursor protein byγ-secretase based on all-atom molecular dynamics *** an incorrect registry of the Notch1 substrate was identified in the cryo-electron microscopy structure of Notch1-boundγ-secretase,molecular dynamics simulations on a resolved model of Notch1-boundγ-secretase that was reconstructed using the amyloid precursor protein-boundγ-secretase as a template successfully capturedγ-secretase activation for proper cleavages of both wildtype and mutant Notch,being consistent with biochemical experimental *** approach could be potentially applied to decipher the processing mechanisms of various substrates byγ-*** addition,controversy over the effects of familial Alzheimer’s disease mutations,particularly the issue of whether they stabilize or destabilizeγ-secretase-substrate complexes,is ***,an outlook is provided for future studies ofγ-secretase,including pathways of substrate binding and product release,effects of modulators on familial Alzheimer’s disease mutations

关键词： Alzheimer’s disease amyloid precursor protein cryo-EM structures drug design intramembrane proteolysis molecular dynamics Notch

Capsaicin(CAP) exerts a protective effect against ethanol-induced oxidative gastric mucosal injury by modulating the chemokine receptor 4 (CCR4)/Src/p47phox signaling pathway both in vitro and in vivo

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Chinese Journal of Natural medicines 2025年第2期23卷 191-202页

作者： Zhiru Yang Haolin Guo Pengfei Zhang Kairui Liu Junli Ba Xue Bai Shiti Shama Bo Zhang Xiaoning Gao Jun Kang School of Life Sciences Tianjin University School of Traditional Chinese medicine Beijing University of Chinese Medicine Tianjin Pharmaceutical and Cosmetic Evaluation and Inspection Center Institute for TCM-X MOE Key Laboratory of Bioinformatics Bioinformatics Division BNRist Department of Automation Tsinghua University Institute of Biomedical Research Henan Academy of Sciences

Ethanol(EtOH) is a common trigger for gastric mucosal diseases, and mitigating oxidative stress is essential for attenuating gastric mucosal damage. Capsaicin(CAP) has been identified as a potential agent to counteract oxidative damage in the gastric mucosa; however, its precise mechanism remains unclear. This study demonstrates that CAP alleviates EtOH-induced gastric mucosal injuries through two primary pathways: by suppressing the chemokine receptor 4(CCR4)/Src/p47phox axis, thereby reducing oxidative stress, and by inhibiting the phosphorylation and nuclear translocation of nuclear factor-κB p65(NF-κB) p65, resulting in diminished inflammatory responses. These findings elucidate the mechanistic pathways of CAP and provide a theoretical foundation for its potential therapeutic application in the treatment of gastric mucosal injuries.

关键词： Capsaicin Chemokine signaling Gastric mucosal damage NF-κB p65

General expert consensus on the application of network pharmacology in the research and development of new traditional Chinese medicine drugs

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Chinese Journal of Natural medicines 2025年第2期23卷 129-142页

作者： Shao Li Wei Xiao Institute of TCM-X/MOE Key Laboratory of bioinformatics Bioinformatics Division BNRist/Department of Automation Tsinghua University State Key Laboratory on Technologies for Chinese medicine Pharmaceutical Process Control and Intelligent Manufacture Jiangsu Kanion Pharmaceutical Co. Ltd.

The research and development of new traditional Chinese medicine(TCM) drugs have progressively established a novel system founded on the integration of TCM theory, human experience, and clinical trials(termed the “Three Combinations”). However, considering TCM's distinctive features of “syndrome differentiation and treatment” and “multicomponent formulations and complex mechanisms”, current TCM drug development faces challenges such as insufficient understanding of the material basis and the overall mechanism of action and an incomplete evidence chain system. Moreover, significant obstacles persist in gathering human experience data, evaluating clinical efficacy, and controlling the quality of active ingredients, which impede the innovation process in TCM drug development. Network pharmacology, centered on the “network targets” theory, transcends the limitations of the conventional“single target” reductionist research model. It emphasizes the comprehensive effects of disease or syndrome biological networks as targets to elucidate the overall regulatory mechanism of TCM prescriptions. This approach aligns with the holistic perspective of TCM, offering a novel method consistent with TCM's holistic view for investigating the complex mechanisms of TCM and developing new TCM drugs. It is internationally recognized as a “next-generation drug research model”. To advance the research of new tools, methods, and standards for TCM evaluation and to overcome fundamental, critical, and cutting-edge technical challenges in TCM regulation, this consensus aims to explore the characteristics, progress, challenges, applicable pathways, and specific applications of network pharmacology as a new theory, method, and tool in TCM drug development. The goal is to enhance the quality of TCM drug research and development and accelerate the efficiency of developing new TCM products.

