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Targeting protein-protein interaction interfaces with antiviral N protein inhibitor in SARS-CoV-2

Biophysical Journal 2024年第4期123卷 478-488页

作者： Hong, Jhen-Yi Lin, Shih-Chao Kehn-Hall, Kylene Zhang, Kai-Min Luo, Shun-Yuan Wu, Hung-Yi Chang, Sui-Yuan Hou, Ming-Hon Institute of Genomics and Bioinformatics and Department of Life Sciences National Chung Hsing University Taichung Taiwan Bachelor Degree Program in Marine Biotechnology College of Life Sciences National Taiwan Ocean University Keelung Taiwan Department of Biomedical Sciences and Pathobiology Virginia-Maryland College of Veterinary Medicine Virginia Polytechnic Institute and State University Blacksburg VA United States Center for Emerging Zoonotic and Arthropod-borne Pathogens Virginia Polytechnic Institute and State University Blacksburg VA United States Department of Chemistry National Chung Hsing University Taichung Taiwan Graduate Institute of Veterinary Pathobiology College of Veterinary Medicine National Chung Hsing University. Taichung Taiwan Department of Clinical Laboratory Sciences and Medical Biotechnology College of Medicine National Taiwan University Taipei Taiwan PhD Program in Medical Biotechnology National Chung Hsing University Taichung Taiwan Biotechnology Center National Chung Hsing University Taichung Taiwan

Coronaviruses not only pose significant global public health threats but also cause extensive damage to livestock-based industries. Previous studies have shown that 5-benzyloxygramine (P3) targets the Middle East respiratory syndrome coronavirus (MERS-CoV) nucleocapsid (N) protein N-terminal domain (N-NTD), inducing non-native protein-protein interactions (PPIs) that impair N protein function. Moreover, P3 exhibits broad-spectrum antiviral activity against CoVs. The sequence similarity of N proteins is relatively low among CoVs, further exhibiting notable variations in the hydrophobic residue responsible for non-native PPIs in the N-NTD. Therefore, to ascertain the mechanism by which P3 demonstrates broad-spectrum anti-CoV activity, we determined the crystal structure of the SARS-CoV-2 N-NTD:P3 complex. We found that P3 was positioned in the dimeric N-NTD via hydrophobic contacts. Compared with the interfaces in MERS-CoV N-NTD, P3 had a reversed orientation in SARS-CoV-2 N-NTD. The Phe residue in the MERS-CoV N-NTD:P3 complex stabilized both P3 moieties. However, in the SARS-CoV-2 N-NTD:P3 complex, the Ile residue formed only one interaction with the P3 benzene ring. Moreover, the pocket in the SARS-CoV-2 N-NTD:P3 complex was more hydrophobic, favoring the insertion of the P3 benzene ring into the complex. Nevertheless, hydrophobic interactions remained the primary stabilizing force in both complexes. These findings suggested that despite the differences in the sequence, P3 can accommodate a hydrophobic pocket in N-NTD to mediate a non-native PPI, enabling its effectiveness against various CoVs. © 2024 Biophysical Society

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Genomic data processing with GenomeFlow

arXiv

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arXiv 2025年

作者： Park, Junseok Maury, Eduardo A. Oh, Changhoon Shin, Donghoon Denisko, Danielle Lee, Eunjung Alice Division of Genetics and Genomics Boston Children’s Hospital 3 Blackfan Circle BostonMA United States Department of Pediatrics Harvard Medical School 25 Shattuck St BostonMA United States Bioinformatics Integrative Genomics Program Harvard/MIT MD-PHD Program Harvard Medical School BostonMA United States Program in Medical and Population Genetics Broad Institute of MIT and Harvard CambridgeMA United States Graduate School of Information Yonsei University 50 Yonsei-ro Seodaemun-gu Seoul Korea Republic of Department of Human Centered Design and Engineering University of Washington SeattleWA United States Department of Biomedical Informatics Harvard Medical School BostonMA United States

Advances in genome sequencing technologies generate massive amounts of sequence data that are increasingly analyzed and shared through public repositories. On-demand infrastructure services on cloud computing platforms enable the processing of such large-scale genomic sequence data in distributed processing environments with a significant reduction in analysis time. However, parallel processing on cloud computing platforms presents many challenges to researchers, even skillful bioinformaticians. In particular, it is difficult to design a computing architecture optimized to reduce the cost of computing and disk storage as genomic data analysis pipelines often employ many heterogeneous tools with different resource requirements. To address these issues, we developed GenomeFlow, a tool for automated development of computing architecture and resource optimization on Google Cloud Platform, which allows users to process a large number of samples at minimal cost. We outline multiple use cases of GenomeFlow demonstrating its utility to significantly reduce computing time and cost associated with analyzing genomic and transcriptomic data from hundreds to tens of thousands of samples from several consortia. Here, we describe a step-by-step protocol on how to use GenomeFlow for a common genomic data processing task. We introduce this example protocol geared toward a bioinformatician with little experience in cloud computing. © 2025, CC BY.

