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Mapping dihydropteroate synthase evolvability through identification of a novel evolutionarily critical substructure

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International Journal of Biological Macromolecules 2025年 311卷 143325页

作者： Sanyal, Dwipanjan Shivram, A. Pandey, Deeptanshu Banerjee, Suharto Uversky, Vladimir N. Muzata, Danny Chivukula, Aneesh Sreevallabh Jasuja, Ravi Chattopadhyay, Krishnananda Chowdhury, Sourav Structural Biology and Bioinformatics Division CSIR-Indian Institute of Chemical Biology Kolkata India Department of Computer Science and Information Systems Birla Institute of Technology and Science-Pilani Hyderabad India Department of Biological Sciences Birla Institute of Technology and Science-Pilani Hyderabad India Max Delbrück Center for Molecular Medicine Berlin Germany Research Program in Men's Health: Aging and Metabolism Brigham and Women's Hospital Harvard Medical School BostonMA United States USF Health Byrd Alzheimer's Research Institute Morsani College of Medicine University of South Florida TampaFL33612 United States

Protein evolution shapes pathogen adaptation-landscape, particularly in developing drug resistance. The rapid evolution of target proteins under antibiotic pressure leads to escape mutations, resulting in antibiotic resistance. A deep understanding of the evolutionary dynamics of antibiotic target proteins presents a plausible intervention strategy for disrupting the resistance trajectory. Mutations in Dihydropteroate synthase (DHPS), an essential folate pathway protein and sulfonamide antibiotic target, reduce antibiotic binding leading to anti-folate resistance. Deploying statistical analyses on the DHPS sequence-space and integrating deep mutational analysis with structure-based network-topology models, we identified critical DHPS subsequences. Our frustration landscape analysis suggests how conformational and mutational changes redistribute energy within DHPS substructures. We present an epistasis-based fitness prediction model that simulates DHPS adaptive walks, identifying residue positions that shape evolutionary constraints. Our optimality analysis revealed a substructure central to DHPS evolvability, and we assessed its druggability. Combining evolution and structure, this integrated framework identifies a DHPS substructure with significant evolutionary and structural impact. Targeting this region may constrain DHPS evolvability and slow resistance emergence, offering new directions for antibiotic development. © 2025

关键词： Topology

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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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Advantages of two quantum programming platforms in quantum computing and quantum chemistry

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Journal of cheminformatics 2025年第1期17卷 77页

作者： Pei-Hua Wang Wei-Yeh Wu Che-Yu Lee Jia-Cheng Hong Yufeng Jane Tseng Undergraduate Program in Intelligent Computing and Big Data Chung Yuan Christian University No. 200 Zhongbei Road Taoyuan 320314 Taiwan. Quantum Information Center Chung Yuan Christian University No. 200 Zhongbei Road Taoyuan 320314 Taiwan. Department of Computer Science and Information Engineering National Taiwan University No. 1 Sec. 4 Roosevelt Road Taipei 10617 Taiwan. Graduate Institute of Biomedical Electronics and Bioinformatics College of Electrical Engineering and Computer Science National Taiwan University No. 1 Sec. 4 Roosevelt Road Taipei 10617 Taiwan. Department of Computer Science and Information Engineering National Taiwan University No. 1 Sec. 4 Roosevelt Road Taipei 10617 Taiwan. yjtseng@csie.ntu.edu.tw. Graduate Institute of Biomedical Electronics and Bioinformatics College of Electrical Engineering and Computer Science National Taiwan University No. 1 Sec. 4 Roosevelt Road Taipei 10617 Taiwan. yjtseng@csie.ntu.edu.tw. Physics Division National Center for Theoretical Sciences No. 1 Sec. 4 Roosevelt Road Taipei 10617 Taiwan. yjtseng@csie.ntu.edu.tw. Center for Quantum Science and Engineering National Taiwan University No. 1 Sec. 4 Roosevelt Road Taipei 10617 Taiwan. yjtseng@csie.ntu.edu.tw.

Quantum computing is at the forefront of technological advancement and has the potential to revolutionize various fields, including quantum chemistry. Choosing an appropriate quantum programming language becomes critical as quantum education and research increase. In this paper, we comprehensively compare two leading quantum programming languages, Qiskit and PennyLane, focusing on their suitability for teaching and research. We delve into their basic and advanced usage, examine their learning curves, and evaluate their capabilities in quantum computing experiments. We also demonstrate using a quantum programming language to build a half adder and a machine learning model. Our study reveals that each language has distinct advantages. While PennyLane excels in research applications due to its flexibility to adjust parameters in detail and access multiple sources of real quantum devices, Qiskit stands out in education because of its web-based graphical user interface and smaller code size. The codes and the dataset used in the studies are available at https://***/wangpeihua1231/quantum-programming-platform .