关键词： Expert consensus Network pharmacology Research and development of new traditional Chinese medicine drugs

The emerging role of mesenchymal stem cell-derived extracellular vesicles to ameliorate hippocampal NLRP3 inflammation induced by binge-like ethanol treatment in adolescence

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Neural Regeneration Research 2025年第4期20卷 1153-1163页

作者： Susana Mellado María JoséMorillo-Bargues Carla Perpiñá-Clérigues Francisco García-García Victoria Moreno-Manzano Consuelo Guerri María Pascual department of Physiology School of Medicine and DentistryUniversity of ValenciaValenciaSpain bioinformatics and Biostatistics Unit Príncipe Felipe Research CenterValenciaSpain Neuronal and Tissue Regeneration Laboratory Príncipe Felipe Research CenterValenciaSpain

Our previous studies have reported that activation of the NLRP3(NOD-,LRR-and pyrin domain-containing protein 3)-inflammasome complex in ethanol-treated astrocytes and chronic alcohol-fed mice could be associated with neuroinflammation and brain *** stem cell-derived extracellular vesicles(MSC-EVs)have been shown to restore the neuroinflammatory response,along with myelin and synaptic structural alterations in the prefrontal cortex,and alleviate cognitive and memory dysfunctions induced by binge-like ethanol treatment in adolescent *** the therapeutic role of the molecules contained in mesenchymal stem cell-derived extracellular vesicles,the present study analyzed whether the administration of mesenchymal stem cell-derived extracellular vesicles isolated from adipose tissue,which inhibited the activation of the NLRP3 inflammasome,was capable of reducing hippocampal neuroinflammation in adolescent mice treated with binge *** demonstrated that the administration of mesenchymal stem cell-derived extracellular vesicles ameliorated the activation of the hippocampal NLRP3 inflammasome complex and other NLRs inflammasomes(e.g.,pyrin domain-containing 1,caspase recruitment domain-containing 4,and absent in melanoma 2,as well as the alterations in inflammatory genes(interleukin-1β,interleukin-18,inducible nitric oxide synthase,nuclear factor-kappa B,monocyte chemoattractant protein-1,and C–X3–C motif chemokine ligand 1)and miRNAs(miR-21a-5p,miR-146a-5p,and miR-141-5p)induced by binge-like ethanol treatment in adolescent *** analysis further revealed the involvement of miR-21a-5p and miR-146a-5p with inflammatory target genes and NOD-like receptor signaling *** together,these findings provide novel evidence of the therapeutic potential of MSC-derived EVs to ameliorate the hippocampal neuroinflammatory response associated with NLRP3 inflammasome activation induced by binge drinking in adolescence.

关键词： adolescence binge-like ethanol treatment extracellular vesicles hippocampus mesenchymal stem cells neuroinflammation NOD-,LRR-and pyrin domain-containing protein 3(NLRP3)

SpaGRA:Graph augmentation facilitates domain identification for spatially resolved transcriptomics

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Journal of Genetics and Genomics 2025年第1期52卷 93-104页

作者： Xue Sun Wei Zhang Wenrui Li Na Yu Daoliang Zhang Qi Zou Qiongye Dong Xianglin Zhang Zhiping Liu Zhiyuan Yuan Rui Gao Center of Intelligent medicine School of Control Science and EngineeringShandong UniversityJinanShandong 250061China MOE Key Lab of bioinformatics and bioinformatics Division of BNRIST Department of AutomationTsinghua UniversityBeijing 100084China Institute of Precision medicine Peking University Shenzhen HospitalShenzhenGuangdong 518036China department of Clinical Laboratory The Second HospitalCheeloo College of MedicineShandong UniversityJinanShandong 250033China Institute of Science and Technology for Brain-Inspired Intelligence Center for Medical Research and InnovationShanghai Pudong HospitalFudan University Pudong Medical CenterFudan UniversityShanghai 200433China