关键词： Cloud platforms

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Global epidemiology and antimicrobial resistance of Enterobacterales harbouring genes encoding OXA-48-like carbapenemases: insights from the results of the Antimicrobial Testing Leadership and Surveillance (ATLAS) programme 2018-2021

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The Journal of antimicrobial chemotherapy 2024年第7期79卷 1581-1589页

作者： Yu-Lin Lee Wei-Yao Wang Wen-Chien Ko Po-Ren Hsueh Division of Infectious Disease Department of Internal Medicine Chung Shan Medical University Hospital Taichung Taiwan. PhD Program in Medical Biotechnology Institute of Genomics and Bioinformatics National Chung-Hsing University Taichung Taiwan. School of Medicine Chung Shan Medical University Taichung Taiwan. Department of Medicine College of Medicine National Cheng Kung University Tainan Taiwan. Departments of Laboratory Medicine and Internal Medicine China Medical University Hospital Chin Medical University Taichung Taiwan. School of Medicine China Medical University Taichung Taiwan. PhD Program for Ageing School of Medicine China Medical University Taichung Taiwan. Departments of Laboratory Medicine and Internal Medicine National Taiwan University Hospital National Taiwan University College of Medicine Taipei Taiwan.

OBJECTIVES:The recent emergence of carbapenem-resistant Enterobacterales poses a major and escalating threat to global public health. This study aimed to analyse the global distribution and antimicrobial resistance of Enterobacterales harbouring variant OXA-48-like carbapenemase-related genes. METHODS:Enterobacterales isolates were collected from the Antimicrobial Testing Leadership and Surveillance (ATLAS) programme during 2018-2021. Comprehensive antimicrobial susceptibility testing and β-lactamase gene detection were also conducted, along with statistical analysis of the collected data. RESULTS:Among the 72 244 isolates, 1934 Enterobacterales isolates were identified to harbour blaOXA-48-like genes, predominantly Klebsiella spp. (86.9%). High rates of multidrug resistance were observed, with only ceftazidime/avibactam and tigecycline showing favourable susceptibility. A discrepancy between the genotype and phenotype of carbapenem resistance was evident: 16.8% (233 out of 1384) of the Enterobacterales isolates with blaOXA-48-like genes exhibited susceptibility to meropenem. Specifically, 37.4% (64/95) of Escherichia coli strains with blaOXA-48-like genes displayed meropenem susceptibility, while the corresponding percentages for Klebsiella pneumoniae and Enterobacter cloacae complex were 25.2% (160/1184) and 0% (0/36), respectively (P < 0.05). Geographical analysis revealed that the highest prevalence of blaOXA-48-like genes occurred in Asia, the Middle East and Eastern Europe. The proportion of K. pneumoniae isolates harbouring blaOXA-232 increased from 23.9% in 2018 to 56.0% in 2021. By contrast, the proportion of blaOXA-48 decreased among K. pneumoniae isolates during 2018-2021. CONCLUSIONS:This study underscores the widespread and increasing prevalence of blaOXA-48-like genes in Enterobacterales and emphasizes the need for enhanced surveillance, improved diagnostic methods and tailored antibiotic stewardship to combat the spread of these resistant pathogens.

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An atlas of single-cell eQTLs dissects autoimmune disease genes and identifies novel drug classes for treatment

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Cell genomics 2025年第4期5卷 100820-100820页

作者： Wang, Lida Markus, Havell Chen, Dieyi Chen, Siyuan Zhang, Fan Gao, Shuang Khunsriraksakul, Chachrit Chen, Fang Olsen, Nancy Foulke, Galen Jiang, Bibo Carrel, Laura Liu, Dajiang J. Department of Public Health Sciences Pennsylvania State University College of Medicine Hershey 17033 PA United States Bioinformatics and Genomics PhD Program Pennsylvania State University College of Medicine Hershey 17033 PA United States Institute for Personalized Medicine Pennsylvania State University College of Medicine Hershey 17033 PA United States Department of Biochemistry and Molecular Biology Pennsylvania State University College of Medicine Hershey 17033 PA United States Department of Medicine Penn State University College of Medicine Hershey 17033 PA United States Department of Dermatology Penn State University College of Medicine Hershey 17033 PA United States

