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Applications of genetic code expansion technology in eukaryotes

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Protein & Cell 2024年第5期15卷 331-363页

作者： Qiao-ru Guo Yu J.Cao State key laboratory of Chemical Oncogenomic Guangdong Provincial Key Laboratory of Chemical GenomicsPeking University Shenzhen Graduate SchoolShenzhen 518055China Institute of Chemical Biology Shenzhen Bay LaboratoryShenzhen 518132China

Unnatural amino acids(UAAs)have gained significant attention in protein engineering and drug development owing to their ability to introduce new chemical functionalities to proteins.In eukaryotes,genetic code expansion(GCE)enables the incorporation of UAAs and facilitates posttranscriptional modification(PTM),which is not feasible in prokaryotic systems.GCE is also a powerful tool for cell or animal imaging,the monitoring of protein interactions in target cells,drug development,and switch regulation.Therefore,there is keen interest in utilizing GCE in eukaryotic systems.This review provides an overview of the application of GCE in eukaryotic systems and discusses current challenges that need to be addressed.

关键词： genetic code expansion unnatural amino acid eukaryotes basic research therapeutic applications

A Heterozygous Phospholamban Variant(p.R14del)Leads to Left Ventricular Involvement and Heart Failure Phenotypes in Arrhythmogenic Right Ventricular Cardiomyopathy

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Phenomics

Phenomics 2024年第1期4卷 13-23页

作者： Han Mo Xiumeng Hua Mengni Bao Zhe Sun Xiao Chen Mengda Xu Jiangping Song shenzhen key laboratory of cardiovascular disease Fuwai Hospital Chinese Academy of Medical SciencesShenzhen 518057China State key laboratory of cardiovascular disease Fuwai HospitalNational Center for Cardiovascular DiseasesChinese Academy of Medical Sciences and Peking Union Medical College167A Beilishi RoadXi Cheng DistrictBeijing 100037China Beijing key laboratory of Preclinical Research and Evaluation for cardiovascular Implant Materials Animal Experimental CentreFuwai HospitalNational Center for Cardiovascular DiseaseChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina

This study aimed to determine the prevalence and clinical features of Arrhythmogenic Right Ventricular Cardiomyopathy(ARVC)caused by pathogenic mutations in the Phospholamban(PLN)gene.The study included 170 patients who had a confrmed diagnosis of ARVC and underwent PLN genetic screening using next-generation sequencing.The fndings of this study provide valuable insights into the association between PLN mutations and ARVC,which can aid in the development of more efective diagnostic and treatment strategies for ARVC patients.Out of the patients evaluated,six had a rare pathogenic mutation in PLN with the same p.R14del variant.Family screening revealed that heterozygous carriers of p.R14del exhibited a defnite ARVC phenotype.In clinical studies,individuals with the p.R14del mutation experienced a similar rate of malignant arrhythmia events as those with classic desmosome mutations.After adjusting for covariates,individuals with PLN mutations had a two point one seven times greater likelihood of experiencing transplant-related risks compared to those who did not possess PLN mutations(95%CI 1.08–6.82,p=0.035).The accumulation of left ventricular fat and fbers is a pathological marker for ARVC patients with p.R14del mutations.In a cohort of 170 Chinese ARVC patients,three point fve percent of probands had the PLN pathogenic variant(p.R14del)and all were female.Our data shows that PLN-related ARVC patients are at high risk for ventricular arrhythmias and heart failure,which requires clinical diferentiation from classic ARVC.Furthermore,carrying the p.R14del mutation can be an independent prognostic risk factor in ARVC patients.

关键词： Arrhythmogenic right ventricular cardiomyopathy Phospholamban Left ventricular involvement Heart failure Risk stratifcation

Characterization of whole genomes from recently emerging Mpox cases in several regions of China,2023

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Science China(Life Sciences) 2024年第5期67卷 1079-1081页

作者： Changcheng Wu Lunbiao Cui Yang Pan Ziquan Lv Mingxiao Yao Wenling Wang Fei Ye Weibang Huo Li Zhao Baoying Huang Fengcai Zhu Roujian Lu Yao Deng Quanyi Wang Wenjie Tan NHC key laboratory of Biosafety National Institute for Viral Disease Control and PreventionChinese Center for Disease Control and PreventionBeijing 102206China NHC key laboratory of Enteric Pathogenic Microbiology Jiangsu Provincial Medical Key Laboratory of Pathogenic Microbiology in Emerging Major Infectious DiseasesJiangsu Provincial Center for Disease Control and PreventionNanjing 210009China Beijing Center for disease Prevention and Control Beijing 100013China Central laboratory Shenzhen Center for Disease Control and PreventionShenzhen 518055China Shandong Center for disease Control and Prevention Jinan 250014China

