Functional & Integrative Genomics最新文献

{"title":"RNA modifications as determinants of cancer cell death: from epitranscriptomic mechanisms to therapeutic targeting","authors":"Anirban Goutam Mukherjee,&nbsp;Ankit Kumar Bharti,&nbsp;Deepthi Maria Mathew,&nbsp;Bhavani Manoj Varma,&nbsp;Sristy Pradhan,&nbsp;Abilash Valsala Gopalakrishnan","doi":"10.1007/s10142-026-02016-6","DOIUrl":"10.1007/s10142-026-02016-6","url":null,"abstract":"<div><p>Epitranscriptomics has rapidly evolved into a central layer of post-transcriptional gene regulation in cancer, yet its mechanistic contribution to regulated cell death remains incompletely resolved. This review critically examines how RNA modifications principally N⁶-methyladenosine (m⁶A), alongside 5-methylcytosine (m⁵C), N⁷-methylguanosine (m⁷G), pseudouridylation (Ψ), and adenosine-to-inosine (A-to-I) editing reprogram apoptotic and ferroptotic thresholds in malignant cells. It highlights that m⁶A does not exert uniform effects; rather, outcomes are dictated by site specificity, reader stoichiometry, and cellular context, with opposing roles observed in the regulation of BCL-2 family signaling and the SLC7A11-GPX4 antioxidant axis. The analysis extends beyond m⁶A to evaluate emerging, yet often under-validated, evidence implicating m⁵C in ferroptosis resistance, A-to-I editing in immune evasion, and m⁷G/Ψ in translational control of survival programs. Importantly, the review integrates tumor microenvironmental pressures including hypoxia, reactive oxygen species, and immune signaling-as dynamic modulators of epitranscriptomic machinery, thereby linking RNA chemistry to adaptive stress responses and therapeutic resistance. Despite rapid technological advances, including MeRIP-seq, crosslinking-based mapping, and nanopore direct RNA sequencing, the field remains constrained by limited resolution, lack of quantitative stoichiometry, and insufficient site-specific functional validation. Many conclusions are derived from global perturbation of epitranscriptomic enzymes, obscuring causal attribution to individual modified transcripts. From a translational perspective, targeting writers, erasers, and readers offers promise for sensitizing tumors to cell death; however, pleiotropy, context dependency, and potential toxicity present significant barriers. Overall, this review argues that while epitranscriptomics represents a compelling regulatory axis in cancer cell death, advancing the field will require integrative, high-resolution, and functionally precise approaches to move beyond correlative frameworks toward mechanistic and clinically actionable insights.</p></div>","PeriodicalId":574,"journal":{"name":"Functional & Integrative Genomics","volume":"26 1","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148838177","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Berberine-associated lipid-inflammatory regulation in atherosclerosis: an integrative transcriptomic, single-cell, and in vivo study","authors":"Diwei Yao,&nbsp;Xianqin Wang,&nbsp;Yihang Li,&nbsp;Yiping Wang,&nbsp;Xue Mao,&nbsp;Yu-E Wang,&nbsp;Yu Qi,&nbsp;Yanning Qiu,&nbsp;Jiale Chen,&nbsp;Lian Shu","doi":"10.1007/s10142-026-02019-3","DOIUrl":"10.1007/s10142-026-02019-3","url":null,"abstract":"<div><p>Atherosclerotic plaques combine disturbed lipid metabolism with myeloid inflammation, yet the human plaque context of berberine (BBR)-related targets remains poorly defined. Paired GSE43292 samples were used to characterize plaque-associated changes, GSE100927 to test reproducibility, and GSE159677 to resolve their cellular distribution. Network pharmacology prioritized BBR-atherosclerosis candidates, with molecular docking and 100-ns molecular dynamics used for structural evaluation. High-fat diet-fed <i>ApoE</i>^{<i>−/−</i>} mice received BBR or nanoliposomal BBR (BNL), with atorvastatin as a comparator. In GSE43292, inflammatory response, TNFA signaling via NF-κB, cholesterol homeostasis, and fatty acid metabolism were enriched in plaques. GSE100927 reproduced inflammatory response at the pathway level; <i>ABCA1, CD36, IL1B</i>, and <i>TNF</i> showed concordant expression changes. <i>ABCA1, CD36</i>, and <i>IL1B</i> were detected mainly in monocyte/macrophage and other myeloid populations. Inflammatory macrophages showed larger disease–control differences in inflammatory response and TNFA/NF-κB module scores. Among 70 overlapping BBR–atherosclerosis