Search Results (1,271)

Salmonella Typhimurium is a major zoonotic pathogen, with pigs and chickens serving as key reservoirs for human infection, yet the genomic determinants of its host adaptation remain incompletely understood. This study integrated comparative genomics, genome-wide association studies (GWASs), and interpretable machine learning on 1654 high-quality genomes of swine- and chicken-origin S. Typhimurium isolates to identify host-associated genetic features. Phylogenetic analysis revealed host-preferred lineages and significantly lower genetic diversity within chicken-adapted subpopulations. Meta-analysis identified distinct host-associated profiles of antimicrobial resistance genes (e.g., higher prevalence of floR and bla_TEM-1 in swine) and virulence factors (e.g., enrichment of allB and the yersiniabactin system in chickens). GWASs pinpointed 1878 host-associated genes and multiple SNPs/indels, functionally enriched in metabolism, regulation, and cell processes. A two-stage Random Forest model, built using the most contributory features, accurately discriminated between swine and chicken origins (AUC = 0.974). These findings systematically revealed the genomic signatures of host adaptation in S. Typhimurium, providing a prioritized set of candidate markers for experimental validation. Full article

DNMT1 variants are linked to complex neurodegenerative syndromes, yet their variant-specific functional and epigenomic consequences remain poorly defined. DNMT1 variants were identified in eight patients using gene-panel or whole-exome sequencing. Functional effects were assessed by site-directed mutagenesis and transient expression in HEK293T cells. Genome-wide methylation profiling of peripheral blood leukocyte DNA was performed using Nanopore sequencing, enabling direct quantification of 5-methylcytosine (5mC). CpG island-level differential methylation and gene set enrichment analysis (GSEA) were conducted. Variants in the replication foci targeting sequence (RFTS) domain (p.Y511H, p.Y540C, p.H569R) exhibited reduced DNMT1 protein expression, decreased enzymatic activity, and cytosolic aggregation. Variants in the C-terminal catalytic domain (p.A1334V and p.P1546S) showed reduced protein expression with relatively mild enzymatic impairment. Patients carrying the p.Y511H variant demonstrated a significant reduction in global 5mC levels compared with controls. Principal component analysis revealed distinct methylomic profiles separating most patients from controls, with marked intra- and inter-familial heterogeneity. CpG island-level analysis identified a single significantly hypomethylated region in p.Y511H carriers, and GSEA revealed differential enrichment of multiple Gene Ontology biological pathways. This study defines domain-dependent functional effects of DNMT1 variants and provides the first nanopore-based methylome analysis, revealing variant-specific and heterogeneous epigenomic alterations. Full article

Background: The ACE Y215C mutation is a common, functionally damaging missense variant (~1.5% allele frequency) associated with reduced plasma ACE levels and increased Alzheimer’s disease (AD) risk. In CHO and HEK cell models, this mutation caused a ~3–6-fold decrease in ACE surface expression, soluble ACE levels, and ACE enzymatic activity compared to those of wild-type ACE. Methods: Circulating ACE levels and activity were measured in EDTA plasma obtained from 84 carriers of the ACE Y215C mutation using a set of mAbs to the ACE. The mAbs 5B3/1G12 binding ratio was revealed as a sensitive marker for the circulating Y215C ACE mutant. Whole-exome and whole-genome sequencing (WES/WGS) were performed to identify genetic variants potentially modifying circulating ACE levels. In parallel, published sequencing and proteomic data from 35,559 Icelanders participants were analyzed to identify genes influencing ACE shedding. Sequence comparison was performed between carriers with elevated and reduced ACE concentrations to identify the potential protective variants that may compensate for decreased ACE levels due to the Y215C mutation itself. Results: Most carriers of the Y215C ACE mutation demonstrated significantly decreased ACE levels (median is 62% of control ACE levels). However, substantial inter-individual variability was observed in plasma ACE activity among carriers. Comparative sequencing analysis revealed 9648 variants unique to individuals with elevated ACE, mapping to 5779 protein-coding genes and enriched for pathways related to intracellular and transmembrane transport. Conclusions: The presence of the damaging ACE mutation Y215C does not invariably result in low plasma ACE or, likely, elevated AD risk. Therefore, combined blood ACE phenotyping and whole-exome sequencing are recommended to more accurately assess ACE-related AD susceptibility in mutation carriers. Full article