Dear Editor,Mpox(formerly known as monkeypox)is a zoonotic disease caused by infection with the monkeypox virus(MPXV).Mpox cases have been sporadic over the past few decades,with outbreaks occurring in only a limited ... 详细信息

关键词： cases primarily imported

Mpox(formerly monkeypox):pathogenesis,prevention,and treatment

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Signal Transduction and Targeted Therapy 2024年第1期9卷 234-248页

作者： Junjie Lu Hui Xing Chunhua Wang Mengjun Tang Changcheng Wu Fan Ye Lijuan Yin Yang Yang Wenjie Tan Liang Shen Xiangyang Central Hospital Affiliated Hospital of Hubei University of Arts and ScienceHubei ProvinceXiangyang 441021China NHC key laboratory of Biosafety National Institute for Viral Disease Control and PreventionChinese Center for Disease Control and PreventionBeijing 102206China College of Biotechnology Tianjin University of Science&TechnologyTianjin 300457China shenzhen key laboratory of Pathogen and Immunity National Clinical Research Center for infectious diseaseState Key Discipline of Infectious DiseaseShenzhen Third People’s HospitalSecond Hospital Affiliated to Southern University of Science and TechnologyShenzhen 518112China

In 2022,a global outbreak of Mpox(formerly monkeypox)occurred in various countries across Europe and America and rapidly spread to more than 100 countries and regions.The World Health Organization declared the outbreak to be a public health emergency of international concern due to the rapid spread of the Mpox virus.Consequently,nations intensified their efforts to explore treatment strategies aimed at combating the infection and its dissemination.Nevertheless,the available therapeutic options for Mpox virus infection remain limited.So far,only a few numbers of antiviral compounds have been approved by regulatory authorities.Given the high mutability of the Mpox virus,certain mutant strains have shown resistance to existing pharmaceutical interventions.This highlights the urgent need to develop novel antiviral drugs that can combat both drug resistance and the potential threat of bioterrorism.Currently,there is a lack of comprehensive literature on the pathophysiology and treatment of Mpox.To address this issue,we conducted a review covering the physiological and pathological processes of Mpox infection,summarizing the latest progress of anti-Mpox drugs.Our analysis encompasses approved drugs currently employed in clinical settings,as well as newly identified small-molecule compounds and antibody drugs displaying potential antiviral efficacy against Mpox.Furthermore,we have gained valuable insights from the process of Mpox drug development,including strategies for repurposing drugs,the discovery of drug targets driven by artificial intelligence,and preclinical drug development.The purpose of this review is to provide readers with a comprehensive overview of the current knowledge on Mpox.

关键词： prevention treatment intensified

Development and performance evaluation of a culture-independent nanopore amplicon-based sequencing method for accurate typing and antimicrobial resistance profiling in Neisseria gonorrhoeae

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Science China(Life Sciences) 2024年第2期67卷 421-423页

作者： Chi Zhang Lulu Zhang Feng Wang Yaling Zeng Liying Sun Di Wang Yamei Li Liqin Wang Junping Peng NHC key laboratory of Systems Biology of Pathogens Institute of Pathogen BiologyChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100176China key laboratory of Respiratory disease Pathogenomics Chinese Academy of Medical SciencesBeijing 100730China shenzhen Center for Chronic disease Control Shenzhen 518020China

Dear Editor,Bacterial antimicrobial resistance(AMR)poses a serious threat to global human health(Antimicrobial Resistance Collaborators,2022).Comprehensive profiling of AMR and accurate molecular typing are important for tracking and controlling the emergence and dissemination of antibiotic-resistant bacteria(Yahara et al.,2021).We previously developed a multiplex amplicon sequencing-based method for directly sequencing AMR-related loci in N.gonorrhoeae from clinical samples(Zhang et al.,2021).

