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Antigen-induced chimeric antigen receptor multimerization amplifies on-tumor cytotoxicity

Signal Transduction and Targeted Therapy 2024年第1期9卷 259-270页

作者： Yan Sun Xiu-Na Yang Shuang-Shuang Yang Yi-zhu Lyu Bing Zhang Kai-Wen Liu Na Li Jia-Chen Cui Guang-Xiang Huang Cheng-Lin Liu Jie Xu Jian-Qing Mi zhu Chen xiao-Hu fan Sai-Juan Chen Shuo Chen Shanghai Institute of Hematology National Research Center for Translational MedicineState Key Laboratory of Medical GenomicsRuijin Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai 200025China Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology ShanghaiTech UniversityShanghai 201210China Department of Hematology Second Hospital of Dalian Medical UniversityDalian 116023China National Facility for Protein Science Shanghai Shanghai Advanced Research InstituteChinese Academy of SciencesShanghai 201210China Legend Biotech China Nanjing 211112China Shanghai Immune Therapy Institute Shanghai Cancer InstituteState Key Laboratory of Oncogenes and Related GenesRenji Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai 200127China Wondercel Biotechnology Shenzhen 518052China

Ligand-induced receptor dimerization or oligomerization is a widespread mechanism for ensuring communication specificity,safeguarding receptor activation,and facilitating amplification of signal transduction across the cellular membrane.However,cell-surface antigeninduced multimerization(dubbed AIM herein)has not yet been consciously leveraged in chimeric antigen receptor(CAR)engineering for enriching T cell-based therapies.We co-developed ciltacabtagene autoleucel(cilta-cel),whose CAR incorporates two B-cell maturation antigen(BCMA)-targeted nanobodies in tandem,for treating multiple myeloma.Here we elucidated a structural and functional model in which BCMA-induced cilta-cel CAR multimerization amplifies myeloma-targeted T cell-mediated cytotoxicity.Crystallographic analysis of BCMA–nanobody complexes revealed atomic details of antigen–antibody hetero-multimerization whilst analytical ultracentrifugation and small-angle X-ray scattering characterized interdependent BCMA apposition and CAR juxtaposition in solution.BCMA-induced nanobody CAR multimerization enhanced cytotoxicity,alongside elevated immune synapse formation and cytotoxicity-mediating cytokine release,towards myeloma-derived cells.Our results provide a framework for contemplating the AIM approach in designing next-generation CARs.

关键词： cytotoxicity Antigen elevated

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Elemene Antitumor Drugs Development Based on "Molecular Compatibility Theory" and Clinical Application: A Retrospective and Prospective Outlook

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Chinese Journal of Integrative Medicine 2024年第1期30卷 62-74页

作者： JIANG xiao-ying SHI Li-ping zhu Jun-long BAI Ren-ren XIE Tian School of Pharmacy Hangzhou Normal UniversityHangzhou(311121)China Key Laboratory of Elemene Class Anti-cancer Chinese Medicines Engineering Laboratory of Development and Application of Traditional Chinese MedicinesCollaborative Innovation Center of Traditional Chinese Medicines of Zhejiang ProvinceHangzhou Normal UniversityHangzhou(311121)China Good Clinical Practice Center Affliliated Hospital of Nanjing University of Chinese MedicineNanjing(210000)China

Elemene, derived from Curcuma wenyujin, one of the "8 famous genuine medicinal materials of Zhejiang province," exhibits remarkable antitumor activity. It has gained wide recognition in clinical practice for effectiveness on tumors. Dr. XIE Tian introduced the innovative concept of "molecular compatibility theory" by combining Chinese medicine principles, specifically the "monarch, minister, assistant, and envoy" theory, with modern biomedical technology. This groundbreaking approach, along with a systematic analysis of Chinese medicine and modern biomedical knowledge, led to the development of elemene nanoliposome formulations. These novel formulations offer numerous advantages, including low toxicity, well-defined composition, synergistic effects on multiple targets, and excellent biocompatibility. Following the principles of the "molecular compatibility theory", further exploration of cancer treatment strategies and methods based on elemene was undertaken. This comprehensive review consolidates the current understanding of elemene's potential antitumor mechanisms, recent clinical investigations, advancements in drug delivery systems, and structural modifications. The ultimate goal of this review is to establish a solid theoretical foundation for researchers, empowering them to develop more effective antitumor drugs based on the principles of "molecular compatibility theory".