Background: The present study set out to identify key miRNAs, TFs and signaling pathways associated with bladder cancer, with a view to elucidating the networks of miRNA-TF-gene interactions that may serve as potential molecular biomarkers for disease diagnosis. Methods: An integrative analysis was conducted using the publicly available microarray dataset GSE130598. Expression profanalyzede analyzed from 42 muscle-invasive bladder cancer (MIBC) tissues and 42 matched adjacent normal bladder tissues. After data preprocessing and normalization, differentially expressed genes (DEGs) were identified. To identify the associated biological processes and signaling pathways, functional enrichment analyses were conducted using the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. Protein–protein interaction (PPI) network analysis was then employed to identify hub genes and key molecular interaction modules associated with bladder cancer. Results: MYC, TP53, SP1, E2F1, E2F3, NFKB1, and TWIST1 were identified as central transcriptional regulators, indicating their roles in controlling genes involved in cell cycle regulation, DNA damage response, and tumor progression. Several miRNA families, including miR-200, miR-17, miR-29, miR-141, and miR-548, have been identified as key post-transcriptional regulators, suggesting their involvement in oncogenic signaling and cellular differentiation. PPI network analysis revealed MAPK3, AKT1, CHEK1, CDK1, AURKA, and AURKB as hub genes associated with cell proliferation, mitotic control, and intracellular signaling. Conclusions: Fundamental molecular processes underlying bladder cancer pathogenesis include cell cycle control, signal transduction, and genomic stability. These findings provide insight into the molecular regulatory landscape of MIBC and highlight potential targets for diagnostic and prognostic applications. Full article

Cremastra appendiculata, a rare medicinal orchid, has extremely low natural seed germination due to immature embryos and dense seed coats, impeding its conservation. Commensal germination with fungi is effective, but the action pathways remain unclear. This study combined morphological observation (scanning electron microscopy and section observation), physiological–biochemical detection (lignocellulolytic enzyme activities, nutrient/hormone contents, FTIR analysis) and transcriptomics to explore Coprinellus radians’ role in C. appendiculata seed germination, with commensal and non-commensal cultures on OMA medium set as experimental and control groups. Results showed C. radians significantly promoted C. appendiculata seed germination and protocorm development (superior to non-commensal conditions). Morphologically, C. radians hyphae invaded seed coats at 6 days post-inoculation; embryos broke through coats and formed apical meristems at 12 days, developing into peloton-containing protocorms at 25 days (breaking dormancy). Physiologically, C. radians secreted lignocellulolytic enzymes (laccase, cellulase, xylanase) to degrade coats, enhancing permeability and water uptake, while driving nutrient accumulation (starch, soluble sugars) and hormone balance. Transcriptomically, symbiosis activated carbon/energy metabolism genes, enriching starch-sucrose metabolism and glycolysis pathways. This study clarifies C. radians’ multi-dimensional action pathways in promoting C. appendiculata germination, providing support for rare orchid conservation. Full article

