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Tumor-derived exosomes induce initial activation by exosomal CD19 antigen but impair the function of CD19-specific CAR T-cells via TGF-βsignaling

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Frontiers of medicine 2024年第1期18卷 128-146页

作者： Yuanyuan Hao Panpan Chen Shanshan Guo Mengyuan Li Xueli Jin Minghuan Zhang Wenhai Deng Ping Li Wen Lei Aibin Liang Wenbin Qian Department of Hematology The Second Affiliated HospitalCollege of MedicineZhejiang UniversityHangzhou310009China Department of Hematology Henan Provincial People’s HospitalZhengzhou University People’s HospitalZhengzhou450003China key laboratory of laboratory medicine Ministry of EducationSchool of Laboratory Medicine and Life SciencesWenzhou Medical UniversityWenzhou325000China Department of Hematology Tongji Hospital of Tongji UniversityShanghai200065China

Tumor-derived exosomes (TEXs) enriched in immune suppressive molecules predominantly drive T-cell dysfunction and impair antitumor immunity. Chimeric antigen receptor (CAR) T-cell therapy has emerged as a promising treatment for refractory and relapsed hematological malignancies, but whether lymphoma TEXs have the same impact on CAR T-cell remains unclear. Here, we demonstrated that B-cell lymphoma-derived exosomes induce the initial activation of CD19-CAR T-cells upon stimulation with exosomal CD19. However, lymphoma TEXs might subsequently induce CAR T-cell apoptosis and impair the tumor cytotoxicity of the cells because of the upregulated expression of the inhibitory receptors PD-1, TIM3, and LAG3 upon prolonged exposure. Similar results were observed in the CAR T-cells exposed to plasma exosomes from patients with lymphoma. More importantly, single-cell RNA sequencing revealed that CAR T-cells typically showed differentiated phenotypes and regulatory T-cell (Treg) phenotype conversion. By blocking transforming growth factor β (TGF-β)-Smad3 signaling with TGF-β inhibitor LY2109761, the negative effects of TEXs on Treg conversion, terminal differentiation, and immune checkpoint expression were rescued. Collectively, although TEXs lead to the initial activation of CAR T-cells, the effect of TEXs suppressed CAR T-cells, which can be rescued by LY2109761. A treatment regimen combining CAR T-cell therapy and TGF-β inhibitors might be a novel therapeutic strategy for refractory and relapsed B-cell lymphoma.

关键词： tumor-derived exosome chimeric antigen receptor T-cell lymphoma TGF-β

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Lactate regulates major zygotic genome activation by H3K18 lactylation in mammals

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National Science Review 2024年第2期11卷 124-134页

作者： Jingyu Li Weibo Hou Qi Zhao Wei Han Hongdi Cui Songling Xiao Ling Zhu Jiadan Qu Xiaoyu Liu Weitao Cong Jingling Shen Yuzheng Zhao Shaorong Gao Guoning Huang Qingran Kong Chongqing key laboratory of Human Embryo Engineering Center for Reproductive Medicine Chongqing Health Center for Women and ChildrenWomen and Children's Hospital of Chongqing Medical University Oujiang laboratory Zhejiang Provincial Key Laboratory of Medical Genetics Key Laboratory of Laboratory MedicineMinistry of EducationSchool of Laboratory Medicine and Life Sciences Wenzhou Medical University Frontier Science Center for Stem Cell Research School of Life Sciences and Technology Tongji University School of Pharmaceutical Science Wenzhou Medical University Institute of Life Sciences College of Life and Environmental Sciences Wenzhou University Optogenetics&Synthetic Biology Interdisciplinary Research Center State Key Laboratory of Bioreactor Engineering Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism School of Pharmacy East China University of Science and Technology

Lactate is present at a high level in the microenvironment of mammalian preimplantation embryos in vivo and in vitro. However, its role in preimplantation development is unclear. Here, we report that lactate is highly enriched in the nuclei of early embryos when major zygotic genome activation(ZGA) occurs in humans and mice. The inhibition of its production and uptake results in developmental arrest at the 2-cell stage, major ZGA failure, and loss of lactate-derived H3K18lac, which could be rescued by the addition of Lac-Co A and recapitulated by overexpression of H3K18R mutation. By profiling the landscape of H3K18lac during mouse preimplantation development, we show that H3K18lac is enriched on the promoter regions of most major ZGA genes and correlates with their expressions. In humans, H3K18lac is also enriched in ZGA markers and temporally concomitant with their expressions. Taken together, we profile the landscapes of H3K18lac in mouse and human preimplantation embryos, and demonstrate the important role for H3K18lac in major ZGA, showing that a conserved metabolic mechanism underlies preimplantation development of mammalian embryos.