关键词： PennyLane Qiskit Quantum chemistry Quantum computing Quantum programming language

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SIRT1/PARP1 crosstalk: Connecting DNA damage and metabolism

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Genome Integrity 2013年第1期4卷 1-11页

作者： Luna, Augustin Aladjem, Mirit I. Kohn, Kurt W. Laboratory of Molecular Pharmacology Center for Cancer Research National Cancer Institute NIH Bethesda MD 20892 United States Bioinformatics Program Boston University Boston MA 02215 United States

An intricate network regulates the activities of SIRT1 and PARP1 proteins and continues to be uncovered. Both SIRT1 and PARP1 share a common co-factor nicotinamide adenine dinucleotide (NAD+) and several common substrates, including regulators of DNA damage response and circadian rhythms. We review this complex network using an interactive Molecular Interaction Map (MIM) to explore the interplay between these two proteins. Here we discuss how NAD + competition and post-transcriptional/translational feedback mechanisms create a regulatory network sensitive to environmental cues, such as genotoxic stress and metabolic states, and examine the role of those interactions in DNA repair and ultimately, cell fate decisions. © 2013 Luna et al.;licensee BioMed Central Ltd.

关键词： Circadian rhythms DNA damage repair Metabolism Nicotinamide Adenine Dinucleotide (NAD+) competition PARP1 Poly-(ADP) polymerases Post-translational modifications SIRT1 Sirtuins Transcriptional regulation

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Application of Random Forest in Limited Size Human Long Non-coding RNAs Identification with Secondary Structure Features 23

Application of Random Forest in Limited Size Human Long Non-...

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23rd International Computer Science and Engineering Conference, ICSEC 2019

作者： Anuntakarun, Songtham Wattanapornprom, Warin Lertampaiporn, Supatcha King Mongkut's University of Technology Thonburi Bioinformatics and Systems Biology Program Bangkok Thailand University of Technology Thonburi Department of Mathematics Bangkok Thailand Bangkok Thailand

ISBN: (纸本)9781728125442

In this work, preliminary experiments of using diverse machine learning algorithms and testing of multiple relevant features to discriminate between human lncRNAs and coding/partial coding sequences was performed. This research limited the size of human lncRNAs such that they are shorter than 1000 nucleotides. Various significant features in describing RNA sequence including sequenced based features, secondary structure features, base-pair features and structural robustness features were used in this study. Then, the top 20 significant features were selected using Wilcoxon rank-sum test and discovered that the secondary structure features are the unique characteristics for identifying the human lncRNAs which are quite difference with those in the groups of shorter and longer types of ncRNAs. Such features are suitable with the rule-based classifiers like Random Forest. According to 10-folding cross validation, the random forest model has shown the highest accuracy, sensitivity and specificity as well as the lowest false positive rate among all competitors. Furthermore, the model was compared with other state-of -the-art approaches such as CPC, CPAT, RNAcon and achieved the highest accuracy of 84.5% among all the participants. © 2019 IEEE.

关键词： RNA

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Using dnase digestion data to accurately identify transcription factor binding sites 18

Using dnase digestion data to accurately identify transcript...

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18th Pacific Symposium on Biocomputing, PSB 2013

作者： Luo, Kaixuan Hartemink, Alexander J. Program in Computational Biology and Bioinformatics Duke University DurhamNC27708 United States Department of Computer Science Duke University DurhamNC27708 United States

Identifying binding sites of transcription factors (TFs) is a key task in deciphering transcriptional regulation. ChIP-based methods are used to survey the genomic locations of a single TF in each experiment. But methods combining DNase digestion data with TF binding specificity information could potentially be used to survey the locations of many TFs in the same experiment, provided such methods permit reasonable levels of sensitivity and specificity. Here, we present a simple such method that outperforms a leading recent method, centipede, marginally in human but dramatically in yeast (average auROC across 20 TFs increases from 74% to 94%). Our method is based on logistic regression and thus benefits from supervision, but we show that partially and completely unsupervised variants perform nearly as well. Because the number of parameters in our method is at least an order of magnitude smaller than centipede, we dub it millipede.

关键词： Transcription factors

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Measurement of renal blood flow in a rat model using diffuse correlation spectroscopy

Measurement of renal blood flow in a rat model using diffuse...

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Microscopy Histopathology and Analytics, Microscopy 2024 - Part of Optica Biophotonics Congress: Biomedical Optics

作者： Nakabayashi, Mikie Ono, Yumie Electrical Engineering Program Graduate School of Science and Technology Meiji University Kanagawa Japan Department of Electronics and Bioinformatics School of Science and Technology Meiji University Kanagawa Japan

ISBN: (纸本)9781957171340

关键词： Detectors Laser sources Lasers Near infrared Photon counting Spectroscopy

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ExpHTS: Analysis of high throughput sequence data in an experimental framework 15

ExpHTS: Analysis of high throughput sequence data in an expe...