Background: Tic spectrum disorder (TSD), encompassing Tourette syndrome and chronic tic disorder, is a childhood-onset neurodevelopmental condition with complex genetic and environmental contributions. Heritable components have been implicated in TSD, but no clear genetic mechanisms have been identified. Significant aspects of TSD etiology remain unclear, with key uncertainties concerning the role of environmental influences in its development. In this study, we aimed to identify environmentally induced epigenomic and transcriptomic changes contributing to TSD pathology by investigating genetically similar monozygotic twins discordant for TSD. Methods: To investigate environmentally driven mechanisms, we analyzed peripheral blood from eleven monozygotic twin pairs, either discordant or concordant for TSD, using RNA sequencing and DNA methylation analysis. Results: Differential expression analysis identified a dozen differentially expressed genes between TSD and non-TSD individuals, most of which were long non-coding RNAs or pseudogenes. Expression of the small RNA gene RNY1 was significantly associated with tic severity, suggesting involvement of immune-related processes. DNA methylation (DNAm) analysis revealed ~30,000 probes with a nominal p < 0.05, however none of these were significant after multiple testing correction. Expression quantitative trait methylation (eQTM) analysis identified 236 methylation-associated genes. Gene set enrichment analysis demonstrated broad downregulation in TSD individuals for pathways related to translation, RNA processing, and neurobiological functions, with Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways including ribosome, nucleocytoplasmic transport, pluripotency signaling, and nicotine addiction. Conclusions: These results suggest that environmentally influenced gene expression may contribute to TSD pathogenesis through dysregulation of immune and neuronal pathways. Despite a small sample size, the monozygotic twin design provides strong control for genetic background and identifies significant differences that contribute to the understanding of the underlying molecular mechanisms of TSD. Full article

Background/Objectives: Vedolizumab (VDZ), a monoclonal antibody targeting α4β7 integrin, is used in Crohn’s disease (CD) management, yet patients’ responses vary, underscoring the need for pharmacogenomic (PGx) markers. This study aimed to identify PGx pathways associated with suboptimal VDZ response using a rare-variant analytical framework. Methods: DNA from 63 CD patients treated with VDZ as first-line advanced therapy underwent whole-exome sequencing. Clinical response at week 14 classified patients as optimal responders (ORs) or suboptimal responders (SRs). Sequencing data were processed using GATK Best Practices, annotated with variant effect predictors, and filtered for rare damaging variants (damaging missense and high-confidence loss-of-function; minor allele frequency < 0.05). Variants were mapped to genes specific for SRs and ORs, and analyzed for pathway enrichment using the Reactome database. Rare-variant burden and composition differences were assessed with Fisher’s exact test and SKAT-O gene-set association analysis. Results: Suboptimal VDZ response was associated with pathways related to membrane transport (ABC-family proteins, ion channels), L1–ankyrin interactions, and bile acid recycling, while optimal response was associated with pathways involving MET signaling. SKAT-O identified lipid metabolism-related pathways as significantly different—SRs harbored variants in pro-inflammatory lipid signaling and immune cell trafficking genes (e.g., PIK3CG, CYP4F2, PLA2R1), whereas ORs carried variants in fatty acid oxidation and detoxification genes (e.g., ACADM, CYP1A1, ALDH3A2, DECR1, MMUT). Conclusions: This study underscores the potential of exome-based rare-variant analysis to stratify CD patients and guide precision medicine approaches. The identified genes and pathways are potential PGx markers for CD patients treated with VDZ. Full article

Dendritic cells (DCs) are essential for antiviral immunity but are also susceptible to HIV-1 infection. Although sensing and restriction pathways in DCs are well described, the mechanisms underlying latent infection and its functional consequences remain unclear. In this study, we performed transcriptomic profiling of monocyte-derived DCs harboring transcriptionally active (Active-HIV) or latent HIV-1 (Latent-HIV) proviruses using a dual-reporter virus. Gene set enrichment analysis revealed suppression of metabolic and stress-modulatory programs in Active-HIV compared to unexposed DCs. In contrast, Latent-HIV showed broad downregulation of pathways, including interferon and innate responses and metabolic programs, indicating a hyporesponsive and dampened antiviral state despite the absence of differentially expressed genes (DEGs). DEG analysis of Active-HIV versus Latent-HIV showed that active transcription associates with cellular stress, cytoskeletal remodeling, and RNA processing. Functional analyses further demonstrated the activation of RNA processes, the suppression of antigen-presentation pathways, and altered membrane and cytoskeletal signaling in Active-HIV. These pathways suggest that transcriptionally active HIV-1 is linked to cellular programs supporting replication, coinciding with a metabolically strained yet immunologically engaged state that may impair antigen presentation. Conversely, latently infected DCs display a hyporesponsive state consistent with proviral silencing. This dichotomy reveals distinct mechanisms of DC dysfunction that may facilitate HIV-1 persistence and immune evasion. Full article