Most variants identified from genome-wide association studies (GWASs) are non-coding and regulate gene expression. However, many risk loci fail to colocalize with expression quantitative trait loci (eQTLs), potentially due to limited GWAS and eQTL analysis power or cellular heterogeneity. Population-scale single-cell RNA-sequencing (scRNA-seq) datasets are emerging, enabling mapping of eQTLs in different cell types (sc-eQTLs). Compared to eQTL data from bulk tissues (bk-eQTLs), sc-eQTL datasets are smaller. We propose a joint model of bk-eQTLs as a weighted sum of sc-eQTLs (JOBS) from constituent cell types to improve power. Applying JOBS to One1K1K and eQTLGen data, we identify 586% more eQTLs, matching the power of 4× the sample sizes of OneK1K. Integrating sc-eQTLs with GWAS data creates an atlas for 14 immune-mediated disorders, colocalizing 29.9% or 32.2% more loci than using sc-eQTL or bk-eQTL alone. Extending JOBS, we develop a drug-repurposing pipeline and identify novel drugs validated by real-world data. © 2025 The Author(s)

关键词： autoimmune disease bulk eQTL colocalization drug repurposing GWAS scRNAseq sequencing design single cell eQTL transcriptome

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Artificial intelligence in gastrointestinal radiology: A review with special focus on recent development of magnetic resonance and computed tomography

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Artificial Intelligence in Gastroenterology 2021年第2期2卷 27-41页

作者： Kai-Po Chang Shih-Huan Lin Yen-Wei Chu PhD Program in Medical Biotechnology National Chung Hsing UniversityTaichung 40227Taiwan Department of Pathology China Medical University HospitalTaichung 40447Taiwan Institute of Genomics and Bioinformatics National Chung Hsing UniversityTaichung 40227Taiwan Institute of Molecular Biology National Chung Hsing UniversityTaichung 40227Taiwan Agricultural Biotechnology Center National Chung Hsing UniversityTaichung 40227Taiwan Biotechnology Center National Chung Hsing UniversityTaichung 40227Taiwan PhD Program in Translational Medicine National Chung Hsing UniversityTaichung 40227Taiwan Rong Hsing Research Center for Translational Medicine Taichung 40227Taiwan

Artificial intelligence(AI),particularly the deep learning technology,have been proven influential to radiology in the recent *** ability in image classification,segmentation,detection and reconstruction tasks have substantially assisted diagnostic radiology,and has even been viewed as having the potential to perform better than radiologists in some *** radiology,an important subspecialty dealing with complex anatomy and various modalities including endoscopy,have especially attracted the attention of AI researchers and engineers ***,recently many tools have been developed for lesion detection and image construction in gastrointestinal radiology,particularly in the fields for which public databases are available,such as diagnostic abdominal magnetic resonance imaging(MRI)and computed tomography(CT).This review will provide a framework for understanding recent advancements of AI in gastrointestinal radiology,with a special focus on hepatic and pancreatobiliary diagnostic radiology with MRI and *** fields where AI is less developed,this review will also explain the difficulty in AI model training and possible strategies to overcome the technical *** authors’insights of possible future development will be addressed in the last section.

关键词： Artificial intelligence Deep learning Image diagnosis Radiology Magnetic resonance imaging Computed tomography

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Emergence of ceftazidime-avibactam resistance through in-vivo bla KPC-2 to bla KPC-33 conversion during treatment of ST11 Klebsiella pneumoniae associated infections

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International Journal of Antimicrobial Agents 2024年第2期64卷

作者： Yi-Chyi Lai Luo-Wei Lin Yu-Lin Lee Department of Internal Medicine Chung Shan Medical University Hospital Taichung Taiwan Department of Microbiology and Immunology School of Medicine Chung Shan Medical University Taichung Taiwan PhD Program in Medical Biotechnology Institute of Genomics and Bioinformatics National Chung-Hsing University Taichung Taiwan School of Medicine Chung Shan Medical University Taichung Taiwan

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An integrative and multiscale approach to study dengue virus-like particle dynamics

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Biophysical Journal 2023年第3期122卷 44a-44a页

作者： Venkata Raghuvamsi Palur Gielenny Salem Fan-Chi Chen Shang-Rung Wu Peter J. Bond Day-Yu Chao Jan K. Marzinek Bioinformatics Institute (A∗STAR) Singapore Republic of Singapore Graduate Institute of Microbiology and Public Health College of Veterinary Medicine National Chung Hsing University Taichung City Taiwan Microbial Genomics PhD Program National Chung Hsing University and Academia Sinica Taichung City Taiwan Department of Dentistry & Institute of Oral Medicine National Cheng Kung University Tainan Taiwan Department of Biological Sciences National University of Singapore Singapore Republic of Singapore