关键词： mammalian preimplantation development lactate epigenetic remodeling histone lactylation zygotic genome activation

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Intermittent fasting boosts antitumor immunity by restricting CD11b^(+)Ly6C^(low)Ly6G^(low) cell viability through glucose metabolism in murine breast tumor model

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Food Science and Human Wellness 2024年第4期13卷 2327-2345页

作者： Chenghao Fu Zhehao Liang Zemiao Niu Ning Chen Yuemin Li Zhenhua Liang Yanwei Huo Hao Xi Rong Wang Yonghuan Yan Xiaoruo Gan Mengtian Wang Yun Huang Yan Zhang Mingming Gao Pin Lü Postdoctoral Station for Basic medicine Cardiovascular Medical Science CenterDepartment of Cell BiologyKey Laboratory of Neural and Vascular Biology of Ministry of EducationHebei Medical UniversityShijiazhuang 050017China Hebei key laboratory of Forensic medicine College of Forensic MedicineHebei Medical UniversityShijiazhuang 050017China Hebei Food Safety key laboratory Hebei Food Inspection and Research InstituteShijiazhuang 050091China laboratory of Lipid Metabolism Department of Biochemistry and Molecular BiologyKey Laboratory of Medical Biotechnology of Hebei ProvinceShijiazhuang 050017China

Intermittent fasting can benefit breast cancer patients undergoing chemotherapy or immunotherapy.However,it is still uncertain how to select immunotherapy drugs to combine with intermittent fasting.Herein we observed that two cycles of fasting treatment significantly inhibited breast tumor growth and lung tissue metastasis,as well as prolonged overall survival in mice bearing 4T1 and 4T07 breast cancer.During this process,both the immunosuppressive monocytic-(M-)and granulocytic-(G-)myeloid-derived suppressor cell(MDSC)decreased,accompanied by an increase in interleukin(IL)7R^(+)and granzyme B^(+)T cells in the tumor microenvironment.Interestingly,we observed that Ly6G^(low)G-MDSC sharply decreased after fasting treatment,and the cell surface markers and protein mass spectrometry data showed potential therapeutic targets.Mechanistic investigation revealed that glucose metabolism restriction suppressed the splenic granulocytemonocyte progenitor and the generation of colony-stimulating factors and IL-6,which both contributed to the accumulation of G-MDSC.On the other hand,glucose metabolism restriction can directly induce the apoptosis of Ly6G^(low)G-MDSC,but not Ly6G^(high)subsets.In summary,these results suggest that glucose metabolism restriction induced by fasting treatment attenuates the immune-suppressive milieu and enhances the activation of CD3^(+)T cells,providing potential solutions for enhancing immune-based cancer interventions.

关键词： Intermittent fasting Ly6G^(low)myeloid-derived suppressor cell apoptosis Extramedullary hematopoiesis Colony stimulating factor Glucose metabolism restriction

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Asymmetric Two-Component Alkenyl Catellani Reaction for the Construction of C—N Axial Chirality

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Chinese Journal of Chemistry 2024年第7期42卷 699-704页

作者： Chenggui Wu Ze-Shui Liu Yong Shang Chang Liu Shuang Deng Hong-Gang Cheng Hengjiang Cong Yinchun Jiao Qianghui Zhou Sauvage Center for Molecular Sciences Engineering Research Center of Organosilicon Compounds&Materials(Ministry of Education)Hubei Key Lab on Organic and Polymeric OptoElectronic MaterialsCollege of Chemistry and Molecular SciencesThe Institute for Advanced Studiesand TaiKang Center for Life and Medical SciencesWuhan UniversityWuhanHubei 430072China key laboratory of Xin'an medicine Ministry of EducationAnhui University of Chinese MedicineHefeiAnhui 230038China School of Chemistry and Chemical Engineering Hunan University of Science and TechnologyXiangtanHunan 411201China

Herein,we report an asymmetric two-component alkenyl Catellani reaction for the construction of C—N axial chirality through a palladium/chiral norbornene cooperative catalysis and an axial-to-axial chirality transfer process.Various partially aromatic iodinated 2-pyridones,quinolones,coumarin and uracil substrates react with 2,6-disubstituted aryl bromides with a tethered amide group,to afford a wide variety of polycyclic C—N atropisomers(38 examples,up to 97%e.e.).The obtained C—N axial chirality originates from the preformed transient C—C axial chirality with high fidelity.The synthetic utility of this chemistry is demonstrated by facile prepa-ration of complex quinoline and pyridine based C—N atropisomers through a N-deprotection and aromatization sequence.In addi-tion,a remote axial-to-central diastereoinduction process dictated by C—N axial chirality is observed with excellent diastereocontrol.