Prostate cancer (PCa) is a common malignancy among men worldwide. After radical prostatectomy (RP) and radical radiotherapy (RT), patients may experience biochemical recurrence (BCR) of prostate cancer, indicating disease progression. Therefore, it is meaningful to predict and accurately assess the risk of BCR, and a machine-learning-based-model for BCR prediction in PCa based on fatty-acid metabolism and cancer-cell stemness was developed. A stemness prediction model and ssGSEA (single-sample gene set enrichment analysis) empirical cumulative distribution function algorithm were used to score the stemness scoring (mRNAsi) and fatty-acid metabolism of prostate-cancer samples, respectively, and further analysis showed that the two scores of the samples were positively correlated. Based on WGCNA (weighted correlation network analysis), we discovered modules significantly associated with both stemness and fatty-acid metabolism and obtained the genes within them. Then, based on this gene set, 101 algorithm combinations of 10 machine-learning methods were used for training and prediction BCR of PCa, and the model with the best prediction effect was named fat_stemness_BCR. Compared with 23 published PCa BCR models, the fat_stemness_BCR model performs better in TCGA and CPGEA data. To facilitate the use of the model, the trained model was encapsulated into an R package and an online service tool (PCaMLmodel, Version 1.0) was built. The newly developed fat_stemness_SCR model enriches the prognostic research of biochemical recurrence in PCa and provides a new reference for the study of other diseases. Full article

Ovarian cancer (OC), the third most common gynecologic malignancy, is characterized by high mortality largely driven by chemotherapy resistance, leading to recurrence and metastasis. Using transcriptomic data from GSE73935, we constructed a weighted gene co-expression network and identified eight hub genes (IGF1R, CDH2, PDGFRA, CDKN1A, SHC1, SPP1, CAV1 and FGF18) associated with cisplatin resistance, among which CDH2 emerged as the most clinically relevant candidate. CDH2 demonstrated moderate diagnostic potential (AUC = 0.792) and was markedly upregulated in cisplatin-resistant A2780/CP70 cells. Independent validation using clinical single-cell RNA-seq data (GSE211956) confirmed its selective enrichment in resistant tumor cell subpopulations. Gene set enrichment analysis linked elevated CDH2 expression to p53 signaling, DNA replication, nucleotide excision repair, and Toll-like receptor pathways, with qPCR supporting upregulation of key downstream genes in resistant cells. Immune deconvolution further indicated that high CDH2 expression correlated with increased infiltration of NK cells, Tregs, macrophages, and neutrophils, and immunohistochemistry verified CDH2 overexpression in cisplatin-resistant tissues. In addition, virtual screening and drug sensitivity profiling identified several FDA-approved agents with potential relevance to CDH2-associated drug response. These findings indicate that CDH2 may serve as a candidate marker associated with cisplatin response in OC, and its association with immune cell infiltration provides further insight into mechanisms potentially underlying chemoresistance. Full article