关键词： gonorrhoeae resistance

Multimorbidity and mortality among older patients with coronary heart disease in shenzhen,China

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Journal of Geriatric Cardiology 2024年第1期21卷 81-89页

作者： Fu-Rong LI Shuang WANG Xia LI Zhi-Yuan CHENG Cheng JIN Chun-Bao MO Jing ZHENG Feng-Chao LIANG Dong-Feng GU shenzhen key laboratory of cardiovascular Health and Precision Medicine Southern University of Science and TechnologyShenzhenGuangdongChina School of Public Health and Emergency Management Southern University of Science and TechnologyShenzhenGuangdongChina shenzhen Health Development Research and Data Management Center ShenzhenChina School of Medicine Southern University of Science and TechnologyShenzhenGuangdongChina

BACKGROUND The current understanding of the magnitude and consequences of multimorbidity in Chinese older adults with coronary heart disease(CHD)is insufficient.We aimed to assess the association and population-attributable fractions(PAFs)between multimorbidity and mortality among hospitalized older patients who were diagnosed with CHD in shenzhen,China.METHODS We conducted a retrospective cohort study of older Chinese patients(aged≥65 years)who were diagnosed with CHD.Cox proportional hazards models were used to estimate the associations between multimorbidity and all-cause and cardiovascular disease(CVD)mortality.We also calculated the PAFs.RESULTS The study comprised 76,455 older hospitalized patients who were diagnosed with CHD between January 1,2016,and August 31,2022.Among them,70,217(91.9%)had multimorbidity,defined as the presence of at least one of the predefined 14 chronic conditions.Those with cancer,hemorrhagic stroke and chronic liver disease had the worst overall death risk,with adjusted HRs(95%CIs)of 4.05(3.77,4.38),2.22(1.94,2.53),and 1.85(1.63,2.11),respectively.For CVD mortality,the highest risk was observed for hemorrhagic stroke,ischemic stroke,and chronic kidney disease;the corresponding adjusted HRs(95%CIs)were 3.24(2.77,3.79),1.91(1.79,2.04),and 1.81(1.64,1.99),respectively.All-cause mortality was mostly attributable to cancer,heart failure and ischemic stroke,with PAFs of 11.8,10.2,and 9.1,respectively.As for CVD mortality,the leading PAFs were heart failure,ischemic stroke and diabetes;the corresponding PAFs were 18.0,15.7,and 6.1,respectively.CONCLUSIONS Multimorbidity was common and had a significant impact on mortality among older patients with CHD in shenzhen,China.Cancer,heart failure,ischemic stroke and diabetes are the primary contributors to PAFs.Therefore,prioritizing improved treatment and management of these comorbidities is essential for the survival prognosis of CHD patients from a holistic public health perspective.

关键词： patients morbidity mortality

A Novel Retrograde AAV Variant for Functional Manipulation of Cortical Projection Neurons in Mice and Monkeys

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Neuroscience Bulletin 2024年第1期40卷 90-102页

作者： Yefei Chen Jingyi Wang Jing Liu Jianbang Lin Yunping Lin Jinyao Nie Qi Yue Chunshan Deng Xiaofei Qi Yuantao Li Ji Dai Zhonghua Lu Department of Anesthesiology Shenzhen Maternity and Child Healthcare HospitalThe First School of Clinical MedicineSouthern Medical UniversityShenzhen 518027China shenzhen Technological Research Center for Primate Translational Medicine Shenzhen Key Laboratory for Molecular Biology of Neural DevelopmentShenzhen-Hong Kong Institute of Brain ScienceShenzhen Institute of Advanced TechnologyChinese Academy of SciencesShenzhen 518055China University of Chinese Academy of Sciences Beijing 100049China CAS key laboratory of Brain Connectome and Manipulation the Brain Cognition and Brain Disease InstituteShenzhen Institute of Advanced TechnologyChinese Academy of SciencesShenzhen 518055China Guangdong Provincial key laboratory of Brain Connectome and Behavior the Brain Cognition and Brain Disease InstituteShenzhen Institute of Advanced TechnologyChinese Academy of SciencesShenzhen 518055China Biomedical Research Institute Hubei University of MedicineShiyan 442000China Faculty of Life and Health Sciences Shenzhen Institute of Advanced TechnologyChinese Academy of SciencesShenzhen 518055China

Retrograde adeno-associated viruses(AAVs)are capable of infecting the axons of projection neurons and serve as a powerful tool for the anatomical and functional characterization of neural networks.However,few retro-grade AAV capsids have been shown to offer access to cor-tical projection neurons across different species and enable the manipulation of neural function in non-human primates(NHPs).Here,we report the development of a novel retro-grade AAV capsid,AAV-DJ8R,which efficiently labeled cortical projection neurons after local administration into the striatum of mice and macaques.In addition,intrastriatally injected AAV-DJ8R mediated opsin expression in the mouse motor cortex and induced robust behavioral alterations.Moreover,AAV-DJ8R markedly increased motor cortical neuron firing upon optogenetic light stimulation after viral delivery into the macaque putamen.These data demonstrate the usefulness of AAV-DJ8R as an efficient retrograde tracer for cortical projection neurons in rodents and NHPs and indicate its suitability for use in conducting functional interrogations.