关键词： Alkenyl Catellani reaction Asymmetric catalysis Atropisomerism Axial-to-axial chirality transfer Heterocycles

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Perspective and challenges of mycorrhizal symbiosis in orchid medicinal plants

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Chinese Herbal medicines 2024年第2期16卷 172-179页

作者： Chunyan Leng Mengyan Hou Yongmei Xing Juan Chen key laboratory of Bioactive Substances and Resource Utilization of Chinese Herbal medicine Ministry of EducationInstitute of Medicinal Plant DevelopmentChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100193China

The family Orchidaceae is of the most diverse taxon in the plant kingdom,and most of its members are highly valuable herbal medicines.Orchids have a unique mycorrhizal symbiotic relationship with specific fungi for carbohydrate and nutrient supplies in their whole lifecycle.The large-scale cultivation of the medicinal plant Gastodia elata is a successful example of using mycorrhizal symbiotic technology.In this review,we adopted G.elata and Dendrobium officinale as examples to describe the characteristics of orchid mycorrhiza and mycorrhizal benefits for host plants’growth and health(e.***.biotic and abiotic stress and secondary metabolite accumulation).The challenges in applying mycorrhizal technology to the cultivation of orchid medicinal plants in the future were also discussed.This review aims to serve as a theoretical guide for the cultivation of mycorrhizal technology in medicinal orchid plants.

关键词： Dendrobium officinale Kimura&Migo ecological cultivation Gastodia elata Blume mycorrhiza orchid medicinal plants symbiosis mechanisms

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MIL-100(V) derived porous vanadium oxide/carbon microspheres with oxygen defects and intercalated water molecules as high-performance cathode for aqueous zinc ion battery

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Journal of Energy Chemistry 2024年第3期90卷 578-589,I0013页

作者： Yuexin Liu Jian Huang Xiaoyu Li Jiajia Li Jinhu Yang Kefeng Cai Shanghai key laboratory of Development and Application for Metal-Functional Materials Key Laboratory of Advanced Civil Engineering MaterialsMinistry of EducationSchool of Materials Science&EngineeringTongji UniversityShanghai 201804China State key laboratory of High Performance Ceramics and Superfine Microstructure Shanghai Institute of CeramicsChinese Academy of SciencesShanghai 201800China Research Center for Translational medicine East HospitalTongji University School of MedicineShanghai 200092China

The development of aqueous zinc ion battery cathode materials with high capacity and high magnification is still a challenge.Herein,porous vanadium oxide/carbon(p-VO_(x)@C,mainly VO_(2) with a small amount of V_(2)O_(3)) core/shell microspheres with oxygen vacancies are facilely fabricated by using a vanadium-based metal-organic framework(MIL-100(V)) as a sacrificial template.This unique structure can improve the conductivity of the VO_(x),accelerate electrolyte diffusion,and suppress structural collapse during circulation.Subsequently,H_(2)O molecules are introduced into the interlayer of VO_(x) through a highly efficient in-situ electrochemical activation process,facilitating the intercalation and diffusion of zinc ions.After the activation,an optimal sample exhibits a high specific capacity of 464.3 mA h g^(-1) at0.2 A g^(-1) and 395.2 mA h g^(-1) at 10 A g^(-1),indicating excellent rate performance.Moreover,the optimal sample maintains a capacity retention of about 89.3% after 2500 cycles at 10 A g^(-1).Density functional theory calculation demonstrates that the presence of oxygen vacancies and intercalated water molecules can significantly reduce the diffusion barrier for zinc ions.In addition,it is proved that the storage of zinc ions in the cathode is achieved by reversible intercalation/extraction during the charge and discharge process through various ex-situ analysis technologies.This work demonstrates that the p-VO_(x)@C has great potential for applications in aqueous ZIBs after electrochemical activation.

关键词： Metal-organic frameworks Vanadium oxide Carbon Zn-ion batteries Electrochemical activation

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CHIT1-positive microglia act as culprits for spinal motor neuron aging

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Science China(Life Sciences) 2024年第4期67卷 847-848页

作者： Zhao Wang Wantong Cai Weihong Song Oujiang laboratory(Zhejiang Lab for regenerative medicine Vision and Brain Health)Institute of AgingKey Laboratory of Alzheimer’s Disease of Zhejiang ProvinceThe Second Affiliated HospitalWenzhou Medical UniversityWenzhou 325035China

Aging is one of the primary factors in spinal cord-associated disorders(Roberts,1990).However,the effects of aging on the spinal cord and the age-specific mechanisms underlying this relationship remain unclear.Motor n... 详细信息

关键词： aging Roberts positive

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A rapid and visual detection method for Crimean-Congo hemorrhagic fever virus by targeting S gene