Adiposity-Based Chronic Disease (ABCD) is known to increase the risk of aggressive prostate cancer (PCa), recurrent disease after treatment for localized PCa, and PCa mortality. A key mechanistic link contributing to this enhanced risk is chronic inflammation originating from excess white visceral adipose tissue (WAT; VAT) and periprostatic adipose tissue (ppWAT). Contributing to systemic inflammation is gut dysbiosis, which itself may be caused by ABCD as well as background local inflammation (prostatitis), which is common in aging men and may be exacerbated by the urinary microbiome. Investigating the molecular biology driving inflammation and its association with increased PCa risk, a recent paper applied a network and gene set enrichment to adipokine drivers in the ABCD-PCa network. It found prominent roles for MCP-1, IL-1β, and CXCL-1 in addition to confirming the importance of exposure to lipopolysaccharides and bacterial components, corroborating the role of gut dysbiosis. To further unravel the mechanistic links between ABCD and PCa risk, this critical review will discuss the current literature on prominent inflammatory signaling pathways activated in ABCD; the influence of gut dysbiosis, the urinary microbiome, and chronic prostatitis; and current hypotheses on how these domains may result in the development of aggressive PCa over a man’s life. Moreover, we performed a novel pathway enrichment analysis to further evaluate the associations between ABCD, PCa risk, gut dysbiosis, and the prostate microbiome, the results of which were partitioned into extracellular and intracellular signaling pathways. In the extracellular space, novel mechanistic links between gut dysbiosis and MCP-1, IL-1β, CXCL1, and leptin via bacterial pathogen signaling and the intestinal immune network (for IgA production), crucial for gut immune homeostasis, were found. Within the intracellular space, there were downstream signals activating chemokine and type 2 interferon pathways, focal adhesion PI3K/Akt/mTOR pathways, as well as the JAK/STAT, NF-κB, and PI3K/Akt pathways. Overall, these findings point to an emerging molecular pathway for PCa oncogenesis influenced by ABCD, gut dysbiosis, and inflammation, and further research, possibly with lifestyle program-based clinical trials, may discover novel biomarker panels and molecular targeted therapies for the prevention and treatment of PCa. Full article

Precocious-fruiting Amomum villosum Lour. is characterized by early fruit set, rapid yield formation, and shortened economic return cycles, indicating strong cultivation potential. However, the molecular mechanisms underlying its flowering transition remain unclear. To elucidate the flowering mechanism of A. villosum, we used the Illumina NovaSeq X Plus platform to compare gene expression profiles in three tissues (Rhizomes, R; Stems, S; Leaves, L) during the vegetative stage and three tissues (Rhizomes and Inflorescences, R&I; Stems, S; Leaves, L) during the flowering stage of individual plants: VS-R vs. FS-R&I, VS-S vs. FS-S, and VS-L vs. FS-L. We obtained 52.5 Gb clean data and 789 million reads, and identified 2963 novel genes. The 3061 differentially expressed genes (DEGs, FDR ≤ 0.05 and |log2FC| ≥ 1) identified in the three comparison groups included six overlapping genes. The DEGs were enriched primarily in GO terms related to cellular process, metabolic process, binding, catalytic activity, and cellular anatomical entity, as well as multiple terms associated with development and reproduction. KEGG enrichment analysis revealed enrichment primarily in metabolic pathways, including global and overview maps, energy metabolism, and carbohydrate metabolism. Moreover, the most significantly enriched core pathways included metabolic pathways, photosynthesis, and carbon assimilation. Among all alternative splicing (AS) events, skipped exons (SEs) accounted for the largest proportion (59.5%), followed by retained introns (RI, 19.4%), alternative 3′ splice sites (A3SS, 10.7%), alternative 5′ splice sites (A5SS, 6.8%), and mutually exclusive exons (MXE, 3.6%). A preliminary set of 43 key DEGs was predicted, displaying spatiotemporal expression specificity and strong interactions among certain genes. Nine genes were further selected for RT-qPCR validation to confirm the reliability of the RNA-seq results. This study established a foundational framework for elucidating the flowering mechanism of precocious-fruiting A. villosum. Full article

