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Cobalamin-dependent radical S-adenosyl-L-methionine protein functions with a partner to successively methylate tricyclic indole alkaloid for chuangxinmycin maturation and derivatization

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Science China Chemistry 2025年第1期 308-316页

作者： Sili Wang Jiancheng Huang Yanan Du Wei Huang Yufeng xue Xiaokun Xu Guannan Zhong yuanyuan shi Bin Hong Xiaoying Bian wen Liu State Key Laboratory of Chemical Biology Shanghai Institute of Organic Chemistry University of Chinese Academy of SciencesChinese Academy of Sciences State Key Laboratory of Microbial Technology Shandong University National health Commission (NHC) Key Laboratory of Biotechnology for Microbial Drugs Institute of Medicinal BiotechnologyChinese Academy of Medical Science & Peking Union Medical College

Cobalamin(Cbl)-dependent radical S-adenosyl-L-methionine(SAM) proteins constitute the largest collection of the radical SAM superfamily that has hundreds of thousands of individual members. Many of these proteins are involved in the biosynthesis of pharmaceutically important natural products to catalyze chemically demanding reactions. In the biosynthetic pathway of chuangxinmycin(CXM), a unique indole alkaloid antibiotic with potent anti-infective activity, functionalization of the characteristic thiopyrano[4,3,2-cd]indole scaffold by regio-and stereoselective C3-methylation is believed to rely on a Cbl-dependent radical process, which, however, remained to be reconstituted biochemically. We here report the dissection of this enzymatic process, which requires the incorporation of Cxm8, a Cbl-dependent radical SAM protein, with Cxm9, a DUF5825family protein that shares no homology to any proteins of known functions. Cxm8 and Cxm9 function together by forming an unexpected heterodimeric complex that selectively catalyzes C3-methylation of the tricyclic indole-S-hetero ring system in a successive manner, achieving CXM and a recently identified, C3-dimethylated congener. Detailed biochemical characterization,isotope labeling, structural simulation and bioinformatics analysis rationalized the catalysis of the Cxm8/Cxm9 complex and particularly the necessity of the DUF5825 protein for C3-methylase activity. This is the first example that a Cbl-dependent protein acts with a partner to exhibit radical SAM activity.

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Drosophila models used to simulate human ATP1A1 gene mutations that cause Charcot-Marie-Tooth type 2 disease and refractory seizures

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Neural Regeneration Research 2025年第1期20卷 265-276页

作者： Yao yuan Lingqi Yu Xudong Zhuang Dongjing wen Jin he Jingmei Hong Jiayu Xie Shengan Ling Xiaoyue Du wenfeng Chen Xinrui Wang Institute of Life Sciences College of Biological Science and EngineeringFuzhou UniversityFuzhouFujian ProvinceChina NHC Key Laboratory of Technical Evaluation of Fertility Regulation for Non-human Primate(Fujian Maternity and Child health Hospital) FuzhouFujian ProvinceChina Medical Research Center Fujian Maternity and Child Health HospitalCollege of Clinical Medicine for Obstetrics&Gynecology and PediatricsFujian Medical UniversityFuzhouFujian ProvinceChina Department of Neurology and Institute of Neurology of The First Affiliated Hospital Institute of Neuroscienceand Fujian Key Laboratory of Molecular NeurologyFujian Medical UniversityFuzhouFujian ProvinceChina

Certain amino acids changes in the human Na^(+)/K^(+)-ATPase pump,ATPase Na^(+)/K^(+)transporting subunit alpha 1(ATP1A1),cause Charcot-Marie-Tooth disease type 2(CMT2)disease and refractory *** develop in vivo models to study the role of Na^(+)/K^(+)-ATPase in these diseases,we modified the Drosophila gene homolog,Atpα,to mimic the human ATP1A1 gene mutations that cause *** located within the helical linker region of human ATP1A1(I592T,A597T,P600T,and D601F)were simultaneously introduced into endogenous Drosophila Atpαby CRISPR/Cas9-mediated genome editing,generating the Atpα^(TTTF)*** addition,the same strategy was used to generate the corresponding single point mutations in flies(Atpα^(I571T),Atpα^(A576T),Atpα^(P579T),and Atpα^(D580F)).Moreover,a deletion mutation(Atpα^(mut))that causes premature termination of translation was generated as a positive *** these alleles,we found two that could be maintained as homozygotes(Atpα^(I571T)and Atpα^(P579T)).Three alleles(Atpα^(A576T),Atpα^(P579)and Atpα^(D580F))can form heterozygotes with the Atpαmut *** found that the Atpαallele carrying these CMT2-associated mutations showed differential phenotypes in *** heterozygous for Atpα^(TTTF)mutations have motor performance defects,a reduced lifespan,seizures,and an abnormal neuronal *** Drosophila models will provide a new platform for studying the function and regulation of the sodium-potassium pump.