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Journal of Integrative Agriculture 2024年第6期23卷 2149-2153页

作者： Xingqi Liu Zengguo Cao Boyi Li Pei Huang Yujie Bai Jingbo Huang Zanheng Huang Yuanyuan Zhang Yuanyuan Li Haili Zhang Hualei Wang State key laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases/key laboratory for Zoonosis Research of the ministry of education Institute of ZoonosisCollege of Veterinary MedicineJilin UniversityChangchun 130062China key laboratory of Special Pathogens and Biosafety Wuhan Institute of VirologyCenter for Biosafety Mega-ScienceChinese Academy of SciencesWuhan 430071China

Crimean-Congo hemorrhagic fever(CCHF)is a zoonotic disease caused by the CCHF virus(CCHFV),which is primarily transmitted by ticks(Lorenzo Juanes et al.2023).It is an emerging disease that occurs sporadically in Africa,Asia,and Europe,with a high morbidity and mortality rate,as high as 30%in humans(Ceylan et al.2013).CCHFV,belonging to genus Nairovirus,family Bunyaviridae,was first identified in the Congo in the 1960s.

关键词： hemorrhagic al. fever

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Ultratough Yet Dynamic Crystalline Poly(thiourethane)Network Directly from Low Viscosity Precursors

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CCS Chemistry 2024年第3期6卷 682-692页

作者： Haijun Feng Yi Sheng Guancong Chen Binjie Jin Zizheng Fang Bo Yang Xiaorui Zhou Wenxuan Wu Tao Xie Ning Zheng State key laboratory of Chemical Engineering College of Chemical and Biological EngineeringZhejiang UniversityHangzhou 310058 Department of Colorectal Surgery and Oncology Key Laboratory of Cancer Prevention and InterventionMinistry of EducationThe Second Affiliated HospitalZhejiang University School of MedicineHangzhou 310027

Thermosets based on direct curing of multifunctional monomers offer processing flexibility that thermoplastics cannot provide.However,this type of thermoset is typically amorphous since it is difficult to meet the stringent requirement of long-range molecular regularity for crystallization.However,we report here a crystallizable poly(thiourethane)thermoset synthesized directly from the curing of low-viscosity liquid precursors that does not employ any solvent.Its crystalline nature results in superior toughness,comparable to commercial high-density polyethylene,in sharp contrast to the brittleness of the typical,rigid,glassy thermoset materials.Beyond that,the network polymer exhibits shape-memory behavior in which the crystalline transition is utilized for temporary shape fixing/recovery whereas the dynamic thiourethane bonds can be activated for bond exchange as a mechanism for complex shape manipulation.Materials with these combined features represent attractive options for demanding engineering applications due to their high performance and multifunctinality.

关键词： thermosets crystalline polymer thiourethane thermadapt

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The combined application of stem cells and three-dimensional bioprinting scaffolds for the repair of spinal cord injury

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Neural Regeneration Research 2024年第8期19卷 1751-1758页

作者： Dingyue Ju Chuanming Dong Department of Anatomy Medical College of Nantong UniversityNantongJiangsu ProvinceChina key laboratory of Neuroregeneration of Jiangsu and ministry of education Co-innovation Center of NeuroregenerationNantong UniversityNantongJiangsu ProvinceChina

Spinal cord injury is considered one of the most difficult injuries to repair and has one of the worst prognoses for injuries to the nervous system.Following surgery,the poor regenerative capacity of nerve cells and the generation of new scars can make it very difficult for the impaired nervous system to restore its neural functionality.Traditional treatments can only alleviate secondary injuries but cannot fundamentally repair the spinal cord.Consequently,there is a critical need to develop new treatments to promote functional repair after spinal cord injury.Over recent years,there have been seve ral developments in the use of stem cell therapy for the treatment of spinal cord injury.Alongside significant developments in the field of tissue engineering,three-dimensional bioprinting technology has become a hot research topic due to its ability to accurately print complex structures.This led to the loading of three-dimensional bioprinting scaffolds which provided precise cell localization.These three-dimensional bioprinting scaffolds co uld repair damaged neural circuits and had the potential to repair the damaged spinal cord.In this review,we discuss the mechanisms underlying simple stem cell therapy,the application of different types of stem cells for the treatment of spinal cord injury,and the different manufa cturing methods for three-dimensional bioprinting scaffolds.In particular,we focus on the development of three-dimensional bioprinting scaffolds for the treatment of spinal cord injury.

关键词： biomaterials embryonic stem cells induced pluripotent stem cells mesenchymal stem cells nerve regeneration spinal cord injury stem cell therapy stem cells three-dimensional bioprinting

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