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6th ACM Conference on bioinformatics, Computational Biology, and Health Informatics, BCB 2015

作者： Streett, David A. Petersen, Kristen R. Gerritsen, Alida T. Hunter, Samuel S. Settles, Matthew L. Program in Bioinformatics and Computational Biology University of Idaho MoscowID83844-3051 United States Institute for Bioinformatics and Evolutionary Studies University of Idaho MoscowID83844-3051 United States Department of Biological Sciences University of Idaho MoscowID83844-3051 United States

ISBN: (纸本)9781450338530

Analysis time and storage space are critical bottlenecks when analyzing multi-sample, comparative high throughput sequence experiments. The experimental High Throughput Sequencing (expHTS) pipeline mitigates these bottlenecks by streaming external application data, speeding analysis, and reducing storage space by eliminating intermediate, un-analyzed files. This creates faster run times, less storage space on the machine, and improves uniformity of sample analysis. Copyright 2015 ACM.

关键词： Pipelines

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Super deduper, fast PCR duplicate detection in fastq files. 15

Super deduper, fast PCR duplicate detection in fastq files.

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6th ACM Conference on bioinformatics, Computational Biology, and Health Informatics, BCB 2015

作者： Petersen, Kristen R. Streett, David A. Gerritsen, Alida T. Hunter, Samuel S. Settles, Matthew L. Program in Bioinformatics and Computational Biology University of Idaho MoscowID83844-3051 United States Institute for Bioinformatics and Evolutionary Studies University of Idaho MoscowID83844-3051 United States Department of Biological Sciences University of Idaho MoscowID83844-3051 United States

ISBN: (纸本)9781450338530

Our goal was to explore the accuracy and utility of identifying and removing PCR duplicates from HTS data using Super Deduper. Super Deduper is a pre-alignment, sequence read based technique developed at the University of Idaho, which examines and uses only a small portion of each read's sequence in order to identify and remove PCR and/or optical duplicates. Through comparisons with well-known pre and post-alignment techniques, Super Deduper's parameters were optimized and its performance assessed. The results conclude that Super Deduper is a viable prealignment alternative to post-alignment techniques. Super Deduper is both independent of a reference genome and choice in alignment application, allowing for its use in a greater variety of HTS applications. Super Deduper is an open source application and can be found at https://***/dstreett/Super-Deduper. Copyright 2015 ACM.

关键词： Alignment

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Resistance to BRAF inhibitors drives melanoma sensitivity to Chk1 inhibition

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Pharmacological Research 2025年 217卷 107797页

作者： Danielle G. Carvalho Juliana C.N. Kenski Daniel A. Moreira Matheus A. Rajão Oscar Krijgsman Carolina Furtado Mariana Boroni João P.B. Viola Daniel S. Peeper Patricia A. Possik Program of Immunology and Tumor Biology Division of Basic and Experimental Research Brazilian National Cancer Institute Rio de Janeiro Brazil Division of Molecular Oncology and Immunology Oncode institute The Netherlands Cancer Institute Amsterdam the Netherlands Laboratory of Bioinformatics and Computational Biology Division of Basic and Experimental Research Brazilian National Cancer Institute Rio de Janeiro Brazil Bioinformatics Core Facility Oswaldo Cruz Foundation Rio de Janeiro Brazil Genomics core facility Brazilian National Cancer Institute Rio de Janeiro Brazil Wellcome Sanger Institute Hinxton Cambridgeshire United Kingdom

BRAF inhibitor-resistant melanomas (BRAFiR) acquire (epi)genetic and functional alterations that enable them to evade alternative treatments. Identifying these alterations is critical to advancing treatment strategies. Here, we explored the effect of Chk1 inhibition (Chk1i) on BRAFiR cells, revealing higher sensitivity compared to treatment-naïve cells both in vitro and in vivo . Using FUCCI-labeling and time-lapse microscopy, we show that S phase progression is required for Chk1i-induced cytotoxicity in BRAFiR cells, but not in treatment-naïve cells. Replication stress markers, including reduced BrdU incorporation and increased phospho-RPA and γH2AX, were observed mostly in BRAFiR cells with increased sensitivity to Chk1i. Untreated BRAFiR cells exhibited upregulated DNA replication genes, reduced progressing forks and increased origin firing, suggesting intrinsic replication changes. MAPK pathway reactivation in treatment-naïve cells mimicked BRAFiR traits, increasing sensitivity to Chk1i. These findings indicate that Chk1i exploits elevated replication stress specifically in BRAFiR cells, highlighting its therapeutic potential in overcoming MAPK inhibitor resistance in BRAF 600 -mutant melanoma.

关键词： BRAF V-Raf Murine Sarcoma Viral Oncogene Homolog B MAPK Mitogen-activated protein kinase Chk1 Checkpoint kinase 1 PMA Phorbol myristate acetate RAS RAS GTPase RPA Replication Protein A γH2AX Phosphorylated H2A histone family member X ATR Ataxia Telangiectasia and Rad3-related protein FUCCI Fluorescent ubiquitination-based cell cycle indicator POL Polimerases P53 tumor protein 53 MPAS MAPK Pathway Activity Score Melanoma BRAF Targeted therapy Replication Stress

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