关键词： ATP1A1 Atpα bang-sensitive paralysis Charcot-Marie-Tooth disease type 2 CRISPR/Cas9 homology-directed repair Na^(+)/K^(+)-ATPase point mutation seizures sodium pump

3D Printing of Tough Hydrogel Scaffolds with Functional Surface Structures for Tissue Regeneration

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Nano-Micro Letters 2025年第2期17卷 18-45页

作者： Ke Yao Gaoying Hong Ximin yuan Weicheng Kong Pengcheng Xia yuanrong Li Yuewei Chen Nian Liu Jing he Jue shi Zihe Hu Yanyan Zhou Zhijian Xie Yong he State Key Laboratory of Fluid Power and Mechatronic Systems School of Mechanical EngineeringZhejiang UniversityHangzhou 310027People’s Republic of China Liangzhu Laboratory Zhejiang UniversityHangzhou 310027People’s Republic of China Key Laboratory of 3D Printing Process and Equipment of Zhejiang Province College of Mechanical EngineeringZhejiang UniversityHangzhou 310027People’s Republic of China Stomatology Hospital School of StomatologyZhejiang University School of MedicineHangzhou 310027People’s Republic of China State Key Laboratory of Advanced Welding and Joining Harbin Institute of TechnologyHarbin 150001People’s Republic of China Institute of Digital Medicine Nanjing First HospitalNanjing Medical UniversityNanjing 210006People’s Republic of China

Hydrogel scaffolds have numerous potential applications in the tissue engineering ***,tough hydrogel scaffolds implanted in vivo are seldom reported because it is difficult to balance biocompatibility and high mechanical *** by Chinese ramen,we propose a universal fabricating method(printing-P,training-T,cross-linking-C,PTC&PCT)for tough hydrogel scaffolds to fill this ***,3D printing fabricates a hydrogel scaffold with desired structures(P).Then,the scaffold could have extraordinarily high mechanical properties and functional surface structure by cycle mechanical training with salting-out assistance(T).Finally,the training results are fixed by photo-cross-linking processing(C).The tough gelatin hydrogel scaffolds exhibit excellent tensile strength of 6.66 MPa(622-fold untreated)and have excellent ***,this scaffold possesses functional surface structures from nanometer to micron to millimeter,which can efficiently induce directional cell ***,this strategy can produce bionic human tissue with mechanical properties of 10 kPa-10 MPa by changing the type of salt,and many hydrogels,such as gelatin and silk,could be improved with PTC or PCT *** experiments show that this scaffold can effectively promote the new generation of muscle fibers,blood vessels,and nerves within 4 weeks,prompting the rapid regeneration of large-volume muscle loss injuries.

关键词： 3D printing Tough hydrogel scaffold Functional surface structure Tissue regeneration Biomaterials

Wafer-Scale Ag₂S-Based Memristive Crossbar Arrays with Ultra-Low Switching-Energies Reaching Biological Synapses

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NANO-MICRO LETTERS 2025年第1期17卷 1-12页

作者： Zhu, yuan Nyberg, Tomas Nyholm, Leif Primetzhofer, Daniel shi, Xun Zhang, Zhen Uppsala Univ Dept Elect Engn Div Solid State Elect S-75121 Uppsala Sweden Uppsala Univ Dept Chem Uppsala Sweden Uppsala Univ Dept Phys & Astron Uppsala Sweden Chinese Acad Sci Shanghai Inst Ceram State Key Lab High Performance Ceram & Superfine M Shanghai 200050 Peoples R China