关键词： molecular compatibility theory Chinese integrative medicine elemene antitumor activity drug delivery structural modification

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Field-based evidence for the enrichment of intrinsic antibiotic resistome stimulated by plant-derived fertilizer in agricultural soil

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Journal of Environmental Sciences 2024年第1期135卷 728-740页

作者： Shihai Liu Ziming Han Dong zhu xiao Luan Liujie Deng Liping Dong Min Yang Yu Zhang State Key Laboratory of Environmental Aquatic Chemistry Research Center for Eco-Environmental SciencesChinese Academy of SciencesBeijing 100085China State Key Laboratory of Urban and Regional Ecology Research Center for Eco-Environmental SciencesChinese Academy of SciencesBeijing 100085China State Environmental Protection Engineering Center for Harmless Treatment and Resource Utilization of Antibiotic Residues Khorgos 835007China University of Chinese Academy of Sciences Beijing 100049China

Animal manures have been demonstrated to enhance antibiotic resistance in agricultural soils.However,little is known about the effects of plant-derived fertilizer on soil antibiotic resistome.Herein,metagenomic sequencing was used to investigate the effects of a plantderived fertilizer processed from sugarcane and beet on soil antibiotic resistance genes(ARGs)in a soybean field along crop growth stages.ARG profiles in the soils amended by plant-derived fertilizer were compared with those in the soils amended by chicken manure.The abundance and diversity of total ARGs in the soils amended by plant-derived fertilizer were significantly(P<0.05)elevated at the sprout stage,to a level comparable to that in the manured soils.Whereas,unlike chicken manure mainly introducing manure-borne ARGs to soil,the plant-derived fertilizer was indicated to mainly enrich multidrug resistance genes in soil by nourishing indigenous bacteria.ARGs with abundances in amended soils significantly(P<0.05)higher than in unamended soils at the sprout stage of soybean were considered as enriched ARGs.Decrease in the abundance of the enriched ARGs was observed in both the amended soils from the sprout to the harvest.Network analysis further identified Proteobacteria and Bacteroidetes as the primary bacterial taxa involved in the temporal variation of the enriched ARGs in the soils amended by plant-derived fertilizer,while in manured soils were Firmicutes and Actinobacteria.As revealed by multivariate statistical analyses,variation of the enriched ARGs in the soils amended by plant-derived fertilizer was majorly attributed to the response of co-occurred bacteria to depleting nutrients,which was different from the failed establishment of manure-borne bacteria in the manured soils.Our study provided field-based evidence that plant-derived fertilizer stimulated the intrinsic antibiotic resistome,and proposed attention to the un-perceived risk since some clinically relevant ARGs originate and evolve from natural resistome.

关键词： Organic fertilizer Intrinsic antibiotic resistance Indigenous bacteria Metagenomic sequencing

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Rbm8a regulates neurogenesis and reduces Alzheimer's disease-associated pathology in the dentate gyrus of 5×FAD mice

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Neural Regeneration Research 2024年第4期19卷 863-871页

作者： Chenlu zhu xiao Ren Chen Liu Yawei Liu Yonggang Wang Department of Neurology Lanzhou University Second Hospital Department of Neurology The First Affiliated Hospital of Nanchang University Department of Neurology Xiaogan City Central Hospital Health Service Department of the Guard Bureau of the General Office of the Central Committee of the Communist Party of China Headache Center Department of NeurologyBeijing Tiantan HospitalCapital Medical University

Alzheimer’s disease is a prevalent and debilitating neurodegenerative condition that profoundly affects a patient’s daily functioning with progressive cognitive decline,which can be partly attributed to impaired hippocampal neurogenesis.Neurogenesis in the hippocampal dentate gyrus is likely to persist throughout life but declines with aging,especially in Alzheimer’s disease.Recent evidence indicated that RNA-binding protein 8A(Rbm8a)promotes the proliferation of neural progenitor cells,with lower expression levels observed in Alzheimer’s disease patients compared with healthy people.This study investigated the hypothesis that Rbm8a overexpression may enhance neurogenesis by promoting the proliferation of neural progenitor cells to improve memory impairment in Alzheimer’s disease.Therefore,Rbm8a overexpression was induced in the dentate gyrus of 5×FAD mice to validate this hypothesis.Elevated Rbm8a levels in the dentate gyrus triggered neurogenesis and abated pathological phenotypes(such as plaque formation,gliosis reaction,and dystrophic neurites),leading to ameliorated memory performance in 5×FAD mice.RNA sequencing data further substantiated these findings,showing the enrichment of differentially expressed genes involved in biological processes including neurogenesis,cell proliferation,and amyloid protein formation.In conclusion,overexpressing Rbm8a in the dentate gyrus of 5×FAD mouse brains improved cognitive function by ameliorating amyloid-beta-associated pathological phenotypes and enhancing neurogenesis.