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In vitro activity of cefepime-zidebactam, ceftolozane-tazobactam, ceftazidime-avibactam, imipenem-relebactam, and other comparators against imipenem-non-susceptible Pseudomonas aeruginosa in Taiwan, 2022

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International journal of antimicrobial agents 2025年 107550页

作者： Yu-Lin Lee Mei-Chen Tan Pei-Jing Chen Yih-Ru Shiau Hui-Ying Wang Jui-Fen Lai I-Wen Huang Ya-Sung Yang Shu-Chen Kuo Department of Internal Medicine Chung Shan Medical University Hospital Taichung Taiwan PhD Program in Medical Biotechnology Institute of Genomics and Bioinformatics National Chung-Hsing University Taichung Taiwan School of Medicine Chung Shan Medical University Taichung Taiwan. National Institute of Infectious Diseases and Vaccinology National Health Research Institutes Miaoli Taiwan. Division of Infectious Diseases and Tropical Medicine Department of Internal Medicine Tri-Service General Hospital National Defense Medical Center Taipei Taiwan. Institute of Preventive Medicine National Defense Medical Center Taipei Taiwan. Electronic address: ysyoung4097@***. National Institute of Infectious Diseases and Vaccinology National Health Research Institutes Miaoli Taiwan. Electronic address: sckuo@nhri.edu.tw.

OBJECTIVES:The global expansion of antimicrobial-resistant Pseudomonas aeruginosa, particularly imipenem-non-susceptible (INS) strains poses a formidable health threat. The COVID-19 pandemic has exacerbated antimicrobial resistance trends. We compared the pre- and post-pandemic antibiotic resistance patterns of INS-P. aeruginosa in Taiwan. METHODS:We analyzed 503 P. aeruginosa isolates collected through the Taiwan Surveillance of Antimicrobial Resistance (TSAR) program during 2022. Minimum inhibitory concentrations of various antibiotics were determined by using broth microdilution. Carbapenemase-encoding genes were identified via multiplex PCR. Antimicrobial resistance trends were compared with data from 2018. RESULTS:INS-P. aeruginosa comprised 16.9% (85/503) of isolates and exhibited high-level multi-drug resistance. Novel β-lactam-β-lactamase inhibitor combinations (BL-BLIs) demonstrated the highest activity, with 89.4% of INS isolates susceptible to cefepime-zidebactam. The susceptibility rates of INS-P. aeruginosa isolates to other BL-BLIs and comparators declined between 2018 and 2022. Specifically, susceptibility to ceftazidime-avibactam and imipenem-relebactam decreased from 81.5% and 85.2% during 2018 to 64.7% and 63.5% during 2022, respectively (both p<0.05). Additionally, only 70.6% of isolates obtained during 2022 were susceptible to ceftolozane-tazobactam. Carbapenemase genes were detected in 10.6% of isolates, with a notable increase in bla and bla prevalence compared to pre-pandemic data. CONCLUSION:The COVID-19 pandemic intensified resistance trends in INS-P. aeruginosa in Taiwan, with increasing prevalence and diversity of carbapenemase-encoding genes. Continuous monitoring and expanded research are essential to combat evolving resistance patterns.

关键词： Carbapenem-resistant Pseudomonas aeruginosa TSAR Surveillance β-lactam-β-lactamase inhibitor combination

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In vitro activity of imipenem/relebactam, meropenem/vaborbactam and comparators against Enterobacterales causing urinary tract infection in Taiwan: results from the Study for Monitoring Antimicrobial Resistance Trends (SMART), 2020

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International journal of antimicrobial agents 2023年第6期61卷 106815页

作者： Chih-Yen Chang Yu-Lin Lee Yu-Tsung Huang Wen-Chien Ko Mao-Wang Ho Po-Ren Hsueh Department of Internal Medicine Yuanlin Christian Hospital Changhua Taiwan. Department of Internal Medicine Changhua Christian Hospital Changhua Taiwan and Institute of Genomics and Bioinformatics National Chung Hsing University Taichung Taiwan. Departments of Laboratory Medicine and Internal Medicine National Taiwan University Hospital National Taiwan University College of Medicine Taipei Taiwan. Department of Medicine College of Medicine National Cheng Kung University Tainan Taiwan. Division of Infectious Diseases Department of Internal Medicine China Medical University Hospital China Medical University Taichung Taiwan. Departments of Laboratory Medicine and Internal Medicine National Taiwan University Hospital National Taiwan University College of Medicine Taipei Taiwan Division of Infectious Diseases Department of Internal Medicine China Medical University Hospital China Medical University Taichung Taiwan Center of Laboratory Medicine China Medical University Hospital China Medical University Taichung Taiwan PhD Program for Aging School of Medicine China Medical University Taichung Taiwan. Electronic address: hsporen@***.