targets, <i>PPARG</i> was retained for further evaluation. The predicted BBR–PPARγ pose remained relatively stable during simulation. In mice, BBR and BNL lowered serum total cholesterol and low-density lipoprotein cholesterol, reduced hepatic IL-1β, IL-6, and TNF-α, and attenuated liver lipid deposition. Hepatic PPARγ increased significantly only in the BNL group. These findings delineate the myeloid cellular context of lipid- and inflammation-related signals in human plaques and show that BBR and BNL improve selected lipid and hepatic inflammatory measures in <i>ApoE</i>^{<i>−/−</i>} mice. <i>PPARG</i> remains a candidate for functional investigation. </p></div>","PeriodicalId":574,"journal":{"name":"Functional & Integrative Genomics","volume":"26 1","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148823463","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrated bulk and single-cell transcriptomic analyses identify senescence-related hub genes and microenvironmental remodeling in sarcopenia","authors":"Yan Chen,&nbsp;Kewen Ma,&nbsp;Tianchong Huang,&nbsp;Jing Gao,&nbsp;Xiaodong Feng","doi":"10.1007/s10142-026-02023-7","DOIUrl":"10.1007/s10142-026-02023-7","url":null,"abstract":"&lt;div&gt;&lt;p&gt;Increasing evidence indicates that cellular senescence, metabolic dysfunction, stromal remodeling, and immune perturbation collectively contribute to disease progression. However, senescence-related biomarkers with diagnostic potential and microenvironmental relevance in sarcopenia remain insufficiently defined. We integrated bulk transcriptome data from sarcopenia and control samples, with senescence-associated gene sets from the GenAge and CellAge databases to identify senescence-related differentially expressed genes (DEGs). Transcriptomic landscape was characterized via principal component analysis (PCA), volcano plot visualization, heatmap clustering, functional enrichment analysis, and gene set enrichment analysis (GSEA). Candidate diagnostic genes were screened using three complementary machine learning algorithms: least absolute shrinkage and selection operator (LASSO), support vector machine-recursive feature elimination (SVM-RFE), and random forest (RF). Diagnostic performance was assessed by receiver operating characteristic (ROC) analysis, nomogram construction, and decision curve analysis (DCA). Immune and stromal infiltration patterns were estimated via single-sample gene set enrichment analysis (ssGSEA) and xCell deconvolution. Single-cell RNA sequencing (scRNA-seq), pseudotime trajectory analysis, hub gene-centered GSEA/GSVA, weighted gene co-expression network analysis (WGCNA), immune checkpoint correlation analysis, and ligand-receptor communication analysis were further performed to investigate the cellular localization, dynamic expression patterns, and potential regulatory roles of hub genes. Animal experiment was conducted to validate the reliability of the main analyses. A total of 42 senescence-related DEGs were identified in sarcopenia. Functional enrichment analyses indicated significant involvement of kinase activity regulation, receptor tyrosine kinase-related signaling, JAK-STAT signaling, AMPK signaling, ERK1/2 cascade regulation, and extracellular matrix-related pathways. GSEA revealed positive enrichment of NABA Core Matrisome and negative enrichment of the citric acid cycle and respiratory electron transport pathway in sarcopenia. Integrative machine learning analysis converged on PCK1, EGFR, and MAPKAPK3 as senescence-related hub genes. PCK1 and EGFR were significantly upregulated in sarcopenia, whereas MAPKAPK3 was significantly downregulated. The individual AUC values for diagnosis were 0.777 (PCK1), 0.764 (EGFR), and 0.751 (MAPKAPK3), while the combined three-gene model achieved an improved AUC of 0.801. Immune infiltration analysis showed that PCK1 and EGFR were positively associated with fibroblast-related stromal signatures, while MAPKAPK3 showed an opposite trend and was more closely linked to Th1-cell-related immune features. Single-cell and pseudotime analyses further demonstrated that these hub genes exhibited distinct cellular localization and dynamic expression patterns across the myogenic line","PeriodicalId":574,"journal":{"name":"Functional & Integrative Genomics","volume":"26 1","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148817082","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Systematic