关键词： Retrograde AAV Capsid variant Cortical projection neuron Optogenetics Monkey

Dynamic Response of Foundations during Startup of High-Frequency Tunnel Equipment

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Computer Modeling in Engineering & Sciences 2024年第7期140卷 821-844页

作者： Dawei Ruan Mingwei Hu College of Civil and Transportation Engineering Shenzhen UniversityShenzhen518060China State key laboratory of Intelligent Geotechnics and Tunnelling Shenzhen UniversityShenzhen518060China key laboratory of Coastal Urban Resilient Infrastructures of Ministry of Education Shenzhen UniversityShenzhen518060China Underground Polis Academy Shenzhen UniversityShenzhen518060China shenzhen key laboratory of Green Efficient and Intelligent Construction of Underground Metro StationShenzhen UniversityShenzhen518060China

The specialized equipment utilized in long-line tunnel engineering is evolving towards large-scale,multifunctional,and complex orientations.The vibration caused by the high-frequency units during regular operation is supported by the foundation of the units,and the magnitude of vibration and the operating frequency fluctuate in different engineering contexts,leading to variations in the dynamic response of the foundation.The high-frequency units yield significantly diverse outcomes under different startup conditions and times,resulting in failure to meet operational requirements,influencing the normal function of the tunnel,and causing harm to the foundation structure,personnel,and property in severe cases.This article formulates a finite element numerical computation model for solid elements using three-dimensional elastic body theory and integrates field measurements to substantiate and ascertain the crucial parameter configurations of the finite element model.By proposing a comprehensive startup timing function for high-frequency dynamic machines under different startup conditions,simulating the frequency andmagnitude variations during the startup process,and suggesting functions for changes in frequency and magnitude,a simulated startup schedule function for high-frequency machines is created through coupling.Taking into account the selection of the transient dynamic analysis step length,the dynamic response results for the lower dynamic foundation during its fundamental frequency crossing process are obtained.The validation checks if the structural magnitude surpasses the safety threshold during the critical phase of unit startup traversing the structural resonance region.The design recommendations for high-frequency units’dynamic foundations are provided,taking into account the startup process of the machine and ensuring the safe operation of the tunnel.

关键词： Tunnel equipment high-frequency units startup conditions transient dynamics dynamic response foundation design

Improving error-correcting capability in DNA digital storage via soft-decision decoding

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National Science Review 2024年第2期11卷 135-144页

作者：丁璐璐伍世刚候志浩李阿伦许亚苹冯虎潘玮华阮珏 shenzhen Branch Guangdong Laboratory of Lingnan Modern AgricultureGenome Analysis Laboratory of the Ministry of Agriculture and Rural AffairsAgricultural Genomics Institute at ShenzhenChinese Academy of Agricultural Sciences Guangdong Provincial key laboratory of Plant Molecular Breeding State Key Laboratory for Conservation and Utilization of Subtropical Agro-BioresourcesSouth China Agricultural University

Error-correcting codes(ECCs) employed in the state-of-the-art DNA digital storage(DDS) systems suffer from a trade-off between error-correcting capability and the proportion of redundancy. To address this issue, in this study, we introduce soft-decision decoding approach into DDS by proposing a DNA-specific error prediction model and a series of novel strategies. We demonstrate the effectiveness of our approach through a proof-of-concept DDS system based on Reed-Solomon(RS) code, named as Derrick. Derrick shows significant improvement in error-correcting capability without involving additional redundancy in both in vitro and in silico experiments, using various sequencing technologies such as Illumina, Pac Bio and Oxford Nanopore Technology(ONT). Notably, in vitro experiments using ONT sequencing at a depth of 7× reveal that Derrick, compared with the traditional hard-decision decoding strategy, doubles the error-correcting capability of RS code, decreases the proportion of matrices with decoding-failure by 229-fold, and amplifies the potential maximum storage volume by impressive 32 388-fold. Also, Derrick surpasses ‘state-of-the-art' DDS systems by comprehensively considering the information density and the minimum sequencing depth required for complete information recovery. Crucially, the soft-decision decoding strategy and key steps of Derrick are generalizable to other ECCs' decoding algorithms.

关键词： DNA digital storage (DDS) error-correcting code (ECC) soft-decision decoding error-correcting capability storage volume