OBJECTIVES:Antimicrobial resistance due to β-lactamase production is a worldwide issue, and β-lactamase inhibitors have been developed to overcome the growing problem. This study aimed to evaluate the in vitro activities of two recently introduced carbapenem/β-lactamase inhibitor combinations - imipenem/relebactam and meropenem/vaborbactam - and their comparators against Enterobacterales from patients with urinary tract infections (UTIs). METHODS:Enterobacterales isolates from patients with UTIs in Taiwan and participating in the Study for Monitoring Antimicrobial Resistance Trends (SMART) in 2020 were included. Minimum inhibitory concentrations (MICs) for various antibiotics were determined using the broth microdilution method. Susceptibility was interpreted based on the MIC breakpoints of the Clinical and Laboratory Standards Institute 2022. Genes encoding common β-lactamases, including extended-spectrum β-lactamases, AmpC β-lactamases and carbapenemases, were detected using multiplex polymerase chain reaction. RESULTS:A total of 309 Enterobacterales isolates were included, against which both imipenem/relebactam and meropenem/vaborbactam exerted excellent efficacy (275 of 309, 95% and 288 of 309, 99.3%, respectively). Among imipenem non-susceptible isolates, 17 of 43 (39.5%) and 39 of 43 (90.7%) were susceptible to imipenem/relebactam and meropenem/vaborbactam, respectively. CONCLUSION:Imipenem/relebactam and meropenem/vaborbactam may be appropriate choices for treating UTIs due to Enterobacterales resistant to commonly used antibiotics. Continuous monitoring of antimicrobial resistance is crucial.

关键词： Carbapenem resistance Cross-resistance Enterobacterales Multidrug resistance Novel β-lactam combination agents

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Patterns of somatic structural variation in human cancer genomes (vol 578, pg 112, 2020)

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NATURE 2023年第7948期614卷 E38-E38页

作者： Li, Yilong Roberts, Nicola D. Wala, Jeremiah A. Shapira, Ofer Schumacher, Steven E. Kumar, Kiran Khurana, Ekta Waszak, Sebastian Korbel, Jan O. Haber, James E. Imielinski, Marcin Weischenfeldt, Joachim Beroukhim, Rameen Campbell, Peter J. Cancer Genome Project Wellcome Trust Sanger Institute Hinxton UK Totient Inc Cambridge MA USA Wellcome Sanger Institute Wellcome Genome Campus Hinxton UK Department of Haematology University of Cambridge Cambridge UK Cambridge University Hospitals NHS Foundation Trust Cambridge UK Korea Advanced Institute of Science and Technology Daejeon South Korea Department of Zoology Genetics and Physical Anthropology University of Santiago de Compostela Santiago de Compostela Spain Centre for Research in Molecular Medicine and Chronic Diseases (CIMUS) University of Santiago de Compostela Santiago de Compostela Spain The Biomedical Research Centre (CINBIO) University of Vigo Vigo Spain Centre for Research in Molecular Medicine and Chronic Diseases (CiMUS) Universidade de Santiago de Compostela Santiago de Compostela Spain Department of Zoology Genetics and Physical Anthropology (CiMUS) Universidade de Santiago de Compostela Santiago de Compostela Spain The Biomedical Research Centre (CINBIO) Universidade de Vigo Vigo Spain The Broad Institute of Harvard and MIT Cambridge MA USA Bioinformatics and Integrative Genomics Harvard University Cambridge MA USA Department of Cancer Biology Dana-Farber Cancer Institute Boston MA USA Broad Institute of MIT and Harvard Cambridge MA USA Department of Medical Oncology Dana-Farber Cancer Institute Boston MA USA Harvard Medical School Boston MA USA Massachusetts General Hospital Center for Cancer Research Charlestown MA USA Dana-Farber Cancer Institute Boston MA USA Department of Biostatistics and Computational Biology Dana-Farber Cancer Institute and Harvard Medical School Boston MA USA Weill Cornell Medical College New York NY USA Department of Physiology and Biophysics Weill Cornell Medicine New York NY USA Institute for Computational Biomedicine Weill Cornell Medicine New York NY USA Controlled Department and Institution New York NY USA Englander Institute for Precision Medicine Weill Cornell Medicine Ne

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