review and meta-analysis of circulating microRNAs in dengue infection: biomarkers, pathogenesis, and clinical implications","authors":"Gokulakannan Venkatesan,&nbsp;Wan Suriana Wan Ab Rahman,&nbsp;Wan Nazatul Shima Shahidan,&nbsp;Norliana Ghazali,&nbsp;Hisham Atan Edinur","doi":"10.1007/s10142-026-02014-8","DOIUrl":"10.1007/s10142-026-02014-8","url":null,"abstract":"<div><p>Dengue infection is a mosquito-borne disease that can cause mild illness or severe haemorrhagic fever. Predictive biomarkers for severe cases, especially those with bleeding manifestations or plasma leakage, are currently lacking. This systematic review and meta-analysis synthesises findings from studies on circulating miRNAs in dengue infection, sourced from PubMed, Scopus, Science Direct, and Web of Science, with quality assessed by the Newcastle–Ottawa Scale (PROSPERO: CRD42024521685). Quantitative meta-analyses were conducted using RStudio to evaluate diagnostic Area Under the Curve (AUC) metrics across five eligible studies and Standardised Mean Differences (SMD) for differential miRNA expression. Key miRNAs, such as miR-146a, miR-150, miR-378, miR-21-5p, and miR-1246, were found to regulate immune responses, inflammation, and viral replication. Meta-analysis demonstrated high overall diagnostic accuracy for circulating miRNAs, with individual reported AUC values ranging from 0.79 to 1.00; however, substantial statistical heterogeneity was observed across pooled metrics (I-squared exceeding 89%). SMD analysis highlighted significant upregulation of acute inflammatory drivers, including miR-21-5p (SMD = 4.67) and miR-450b-5p (SMD = 6.76), alongside marked downregulation of endothelial-protective markers such as miR-126-3p (SMD = -1.31). Rather than viewing dysregulated microRNAs as a uniform class of clinical tools, this review highlights that candidate microRNAs span distinct translational tiers. Recognising these validation levels alongside pre-analytical and biological heterogeneity is essential for prioritising the most viable microRNA candidates for future prospective clinical translation and targeted therapies in dengue management.</p></div>","PeriodicalId":574,"journal":{"name":"Functional & Integrative Genomics","volume":"26 1","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148823507","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comprehensive study of the tumor immune microenvironment and the prognostic significance of reticulocalbin-1: a pan-cancer analysis","authors":"JiangLi Zhao,&nbsp;XuChen Liu,&nbsp;QingYuan Sun,&nbsp;ShuJie Peng,&nbsp;ZhiWei Xue,&nbsp;JunZhi Liu,&nbsp;Bin Huang,&nbsp;JiWei Wang,&nbsp;Chao Li,&nbsp;Ning Yang,&nbsp;Xinyu Wang","doi":"10.1007/s10142-026-02017-5","DOIUrl":"10.1007/s10142-026-02017-5","url":null,"abstract":"<div><p>Reticulocalbin-1 (RCN1), an endoplasmic reticulum (ER)-related gene, demonstrates critical regulatory functions in cellular growth. RCN1 has been previously revealed to be closely associated with initiation, metastasis and chemosensitivity in some tumors. However, the prognostic significance of RCN1 and its influence on the cancer immune microenvironment remains unclear. By leveraging multi-omics data from TCGA and GEO, this study delineated the expression profile of RCN1 across various human malignancies and normal tissues. Analysis of RCN1 expression in correlation with tumor immune microenvironment characteristics was performed using CIBERSORT and ssGSEA. Pan-cancer prognostic value was assessed via multiple survival models. In glioma, immunohistochemistry, co-culture, and qPCR were utilized to further investigate the role of RCN1 in tumor immunity and prognosis. Drug-specific responses to RCN1 expression were probed for cisplatin, irinotecan, carmustine and lomustine, which are the common chemotherapeutic agents used in glioma clinical treatment. The results indicate that RCN1 is a key gene with the potential to promote the progression of multiple tumors and is closely associated with tumor immune response, particularly macrophage activation. In glioma, overexpression of RCN1 promotes tumor proliferation and indicates poor prognosis, and is closely related to endoplasmic reticulum stress. Knockdown of RCN1 enhances the chemotherapeutic efficacy of carmustine and lomustine. In conclusion, our research positioned RCN1 as an important oncogene from a pan-cancer perspective and validated its role in glioma. In particular, RCN1 is closely associated with the immune microenvironment and endoplasmic reticulum stress during tumorigenesis. In addition, RCN1 has broad prospects in guiding tumor chemotherapy pending physiological in vivo validation.