关键词： Adora2a Alzheimer’s disease astrocyte cAMP signaling pathway dentate gyrus dystrophic neurites microglia neurogenesis plaque Rbm8a

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Advances in sodium-ion batteries at low-temperature: Challenges and strategies

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Journal of Energy Chemistry 2024年第3期90卷 518-539,I0012页

作者： Haoran Bai xiaohui zhu Huaisheng Ao Guangyu He Hai xiao Yinjuan Chen Key Laboratory of Advanced Catalytic Materials and Technology Advanced Catalysis and Green Manufacturing Collaborative Innovation CenterChangzhou UniversityChangzhou 213164JiangsuChina Department of Chemistry Tsinghua UniversityBeijing 100084China

With the continuing boost in the demand for energy storage,there is an increasing requirement for batteries to be capable of operation in extreme environmental conditions.Sodium-ion batteries(SIBs) have emerged as a highly promising energy storage solution due to their promising performance over a wide range of temperatures and the abundance of sodium resources in the earth's crust.Compared to lithiumion batteries(LIBs),although sodium ions possess a larger ionic radius,they are more easily desolvated than lithium ions.Fu rthermore,SIBs have a smaller Stokes radius than lithium ions,resulting in improved sodium-ion mobility in the electrolyte.Nevertheless,SIBs demonstrate a significant decrease in performance at low temperatures(LT),which constrains their operation in harsh weather conditions.Despite the increasing interest in SIBs,there is a notable scarcity of research focusing specifically on their mechanism under LT conditions.This review explores recent research that considers the thermal tolerance of SIBs from an inner chemistry process perspective,spanning a wide temperature spectrum(-70 to100℃),particularly at LT conditions.In addition,the enhancement of electrochemical performance in LT SIBs is based on improvements in reaction kinetics and cycling stability achieved through the utilization of effective electrode materials and electrolyte components.Furthermore,the safety concerns associated with SIBs are addressed and effective strategies are proposed for mitigating these issues.Finally,prospects conducted to extend the environmental frontiers of commercial SIBs are discussed mainly from three viewpoints including innovations in materials,development and research of relevant theoretical mechanisms,and intelligent safety management system establishment for larger-scale energy storage SIBs.

关键词： Low-temperature Sodium-ion batteries Reaction kinetics Cycle stability Safety concerns of Sodium-ion batteries

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Controlling secondary flow in high-lift low-pressure turbine using boundary-layer slot suction

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Chinese Journal of Aeronautics 2024年第3期37卷 21-33页

作者： xiao QU Liunan LI Yingjie ZHANG Xingen LU Junqiang zhu Yanfeng ZHANG School of Mechanical Engineering Beijing Institute of TechnologyBeijing 100081China Key Laboratory of Light-Duty Gas-Turbine Institute of Engineering ThermophysicsChinese Academy of SciencesBeijing 100190China School of Aeronautics and Astronautics University of Chinese Academy of SciencesBeijing 100190China

The design of high-lift Low-Pressure Turbines(LPTs)causes the separation of the boundary layer on the suction side of the blade and leads to a strong secondary flow.This present study aims to minimize secondary losses through endwall slot suction and incoming wakes in a front-loaded high-lift LPT cascade with Zweifel of 1.58 under low Reynolds number of 25000.Two slotted schemes for the boundary layer of the endwall were designed(Plan A and Plan B),and the effects of suction mass flow on secondary flow were studied.The underlying physics of the endwall boundary layer of the suction and secondary flow under unsteady wakes was discussed.The results show that slot suction at the endwall boundary layer can significantly suppress the secondary flow by removing low-momentum fluids.Plans A and B significantly reduced the secondary kinetic energy by 44.2%and 36.9%,respectively,compared with the baseline cascade at the suction mass flow ratios of 1%.With an increase in the mass flow ratio of suction,the secondary flow was gradually reduced in both Plans A and B.It is more beneficial to control the secondary flow to destroy the intersection of the pressure side and suction side of the horseshoe vortex before it develops into a passage vortex.Under unsteady wakes,the combined effects of incoming wakes and endwall boundary layer suction can further suppress the secondary flow at the suction mass flow ratios of 2%for Plan A,because the positive and negative vorticity inside upstream wakes accelerated the mixing of the main flow and secondary flow and thus increased the energy of secondary vortices.