Memristive crossbar arrays (MCAs) offer parallel data storage and processing for energy-efficient neuromorphic computing. However, most wafer-scale MCAs that are compatible with complementary metal-oxide-semiconductor (CMOS) technology still suffer from substantially larger energy consumption than biological synapses, due to the slow kinetics of forming conductive paths inside the memristive units. here we report wafer-scale Ag2S-based MCAs realized using CMOS-compatible processes at temperatures below 160 degrees C. Ag2S electrolytes supply highly mobile Ag+ ions, and provide the Ag/Ag2S interface with low silver nucleation barrier to form silver filaments at low energy costs. By further enhancing Ag+ migration in Ag2S electrolytes via microstructure modulation, the integrated memristors exhibit a record low threshold of approximately - 0.1 V, and demonstrate ultra-low switching-energies reaching femtojoule values as observed in biological synapses. The low-temperature process also enables MCA integration on polyimide substrates for applications in flexible electronics. Moreover, the intrinsic nonidealities of the memristive units for deep learning can be compensated by employing an advanced training algorithm. An impressive accuracy of 92.6% in image recognition simulations is demonstrated with the MCAs after the compensation. The demonstrated MCAs provide a promising device option for neuromorphic computing with ultra-high energy-efficiency.

关键词： Wafer-scale Ag2S films Reactive sputter Silver nucleation Ag+ migration Energy-efficient neuromorphic computing

Identification of a dual functional betulinic acid analog for the treatment of osteoarthritis by phenotypic screening

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Science China Life Sciences 2025年第1期 300-302页

作者： Ze-Min Lin Mai Xiang wen-Hui Wei Shu-Hui Fan Li Chen Jie Wang Xiao-Qian Yang Chun-Hao Yang shi-Jun he Jian-Ping Zuo Laboratory of Immunopharmacology State Key Laboratory of Drug ResearchShanghai Institute of Materia MedicaChinese Academy of Sciences School of Pharmacy University of Chinese Academy of Sciences School of Pharmacy Nanjing University of Chinese Medicine State Key Laboratory of Drug Research Department of Medicinal ChemistryShanghai Institute of Materia MedicaChinese Academy of Sciences Innovation Research Institute of Traditional Chinese Medicine Shanghai University of Traditional Chinese Medicine Experiment Center for Science and Technology Shanghai University of Traditional Chinese Medicine

Dear Editor, Phenotypic drug discovery, which observes compound effects on physiology,has given way to targeting specific molecules, but has revived by using modern methods to find drugs based on therapeutic outcomes in disease models(Vincent et al., 2022). Osteoarthritis(OA) is a prevalent chronic joint disorder, primarily affecting knee joints, with osteoclast activation due to low-grade inflammation resulting in increased bone resorption and structural changes in the joint(Katz et al.,2021).

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Comparing the Genotype and Drug Susceptibilities between Mycobacterium avium and Mycobacterium intracellulare in China

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Biomedical and Environmental Sciences 2017年第7期30卷 517-525页

作者： ZheNG Hui wen PANG Yu he Guang xue song yuan yuan ZHAO Yan Lin National institute for communicable disease control and prevention Chinese center for disease control and prevention Beijing 102206 China National Tuberculosis Reference Laboratory Chinese Center for Disease Control and Prevention Beijing 102206 China Science and Technology Department Chinese Center for Disease Control and Prevention Beijing 102206 China

Objective Mycobacterium avium （M. avium） and Mycobacterium intracellulare （M. intracellulare） are the major causative agents of nontuberculous mycobacteria （NTM）-related pulmonary infections. However, little is known about the differences in drug susceptibility profiles between these two species. Methods A total of 393 NTM isolates were collected from Shanghai Pulmonary Disease Hospital. Sequencing of partial genes was performed to identify the strains at species level. The minimum inhibitory concentration （MIC） was used to evaluate the drug susceptibility against 20 antimicrobial agents. Variable number of tandem repeat （VNTR） typing was conducted to genotype these two species. Results A total of 173 （44.0%） M. avium complex （MAC） isolates were identified, including 41 （10.4%） M. avium isolates and 132 （33.6%） M. intracellulare isolates. Clarithromycin and amikacin were the two most effective agents against MAC isolates. The Hunter-Gaston Discriminatory Index （HGDI） values for VNTR typing of M. avium and M. intracellulare isolates were 0.993 and 0.995, respectively. Levofloxacin resistance was more common among the unclustered strains than among the clustered strains of M. intracellulare. Conclusion M. intrecellulare was the most common NTM species in China. Clarithromycin and amikacin had high antimicrobial activities against MAC. VNTR typing of MAC isolates revealed a high discriminatory power. Levofloxacin resistance was associated with unclustered strains of M. intracellulare.