</p></div>","PeriodicalId":574,"journal":{"name":"Functional & Integrative Genomics","volume":"26 1","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s10142-026-02017-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148823448","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sucrose and starch metabolism pathways as candidate regulatory pathways in the salt stress response revealed by transcriptomic and metabolomic analysis during soybean (Glycine max) germination","authors":"Jiayuan Zhang,&nbsp;Zhen Wang,&nbsp;Xue He,&nbsp;Xianya Dong,&nbsp;Yitong Yin,&nbsp;Huixian Zheng,&nbsp;Shaokun Zhang,&nbsp;Kehan Duan,&nbsp;Xin Ding,&nbsp;Conghe Liu,&nbsp;Chongzhuo Zhan,&nbsp;Wentao Cai,&nbsp;Di Cao,&nbsp;Qi Zhang,&nbsp;Ziyi Yang,&nbsp;Yanjie Li,&nbsp;Lichun Huang","doi":"10.1007/s10142-026-01998-7","DOIUrl":"10.1007/s10142-026-01998-7","url":null,"abstract":"<div><p>Soybean is a globally important grain and oil crop, and salt stress severely restricts its germination and seedling establishment, ultimately reducing yields. However, the core metabolic regulatory network underlying its salt-stress response and during seed germination remains poorly understood. In this study, the soybean cultivar ‘Heihe 91’ was cultivated under control (0 mmol/L NaCl) and 150 mmol/L NaCl salt treatments. Phenotypic and physiological assays combined with transcriptomic and non-targeted metabolomic analyses were performed to explore the salt response mechanism during germination. Salt stress significantly inhibited seedling growth, induced oxidative damage, and activated the antioxidant enzyme system. A total of 6,410 differentially expressed genes and numerous differentially accumulated metabolites were identified, both of which were significantly enriched for annotations to the starch and sucrose metabolism pathway. Salt stress significantly reduced starch content by 32.74% and increased sucrose content, with upregulation of key rate-limiting enzyme genes, including sucrose synthase, β-amylase, and glycogen phosphorylase. RT-qPCR and physiological quantification confirmed the reliability of the omics results. This study demonstrates that the starch and sucrose metabolism pathway is the core regulatory pathway through which soybeans respond to salt stress during germination, thus mediating carbon partitioning reprogramming from storage substance accumulation to osmotic adjustment and stress defense. These findings provide key candidate genes and an empirical basis for salt tolerance genetic improvement of soybean at the germination stage.</p></div>","PeriodicalId":574,"journal":{"name":"Functional & Integrative Genomics","volume":"26 1","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148817072","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bioinformatic identification of THY1 as a target in osteoarthritis and its effects on chondrocyte senescence and apoptosis","authors":"Liangkun Huang,&nbsp;Ya Wen,&nbsp;Hanzhe Xu,&nbsp;Ze Zhang,&nbsp;Zijie Pei,&nbsp;Piqian Zhao,&nbsp;Fengpo Sun","doi":"10.1007/s10142-026-02020-w","DOIUrl":"10.1007/s10142-026-02020-w","url":null,"abstract":"<div><p>Osteoarthritis (OA) is the most prevalent degenerative joint disease worldwide and imposes a substantial public health burden due to the lack of effective disease-modifying drugs. Exosome-related genes participate in exosome biogenesis, cargo sorting, and secretion, serving as critical regulatory elements in exosome-mediated intercellular communication. However, their systematic characterization in OA and their potential as diagnostic or therapeutic targets remain largely unexplored. We obtained OA and normal control samples from the GEO database. Using exosome-related gene signatures as a filtering strategy, we integrated differential expression analysis, protein–protein interaction network assessment, and machine learning algorithms to screen for key diagnostic genes, and constructed and externally validated diagnostic models and nomograms. Enrichment analysis and immune infiltration assessment were performed to explore biological functions and immune microenvironment features. Cellular