关键词： Low-pressure turbine Secondary flow Flow control Boundary-layer suction Incoming wake

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Unconventional Fluorescent and Multi-responsive Polysiloxane:Synthesis,Characterization and Biological Applications

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Chinese Journal of Polymer Science 2024年第5期42卷 579-590,I0006页

作者： xiao-Di Li Shu-Sheng Li Xu-Bao Jiang xiao-Li zhu Xiang Zheng Kong College of Chemistry and Chemical Engineering University of JinanJinan250022China College of Chemical Engineering Tianjin UniversityTianjin300072China Foshan(Southern China)Institute for New Materials Foshan528200China

Owing to their high significance in fundamental study and diverse applications,stimuli-responsive and fluorescent polymers,particularly those with cluster-triggered emission(CTE)featured by non-conjugated chromophores,have drawn tremendous attention in recent years.In this work,fluorescent and multi-responsive polysiloxane(FRPS)was synthesized by hydrolytic condensation polymerization of 3-aminopropyl methyl diethoxysilane(APMS)with 3-(N-isopropyl propionamide)iminopropyl methyl diethoxysilane(APMS-NIP),which was formed in situ through aza-Michael addition between APMS and N-isopropyl acrylamide.FRPS was not only highly sensitive to temperature,pH and CO_(2) in water,but also showed an enhanced and stimuli-adjustable fluorescence emission.The effects of monomer feeding,pH and CO_(2) on its lower critical solution temperature and fluorescent property were investigated.FRPS fluorescence emission was ascribed to CTE mechanism.In addition,FRPS was shown to be highly potential as physiological indicator for cell imaging,and for controlled release and trace detection of doxorubicin.This study provides therefore a type of stimuli-responsive and fluorescent material for potential applications in biomedical fields,and it is also of great significance for understanding of the fluorescence mechanism of polysiloxane-based stimuli-responsive polymers.

关键词： Polysiloxane Multi-responsiveness Cluster-triggered emission Cell imaging Controlled drug release

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Paleoenvironmental reconstruction and organic matter accumulation of the paleogene shahejie oil shale in the Zhanhua Sag, Bohai Bay Basin, Eastern China

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Petroleum Science 2024年第3期21卷 1552-1568页

作者： xiao-Lin Wang xiao-Min zhu Jin Lai Xing-Yue Lin Xiang Wang Yu-Shan Du Chao Huang Yu-Rui zhu State Key Laboratory of Petroleum Resources and Engineering China University of Petroleum (Beijing) College of Geosciences China University of Petroleum (Beijing) Shengli Oilfield SINOPEC

The controlling factors of organic-rich shale accumulation is essential for the exploration and development of shale oil and gas resources. The sedimentary environment plays a vital role in the formation of organic-rich sediments in lacustrine facies. This article unravels the mineralogy, geochemistry, and paleoenvironmental evolution during the deposition of the Paleogene Shahejie Formation(Es3L). It discusses the effects of paleoclimate, paleosalinity, paleoredox conditions, paleowater depth, and paleoproductivity on organic matter(OM) enrichment. Finally, the OM enrichment model was established. The results show that the mineralogical compositions are mainly composed of calcite(avg. 40.13%), quartz(avg. 21.64%) and clay minerals(avg. 24.07%), accompanied by dolomite(avg. 7.07%), feldspar(avg. 6.36%)and pyrite(avg. 2.95%). The Es3Lshale has a high abundance of OM, with total organic carbon(TOC)ranging from 1.07% to 5.12%. The organic matter type is mainly composed of type I-II1kerogen, which is generally considered a good-quality source rock. The source of OM is a mixture of lower bacteria, algae,and plants. During the early sedimentary period, the paleoclimate was dry and cold, with high salinity,intense reducibility, and relatively low productivity. During the late sedimentary period, the climate became warmer and more humid. As a result, the salinity decreased to a level that was suitable for biological reproduction, and productivity increased gradually due to the input of terrigenous plants.Paleosalinity and paleoclimate determined the environment of the sedimentary period, in addition,paleoproductivity and paleoredox condition indicated the formation and preservation conditions of OM.The warm and humid climate, brackish water, suitable reduction conditions and high productivity are the favorable conditions for the generation and preservation of organic matter. The research results may have implications for the genetic mechanisms of organic matter accumulation. They will provide theoretical and technical in