Recent advances in spatially resolved transcriptomics(SRT)have provided new opportunities for characterizing spatial structures of various ***-based geometric deep learning has gained widespread adoption for spatial domain identification ***,most methods define adjacency relation between cells or spots by their spatial distance in SRT data,which overlooks key biological interactions like gene expression similarities,and leads to inaccuracies in spatial domain *** tackle this challenge,we propose a novel method,SpaGRA(https://***/sunxue-yy/SpaGRA),for automatic multi-relationship construction based on graph *** uses spatial distance as prior knowledge and dynamically adjusts edge weights with multi-head graph attention networks(GATs).This helps SpaGRA to uncover diverse node relationships and enhance message passing in geometric contrastive ***,SpaGRA uses these multi-view relationships to construct negative samples,addressing sampling bias posed by random *** results show that SpaGRA presents superior domain identification performance on multiple datasets generated from different *** SpaGRA,we analyze the functional regions in the mouse hypothalamus,identify key genes related to heart development in mouse embryos,and observe cancer-associated fibroblasts enveloping cancer cells in the latest Visium HD ***,SpaGRA can effectively characterize spatial structures across diverse SRT datasets.

关键词： Spatial domain identification Spatially resolved transcriptomics Multi-head graph attention networks Graph augmentation Geometric contrastive learning

Single-cell technologies: current and near future

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Science China(Life Sciences) 2025年第1期68卷 1-4页

作者： Chenfei Wang Qi Liu Xiaohui Fan Tieliu Shi KeyLaboratory of Spine and Spinal CordInjury Repairand Regeneration Ministry of EducationOrthopedics DepartmentTongji HospitalBioinformatics DepartmentSchoolofLifeSciencesandTechnologyTongji UniversityShanghai 200082China Frontier Science Center for Stem Cells School of Life Sciences and TechnologyTongji UniversityShanghai 200092China Translational Medical Center for Stem Cell Therapy and Institute for Regenerative medicine Shanghai East HospitalBioinformatics DepartmentSchool of Life Sciences and TechnologyTongji UniversityShanghai 200082China Research Institute of Intelligent Computing Zhejiang LabHangzhou 311121China Pharmaceutical Informatics Institute College of Pharmaceutical SciencesZhejiang UniversityHangzhou 310058China National Key Laboratory of Chinese medicine Modernization Innovation Center of Yangtze River DeltaZhejiang UniversityJiaxing 314103China Center for bioinformatics and computational Biology Shanghai Key Laboratory of Regulatory Biologythe Institute of Biomedical Sciences and School of Life SciencesEast China Normal UniversityShanghai 200241China Key Laboratory of Advanced Theory and Application in Statistics and Data Science(MOE) School of StatisticsEast China Normal UniversityShanghai 200062China

Single-cell technologies enable the indepth exploration of multiple biological hierarchies at the scale of individual cells,which have deepened our knowledge of cellular diversity,tissue organization,and overall organism function(Sun et al.,2024).In 2009,single-cell RNA sequencing(scRNA-seq)was first developed as a powerful tool to dissect gene expression and uncover transcriptional *** the rapid advancement of technology,single-cell approaches have expanded to encompass other omics,such as genomics,epigenomics,proteomics,and ***,multimodal technologies including spatially resolved transcriptomics and clustered regularly interspaced short palindromic repeats(CRISPR)screening at the single-cell level further advanced our ability to comprehensively understand cellular ***-cell methods provide deeper insights into disease mechanisms across various conditions,including cancer,developmental disorders,and aging-associated *** this issue,we focus on topics related to single-cell methods,covering the following four aspects:(i)single-cell multi-omic sequencing technology;(ii)single-cell spatial technology;(iii)singlecell CRISPR screening technology;(iv)applications of single-cell technology.