experiments were conducted to validate the effects of the prioritized gene THY1 on chondrocyte apoptosis, senescence, mitochondrial function, and cell viability. We successfully identified THY1, FAP, and TIMP4 as independent diagnostic markers for OA and constructed a diagnostic model and nomogram with high applicability, whose reliability was validated in an external validation cohort. Enrichment and immune infiltration analyses preliminarily identified two OA subtypes with distinct immune infiltration profiles. Cellular experiments confirmed that THY1 overexpression promoted chondrocyte senescence and apoptosis under OA-like inflammatory conditions, while impairing mitochondrial function and cell viability. Through bioinformatic screening and in vitro experimental validation, this study reveals the pro-apoptotic and pro-senescent regulatory effects of THY1 on chondrocytes under inflammatory conditions, and establishes a diagnostic model and subtyping framework for OA based on three genes, offering new perspectives for stratified diagnosis and future translational research in OA.</p></div>","PeriodicalId":574,"journal":{"name":"Functional & Integrative Genomics","volume":"26 1","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148817093","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrated genome-wide high-throughput screening and functional validation identifies Sm proteins as essential splicing regulators for gastric cancer progression","authors":"Daihong Chen,&nbsp;Jie Wu,&nbsp;Yonggang Zhang,&nbsp;Yubo Chen,&nbsp;Jiacheng Yu,&nbsp;Juan Ye,&nbsp;Dan Li,&nbsp;Lijuan Gu,&nbsp;Juan Li,&nbsp;Xiaoxing Xiong,&nbsp;Zhi Zeng","doi":"10.1007/s10142-026-02015-7","DOIUrl":"10.1007/s10142-026-02015-7","url":null,"abstract":"<div><p>Alternative splicing mediated by Smith antigen (Sm) proteins involving seven small nuclear ribonucleoprotein polypeptides (SNRPs), plays a critical role in cancer progression. Our previous work identified Sm protein B (SNRPB) as an essential gene in gastric cancer (GC) cells. However, the functional roles of the broader Sm proteins and their regulatory mechanisms in GC progression remain unclear. Integrating genome-wide CRISPR-Cas9 and RNA interference proliferation screening data from human GC cell lines, we identified Sm proteins as essential genes for GC growth. Analysis of RNA-seq data from the Cancer Cell Line Encyclopedia and The Cancer Genome Atlas revealed elevated Sm proteins mRNA levels in GC. Further Single-cell RNA sequencing data from the GSE183904 dataset further confirmed Sm proteins overexpression in GC malignant epithelial cells. Functional validation demonstrated that knockdown of SNRPB, SNRPD1, SNRPD2, or SNRPD3 suppressed GC cell proliferation. Specifically, scRNA-seq data analysis and in vitro assays showed that SNRPB depletion modulated the expression of apoptosis-related proteins, thereby impairing cell proliferation and migration while promoting apoptosis. Consistently, SNRPB knockdown markedly inhibited tumor growth in xenograft models. Mechanistically, SNRPB depletion mediated exon skipping in CASP6 pre-mRNA, upregulating CASP6 transcript variant ENST00000352981, which restrained proliferation and induced apoptosis. Clinical analysis of four independent cohorts revealed that SNRPB overexpression in GC tissues was significantly associated with poor patient prognosis. In conclusion, our integrated approach defines the Sm proteins as essential for GC progression. Specifically, SNRPB mediated exon skipping of CASP6 facilitates tumor progression, highlighting the therapeutic potential of targeting this splicing pathway.</p></div>","PeriodicalId":574,"journal":{"name":"Functional & Integrative Genomics","volume":"26 1","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148817107","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dynamics-aware evolutionary profiling uncouples structural rigidity from functional motion to enable enhanced variant interpretation","authors":"Taner Karagöl,&nbsp;Alper Karagöl","doi":"10.1007/s10142-026-02013-9","DOIUrl":"10.1007/s10142-026-02013-9","url":null,"abstract":"<div><p>Evolutionary conservation is a powerful part of mutational intolerance prediction, yet traditional pathogenicity metrics frequently conflate two distinct biophysical constraints: structural stability (rigidity) and functional mechanics (dynamics). We introduce Dynamics-Aware Evolutionary