关键词： Elemental geochemical Paleoenvironment Organic matter accumulation Paleogene shahejie formation Zhanhua Sag Bohai Bay Basin

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Surgically treating a rare and asymptomatic intraductal papillary neoplasm of the bile duct:A case report

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World Journal of Clinical Cases 2024年第2期12卷 367-373页

作者： Shen-Zhen zhu Zhao-Feng Gao xiao-Rong Liu xiao-Guang Wang Fei Chen Department of General Surgery Jiaxing Second HospitalJiaxing 314000Zhejiang ProvinceChina Department of Hepatobiliary Surgery Jiaxing Second HospitalJiaxing 314000Zhejiang ProvinceChina

BACKGROUND Intraductal papillary neoplasms of the bile duct(IPNBs)are rare and characterized by papillary growth within the bile duct lumen.IPNB is similar to obstructive biliary pathology.In this report,we present an unexpected case of asymptomatic IPNB and consolidate our findings with the relevant literature to augment our understanding of this condition.Integrating relevant literature contributes to a more comprehensive understanding of the disease.CASE SUMMARY A 66-year-old Chinese male patient was admitted to our hospital for surgical intervention after gallstones were discovered during a routine physical examination.Preoperative imaging revealed a lesion on the left side of the liver,which raised the suspicion of IPNB.A laparoscopic left hemihepatectomy was performed,and subsequent histopathological examination confirmed the diagnosis of IPNB.At the 3-mo postoperative follow-up,the patient reported good recovery and no metastasis.IPNB can manifest both latently and asymptomatically.Radical surgical resection is the most effective treatment for IPNB.CONCLUSION Hepatic and biliary masses,should be considered to diagnose IPNB.Prompt surgery and vigilant follow-up are crucial in determining prognosis.

关键词： Intraductal papillary neoplasm of the bile duct Tumor Surgical treatment Prognosis Case report

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Hepatocyte growth factor promotes retinal pigment epithelium cell activity through MET/AKT signaling pathway

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International Journal of Ophthalmology(English edition) 2024年第5期17卷 806-814页

作者： Si-Rui Zhou Yu-Sheng zhu Wen-Ting Yuan xiao-Yan Pan Tong Wang xiao-Dong Chen Faculty of Life Sciences and Medicine Northwest UniversityXi’an 710069Shaanxi ProvinceChina First Affiliated Hospital of Northwest University Northwest UniversityXi’an 710069Shaanxi ProvinceChina Department of Ophthalmology Xi’an No.1 HospitalXi’an 710002Shaanxi ProvinceChina Shaanxi Institute of Ophthalmology Shaanxi Provincial Key Lab of OphthalmologyClinical Research Center for Ophthalmology Diseases of Shaanxi ProvinceXi’an 710002Shaanxi ProvinceChina

AIM:To explore the effects of hepatocyte growth factor(HGF)on retinal pigment epithelium(RPE)cell behaviors.METHODS:The human adult retinal pigment epithelial cell line-19(ARPE-19)were treated by HGF or mesenchymalepithelial transition factor(MET)inhibitor SU11274 in vitro.Cell viability was detected by a Cell Counting Kit-8 assay.Cell proliferation and motility was detected by a bromodeoxyuridine incorporation assay and a wound healing assay,respectively.The expression levels of MET,phosphorylated MET,protein kinase B(AKT),and phosphorylated AKT proteins were determined by Western blot assay.The MET and phosphorylated MET proteins were also determined by immunofluorescence assay.RESULTS:HGF increased ARPE-19 cells’viability,proliferation and migration,and induced an increase of phosphorylated MET and phosphorylated AKT proteins.SU11274 significantly reduced cell viability,proliferation,and migration and decreased the expression of MET and AKT proteins.SU11274 suppressed HGF-induced increase of viability,proliferation,and migration in ARPE-19 cells.Additionally,SU11274 also blocked HGF-induced phosphorylation of MET and AKT proteins.CONCLUSION:HGF enhances cellular viability,proliferation,and migration in RPE cells through the MET/AKT signaling pathway,whereas this enhancement is suppressed by the MET inhibitor SU11274.HGF-induced MET/AKT signaling might be a vital contributor of RPE cells survival.

关键词： hepatocyte growth factor mesenchymal epithelial transition factor SU11274 retinal pigment epithelial cells

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