Background: Preeclampsia (PE) is a hypertensive disorder of pregnancy associated with oxidative stress and mitochondrial dysfunction. NRF1 and NRF2 are transcription factors that regulate mitochondrial activity and antioxidant defense. This study investigated their expression patterns in placentas from preeclamptic and severe preeclamptic pregnancies by immunohistochemical and bioinformatical methods. Methods: Placentas from 40 healthy controls, 40 PE, and 40 sPE patients were analyzed by histological and immunohistochemical techniques. Protein–protein interaction networks for NRF1, NRF2, and PE-related proteins were constructed using Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) and Cytoscape software, followed by Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis performed via ShinyGO, with significance set at false discovery rate (FDR) < 0.05. Results: NRF1 expression was significantly decreased in PE and sPE groups compared to controls, with notably negative staining in syncytial knots and fibrinoid areas. Conversely, NRF2 expression significantly increased, showing intense positivity in syncytiotrophoblasts, stromal cells, and vascular structures. Pathway analysis revealed that decreased NRF1 expression was associated with glutathione metabolism, hypoxia inducible factor-1 (HIF-1) signaling, and AMP-Activated Protein Kinase (AMPK) signaling pathways. Increased NRF2 expression was associated predominantly with inflammatory and immune response pathways, including AGE-RAGE signaling and pathogen–response pathways. Conclusions: Differential expressions of NRF1 and NRF2 in preeclamptic placentas reflect distinct yet interconnected responses to oxidative stress and inflammation. These transcription factors have potential clinical relevance as biomarkers for PE severity assessment and as targets for future therapeutic interventions. Full article

Neoadjuvant chemotherapy (NACT) is the standard treatment for muscle-invasive bladder carcinoma (MIBC), but its efficacy varies significantly among patients. The aim of this study is the identification of biomarkers and biological processes related to the response to neoadjuvant chemotherapy (NACT) in muscle-invasive bladder carcinoma (MIBC). Fifty-eight transurethral resection (TURBT) samples and thirty cystectomy samples from NACT non-responders were analyzed using mass spectrometry. Samples were classified with sparse k-means and consensus clustering. Protein networks were built using probabilistic graphical models, grouped into functional nodes, and analyzed for activity differences. Gene set enrichment analysis was applied to identify resistance mechanisms, and results were validated using The Cancer Genome Atlas (TCGA) cohort. Proteomic analysis revealed two independent classifications in TURBT samples. The first (Layer1) divided tumors into three groups, including one NACT non-responder subtype not aligned with traditional luminal or basal classifications but characterized by high expression of targetable markers NECTIN4 and Her2. The second (Layer3) separated luminal-papillary tumors from luminal-infiltrated/luminal and basal tumors. While Layer3 groups did not differ in NACT response, they showed distinct disease-free survival outcomes. Importantly, complete response to NACT was linked to improved survival in luminal subgroups but not in basal tumors, suggesting subtype-specific prognostic implications. Finally, analysis of cystectomy samples identified unique mechanisms of resistance for each subgroup, suggesting tailored therapeutic approaches. Two classification systems were defined as follows: one identified a proteomics-based non-responder group with actionable targets, and the other linked tumor subtype to prognosis. Distinct resistance mechanisms suggest opportunities for subtype-specific therapies, supporting improved management and treatment development for MIBC patients. Full article

Background/Objectives We re-analyzed publicly available gene expression profiles from the male mouse cortex under conditions of sleep deprivation (SD) using tensor decomposition-based unsupervised feature extraction, originally proposed by one of the authors in 2017. Methods We focused on two distinct expression patterns: genes whose levels were altered in SD and failed to normalize during recovery sleep (RS), and genes that overshot normal levels during RS. This selection excluded the expected “altered in SD and recovered in RS” pattern, which was not significantly observed. These two gene sets showed substantial overlap but were still distinct from each other. Results The analysis revealed that the selected gene sets were enriched in various brain regions as evidenced through clustering in the Allen Brain Atlas. This suggests that the successful selection identified biologically meaningful genes. Furthermore, somatostatin (Sst)-expressing neuronal clusters were among the most highly enriched. Conclusions Given that sst is already implicated in SD and RS, our fully data-driven transcriptomic analysis successfully identified the activity of sst during SD and RS. These findings reveal that Sst-expressing neurons may play a key role in SD. These results were further validated using AlphaGenome by uploading the selected genes to it. Full article