Profiling to resolve this ambiguity, integrating Molecular Dynamics with evolutionary conservation and coupling analysis across human/cross-species-proteome of 151 protein structures. By mathematically uncoupling biophysical forces, we define largely independent metrics; the <i>R</i>igid <i>C</i>onserved <i>S</i>core (RCS) for the structural scaffold, and the <i>D</i>ynamic <i>C</i>onserved <i>S</i>core (DCS) for flexible residues. Our analysis reveals a fundamental bifurcation in pathogenicity. RCS serves as a filter for lethal structural failure, isolating hydrophobic core residues whose mutation triggers unfolding. In contrast, DCS identified a rare population of residues that are evolutionarily highly-conserved but structurally mobile; these Dynamic-Conserved sites exhibit intermediate pathogenicity and are enriched in flexible hinge residues (Gly, Pro). Validation against 737 human variants from ClinVar suggests that DCS may capture a distinct pathogenic mechanism regarding essential protein motion. Notably, DCS and RCS correctly flagged some pathogenic variants of NARS1 and PGK1 that were misclassified as benign or ambiguous by AlphaMissense. These results indicate that while the rigid core represents a stability bottleneck, DCS isolates functional sites likely driving allosteric regulation. We provide an open-access web interface (<i>ADEPT</i>) for these metrics. By isolating dynamic-conserved residues, this framework refines the interpretation of Variants of Uncertain Significance in dynamic regions and reveals tunable targets for rational drug design, moving beyond the static optimization of the folded state.</p></div>","PeriodicalId":574,"journal":{"name":"Functional & Integrative Genomics","volume":"26 1","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148783430","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrated genomic analysis of Salmonella Typhi from Pakistan: Antimicrobial resistance determinants, pangenome structure, and reverse vaccinology-driven vaccine target discovery","authors":"Hamza Arshad Dar,&nbsp;Arslan Saleem Chughtai,&nbsp;Ali Hyder Baig,&nbsp;Kashif Asghar","doi":"10.1007/s10142-026-02011-x","DOIUrl":"10.1007/s10142-026-02011-x","url":null,"abstract":"<div><p><i>Salmonella enterica</i> serovar Typhi (<i>S.</i> Typhi) is the aetiologic agent of typhoid fever in humans. The burden of typhoid is highest in low- and middle-income countries such as Pakistan. Moreover, the increasing emergence of antibiotic-resistant and hypervirulent <i>S.</i> Typhi strains highlights the need for deeper genomic understanding as current treatment regimens become progressively less effective. Therefore, this study analyzed publicly available <i>S.</i> Typhi genomes from Pakistan to characterize genomic diversity, sequence types, plasmid content, and antimicrobial resistance and virulence profiles. Subsequently, pangenome analysis identified conserved core proteins, which were screened via reverse vaccinology to prioritize potential vaccine candidates. Analysis of 71 high-quality <i>S.</i> Typhi genomes identified ST-1 and ST-2 as the predominant sequence types, a finding aligned with global trends. While plasmids were detected in 32% (n = 23) of isolates, these strains exhibited significantly higher antimicrobial resistance and virulence factor gene counts compared to plasmid-free strains (p &lt; 0.05). All isolates were found to have the <i>aac(6')-Iaa</i> gene. The isolates harbored Salmonella Pathogenicity Islands (SPIs), including SPI-1 through SPI-10 and SPI-12. Pangenome analysis revealed an open pangenome, with calculated pangenome size of 5912 and core genome size of 3849. Reverse vaccinology analysis prioritized three broad-spectrum <i>S.</i> Typhi antigens STY1784, STY1830, and STY2871 as prime vaccine candidates, with support from cross-pathogen data in the literature. Additionally, our study identified nine antigenic, strong-binding, promiscuous HLA class I epitopes. This study provides updated genomic insights into circulating <i>S.</i> Typhi in Pakistan and proposes novel, computationally validated vaccine targets, laying a crucial foundation for subsequent experimental investigation.</p></div>","PeriodicalId":574,"journal":{"name":"Functional & Integrative Genomics","volume":"26 1","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148782248","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}