关键词： expanded enable insight

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A comprehensive review of phytochemical approaches in treatment of acute myeloid leukemia:Associated pathways and molecular mechanisms

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Chinese Herbal medicines 2025年第1期17卷 41-55页

作者： Mouvanal Sajana T.S.Gopenath Basalingappa M.Kanthesh Division of Molecular Biology School of Life SciencesJSS AHER department of Biotechnology and bioinformatics School of Life SciencesJSS AHER

Acute myeloid leukemia(AML) is a type of cancer that affects the blood and bone *** review conducts a thorough analysis of AML, addressing its genetic *** examination extends to the current therapeutic approaches employed for AML,shedding light on their efficacy and the notable side effects experienced by patients undergoing these treatments,leading to a low overall survival ***,exploring alternative treatments,such as phytochemicals,is ***,the review explores the complex landscape of phytochemicals,categorizing them based on their diverse properties,which include alkaloids,phenols,terpenoids,organo-sulfur compounds,and other compounds,including quinones,and elucidating their mechanisms of *** emphasis is placed on their involvement in critical signaling pathways,with a particular focus on how these phytochemicals impact AML when evaluated across a spectrum of cell *** in-depth exploration aims to uncover potential targets within the molecular landscape of AML where phytochemicals can exert their therapeutic *** review investigates the potential role of plant-derived phytochemicals as adjunctive therapies for *** exploration encompasses the identification of specific phytochemicals that exhibit promising anti-leukemic properties and evaluates their potential in clinical *** conventional treatments,the review explores the integration of complementary and alternative medicine as a holistic approach to managing *** examination encompasses the synergy between conventional therapies and alternative interventions,exploring how these combined strategies may enhance overall therapeutic outcomes and mitigate side *** a forward-looking perspective,the overarching goal is to contribute to the evolving landscape of AML treatment by considering innovative approaches that harness the therapeutic potential of phytochemicals,both independently and in conjunction with establishe

关键词： cell death complementary and alternative medicine leukemia phytochemicals signaling pathways therapeutic targets

Resting-state brain network remodeling after different nerve reconstruction surgeries:a functional magnetic resonance imaging study in brachial plexus injury rats

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Neural Regeneration Research 2025年第5期20卷 1495-1504页

作者： Yunting Xiang Xiangxin Xing Xuyun Hua Yuwen Zhang Xin Xue Jiajia Wu Mouxiong Zheng He Wang Jianguang Xu School of Rehabilitation Science Shanghai University of Traditional Chinese MedicineShanghaiChina Engineering Research Center of Traditional Chinese medicine Intelligent Rehabilitation Ministry of EducationShanghaiChina department of Rehabilitation medicine Yueyang Hospital of Integrated Traditional Chinese and Western MedicineShanghai University of Traditional Chinese MedicineShanghaiChina department of Traumatology and Orthopedics Yueyang Hospital of Integrated Traditional Chinese and Western MedicineShanghai University of Traditional Chinese MedicineShanghaiChina Institute of Science and Technology for Brain-Inspired Intelligence Fudan UniversityShanghaiChina Key Laboratory of computational Neuroscience and Brain-Inspired Intelligence(Fudan University) Ministry of EducationShanghaiChina Human Phenome Institute Fudan UniversityShanghaiChina

Distinct brain remodeling has been found after different nerve reconstruction strategies,including motor representation of the affected ***,differences among reconstruction strategies at the brain network level have not been *** study aimed to explore intranetwork changes related to altered peripheral neural pathways after different nerve reconstruction surgeries,including nerve repair,endto-end nerve transfer,and end-to-side nerve ***–Dawley rats underwent complete left brachial plexus transection and were divided into four equal groups of eight:no nerve repair,grafted nerve repair,phrenic nerve end-to-end transfer,and end-to-side transfer with a graft sutured to the anterior upper ***-state brain functional magnetic resonance imaging was obtained 7 months after *** independent component analysis algorithm was utilized to identify group-level network components of interest and extract resting-state functional connectivity values of each voxel within the *** in intra-network resting-state functional connectivity were compared among the *** muscle reinnervation was assessed by behavioral observation(elbow flexion)and *** results showed that alterations in the sensorimotor and interoception networks were mostly related to changes in the peripheral neural *** repair was related to enhanced connectivity within the sensorimotor network,while end-to-side nerve transfer might be more beneficial for restoring control over the affected limb by the original motor *** thalamic-cortical pathway was enhanced within the interoception network after nerve repair and end-to-end nerve *** areas related to cognition and emotion were enhanced after end-to-side nerve *** study revealed important brain networks related to different nerve *** networks may be potential targets for enhancing motor recovery.

关键词： brain functional networks end-to-end nerve transfer end-to-side nerve transfer independent component analysis nerve repair peripheral plexus injury resting-state functional connectivity