关键词： Nontuberculous mycobacterium, Phenotype Genotype Susceptibility Resistance

Metal-organic frameworks with dinuclear metal centers for synergistically boosting CO2 photoreduction

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Science China Chemistry 2025年第01期 201-208页

作者： Hui-Feng Wang wen-Jie shi Yu-Xin Yang Bao-Xia Dong Tong-Bu Lu Di-Chang Zhong School of Chemistry and Chemical Engineering Yangzhou University Institute for New Energy Materials and Low Carbon Technologies School of Materials Science and Engineering Tianjin University of Technology

Dinuclear metal synergistic catalysis （DMSC） has been proved powerful in boosting CO2reduction,while this has not been achieved in heterogeneous catalysts with long-range order *** this study,we,by introduction of metal catalytic centers into an indium-based metal-organic framework （MOF）,obtained a series of isostructural In-MOFs,including three MOFs with mononuclear metal catalytic center （M-In）,three MOFs with dinuclear homometallic catalytic centers （MM-In）,and three MOFs with dinuclear heterometallic catalytic centers (MM’-In,M/M’=Co（II）,Ni（II）,Zn（II）).It was found that all these MOFs can serve as catalysts for photochemical CO2reduction to *** with M-In,the catalytic activities of MM-In were obviously enhanced,and that of MM’-In was further significantly *** example,the CO yield of Co Zn-In reaches a record value of 12,700μmol g-1h-1,which is 4.0,8.1,9.4,and 18.6-fold higher than that of Co Co-In,Zn Zn-In,Co-In,and Zn-In,***,the catalytic activities of Co Ni-In and Ni Zn-In also show different fold increase than those of corresponding dinuclear homometallic and mononuclear metallic *** results of control experiments and theoretical calculation reveal that the higher catalytic activities of MM-In over M-In can be ascribed to the DMSC effect,and the higher catalytic activity of MM’-In over MM-In can be ascribed to the strengthened DMSC *** work reveals the relationship between DMSC effect and bimetal centers in CO2reduction,which provides new insights into the DMSC and paves a new way to design highly active catalysts for photochemical CO2reduction.

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Association of level of leisure-time physical activity with risks of all-cause mortality and cardiovascular disease in an elderly Chinese population: a prospective cohort study

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Journal of Geriatric Cardiology 2020年第10期17卷 628-637页

作者： Hao ZHAO xue-Ning ZHANG Zhan shi Ling YIN wen-Li ZHANG Kun he xue-Qi HU Xiao-Yan ZHAO song-he shi Department of Epidemiology and Biostatistics College of Public HealthZhengzhou UniversityHenanChina Department of Pharmacy Zhengzhou First People’s HospitalZhengzhouHenanChina Department of Neurology Chinese PLA General HospitalBeijingChina

Background Implementing the current guidelines for leisure-time physical activity(LTPA)provides significant health benefits,especially for middle-aged adults,but it is unclear whether LTPA also translates into cardiovascular health benefits among elderly ***,we aimed to assess the association of LTPA with the risks of cardiovascular disease(CVD),including coronary heart disease(CHD)and stroke,and all-cause mortality in an elderly *** In this prospective cohort study,32,942 participants aged 60 years or older who participated in a health check-up programme in China between 2010 and 2018 were *** evaluated the morbidity and mortality risks through the Cox regression model,competing risk model and restricted cubic spline *** During a median of 6.84 years of follow-up,there were 6,857 elderly people with incident CVD;a total of 6,324 deaths occurred due to all causes and 2,060 deaths occurred due to *** with the inactive group,reductions in CVD morbidity and mortality were observed,with hazard ratios(HRs)of 0.89(95%CI:0.83–0.96)and 0.81(95%CI:0.71–0.92)in the insufficiently active group,0.86(95%CI:0.80–0.92)and 0.79(95%CI:0.69–0.90)in the sufficiently active group,and 0.79(95%CI:0.70–0.89)and 0.58(95%CI:0.45–0.76)in the highly active group,respectively;but no significant reductions were observed in the very highly active group,with HRs of 0.87(95%CI:0.71–1.06)and 0.99(95%CI:0.70–1.40),*** with the inactive group,reductions in all-cause mortality were also observed,with a HR of 0.90(95%CI:0.84–0.97)in the insufficiently active group,0.82(95%CI:0.77–0.89)in the sufficiently active group,0.77(95%CI:0.67–0.87)in the highly active group,and 0.80(95%CI:0.64–0.98)in the very highly active group.A restricted cubic spline diagram showed that there was an L-shaped association between LTPA and the risk of all-cause mortality but a U-shaped or reverse J-shaped relationship between LTPA and the risk of CVD morb

关键词： Cardiovascular disease Chronic coronary disease Leisure-time physical activity Stroke

Tranylcypromine upregulates Sestrin 2 expression to ameliorate NLRP3-related noise-induced hearing loss

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Neural Regeneration Research 2025年第5期20卷 1483-1494页

作者： Xihang Chen Zhifeng Chen Menghua Li Weiwei Guo Shuolong yuan Liangwei Xu Chang Lin Xi shi Wei Chen shiming Yang Senior Department of Otolaryngology head and Neck Surgery Chinese PLA General HospitalChinese PLA Medical SchoolBeijingChina State Key Laboratory of hearing and Balance Science BeijingChina National Clinical Research Center for Otolaryngologic Diseases BeijingChina Key Laboratory of hearing Science Ministry of EducationBeijingChina Beijing Key Laboratory of hearing Impairment Prevention and Treatment BeijingChina Department of Otorhinolaryngology head and Neck Surgery The First Affiliated Hospital of Fujian Medical UniversityFuzhouFujian ProvinceChina Department of Otolaryngology head and Neck Surgery The 940th Hospital of Joint Logistics Support Force of Chinese PLALanzhouGansu ProvinceChina Key Laboratory of Tropical Biological Resources of Ministry of Education School of Pharmaceutical SciencesHainan UniversityHaikouHainan ProvinceChina Academician Workstation of Hainan University School of Pharmaceutical SciencesYazhou BaySanyaHainan ProvinceChina

Noise-induced hearing loss is the primary non-genetic factor contributing to auditory ***,there are currently no effective pharmacological interventions for patients with noise-induced hearing ***,we present evidence suggesting that the lysine-specific demethylase 1 inhibitor–tranylcypromine is an otoprotective agent that could be used to treat noise-induced hearing loss,and elucidate its underlying regulatory *** established a mouse model of permanent threshold shift hearing loss by exposing the mice to white broadband noise at a sound pressure level of 120 d B for 4 *** found that tranylcypromine treatment led to the upregulation of Sestrin2(SESN2)and activation of the autophagy markers light chain 3B and lysosome-associated membrane glycoprotein 1 in the cochleae of mice treated with *** noise exposure group treated with tranylcypromine showed significantly lower average auditory brainstem response hearing thresholds at click,4,8,and 16 k Hz frequencies compared with the noise exposure group treated with *** findings indicate that tranylcypromine treatment resulted in increased SESN2,light chain 3B,and lysosome-associated membrane glycoprotein 1 expression after noise exposure,leading to a reduction in levels of 4-hydroxynonenal and cleaved caspase-3,thereby reducing noise-induced hair cell ***,immunoblot analysis demonstrated that treatment with tranylcypromine upregulated SESN2 expression via the autophagy *** treatment also reduced the production of NOD-like receptor family pyrin domaincontaining 3(NLRP3)*** conclusion,our results showed that tranylcypromine treatment ameliorated cochlear inflammation by promoting the expression of SESN2,which induced autophagy,thereby restricting NLRP3-related inflammasome signaling,alleviating cochlear hair cell loss,and protecting hearing *** findings suggest that inhibiting lysine-specific demethylase 1 is a

关键词： 4-hydroxynonenal apoptosis autophagy cleaved caspase-3 inflammation NOD-like receptor family pyrin domain-containing 3(NLRP3) noise-induced hearing loss oxidative stress Sestrin2 tranylcypromine