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12 pages, 1093 KiB  
Article
Development and Application of a Novel Conserved Signature Protein/Gene-Based qPCR Strategy for Improved Cryptosporidium Surveillance in Recreational Waters
by Faizan Saleem, Enze Li, Kevin L. Tran, Sarah Bello, Susan Weir, Thomas A. Edge, Radhey S. Gupta and Herb E. Schellhorn
Water 2025, 17(17), 2498; https://doi.org/10.3390/w17172498 - 22 Aug 2025
Viewed by 92
Abstract
Cryptosporidium is a major waterborne parasite that causes gastrointestinal illness. Conventional assays, including microscopy and immunological identification, often suffer from false positives or negatives due to non-specific binding or morphological differences between Cryptosporidium species. We developed a novel qPCR assay based on a [...] Read more.
Cryptosporidium is a major waterborne parasite that causes gastrointestinal illness. Conventional assays, including microscopy and immunological identification, often suffer from false positives or negatives due to non-specific binding or morphological differences between Cryptosporidium species. We developed a novel qPCR assay based on a Cryptosporidium-specific Conserved Signature Protein (CSP) to address the limitations of testing complex samples, including those from recreational waters. The CSP (hypothetical protein (cgd2_3830)) was identified as taxonomically unique to Cryptosporidium species. The CSP sequence and designed qPCR assay primers/probe demonstrated high specificity for the targeted Cryptosporidium species when tested against NCBI RefSeq databases. qPCR assay efficiency was determined as 95% and an R2 value of 0.99, with a slope and intercept of −3.4 and 40.1, respectively. Additionally, the Lower Limit of Detection (ALLOD) was determined as three gene copies, suggesting the potential to detect even a single oocyst. No non-specific amplification products or primer dimers were observed when the qPCR assay was evaluated using recreational water, fecal solution, and wastewater, while spike-in-control tests indicated minimal interference with the sensitivity of the assay, highlighting application for testing complex environmental DNA extracts. These findings highlight the application of the novel CSP-based qPCR assay for the rapid and sensitive detection of Cryptosporidium sp., thereby circumventing the sequence variability and multi-copy limitations associated with existing molecular markers. This proof-of-concept study presents a diagnostic framework utilizing CSP-based markers for developing water quality monitoring strategies, with scope for expansion to other microbial pathogens and potential applications in clinical and food safety settings. Full article
(This article belongs to the Section Water Quality and Contamination)
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19 pages, 16639 KiB  
Article
Nucleotide Metabolism and Immune Genes Can Predict the Prognostic Risk of Hepatocellular Carcinoma and the Immune Microenvironment
by Xiaofang Wang, Qinghua Cui and Yuan Zhou
Biology 2025, 14(8), 1079; https://doi.org/10.3390/biology14081079 - 18 Aug 2025
Viewed by 289
Abstract
The overall survival of hepatocellular carcinoma (HCC) remains poor, highlighting the need for better prognostic tools. Nucleotide metabolism fuels tumor progression, while the immune microenvironment dictates therapy response, but integrated models combining both features are lacking. Using TCGA-LIHC transcriptomic/clinical data, we identified nucleotide [...] Read more.
The overall survival of hepatocellular carcinoma (HCC) remains poor, highlighting the need for better prognostic tools. Nucleotide metabolism fuels tumor progression, while the immune microenvironment dictates therapy response, but integrated models combining both features are lacking. Using TCGA-LIHC transcriptomic/clinical data, we identified nucleotide metabolism and immune-related differentially expressed genes (NMIRGs), which stratified HCC patients into two subtypes via non-negative matrix factorization. A nine-gene prognostic risk signature was constructed through LASSO/Cox regression and validated using independent GEO datasets, and the NMIRG signature was further validated experimentally via RT-qPCR in HCC cell lines and independently using the HPA database for protein-level evidence. As evaluated by our risk signature, high-risk patients exhibited altered immune profiles (T cells increasing, neutrophils decreasing), elevated tumor mutation burden and microsatellite instability, and worse predicted immunotherapy response. Gene set enrichment analysis linked high-risk genes to immune pathways and low-risk genes to metabolic processes. Our risk signature predicted HCC prognosis independent of demographic features and outperformed existing signatures with superior C-index accuracy, effectively predicting immune microenvironment status and therapy benefits. Together, this integrated NMIRG signature offers enhanced prognostication and identifies promising biomarkers for personalized HCC management. Full article
(This article belongs to the Special Issue Bioinformatics in RNA Modifications and Non-Coding RNAs)
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30 pages, 3376 KiB  
Article
Olfactory-Guided Behavior Uncovers Imaging and Molecular Signatures of Alzheimer’s Disease Risk
by Hae Sol Moon, Zay Yar Han, Robert J. Anderson, Ali Mahzarnia, Jacques A. Stout, Andrei R. Niculescu, Jessica T. Tremblay and Alexandra Badea
Brain Sci. 2025, 15(8), 863; https://doi.org/10.3390/brainsci15080863 - 13 Aug 2025
Viewed by 480
Abstract
Background/Objectives: Olfactory impairment has been proposed as an early marker for Alzheimer’s disease (AD), yet the mechanisms linking sensory decline to genetic and environmental risk factors remain unclear. We aimed to identify early biomarkers and brain network alterations associated with AD risk by [...] Read more.
Background/Objectives: Olfactory impairment has been proposed as an early marker for Alzheimer’s disease (AD), yet the mechanisms linking sensory decline to genetic and environmental risk factors remain unclear. We aimed to identify early biomarkers and brain network alterations associated with AD risk by multimodal analyses in humanized APOE mice. Methods: We evaluated olfactory behavior, diffusion MRI connectomics, and brain and blood transcriptomics in mice stratified by APOE2, APOE3, and APOE4 genotypes, age, sex, high-fat diet, and immune background (HN). Behavioral assays assessed odor salience, novelty detection, and memory. Elastic Net-regularized multi-set canonical correlation analysis (MCCA) was used to link behavior to brain connectivity. Blood transcriptomics and gene ontology analyses identified peripheral molecular correlates. Results: APOE4 mice exhibited accelerated deficits in odor-guided behavior and memory, especially under high-fat diet, while APOE2 mice were more resilient (ANOVA: APOE x HN, F(2, 1669) = 77.25, p < 0.001, eta squared = 0.08). Age and diet compounded behavioral impairments (diet x age: F(1, 1669) = 16.04, p < 0.001). Long-term memory was particularly reduced in APOE4 mice (APOE x HN, F(2,395) = 5.6, p = 0.004). MCCA identified subnetworks explaining up to 24% of behavioral variance (sum of canonical correlations: 1.27, 95% CI [1.18, 1.85], p < 0.0001), with key connections involving the ventral orbital and somatosensory cortices. Blood eigengene modules correlated with imaging changes (e.g., subiculum diffusivity: r = −0.5, p < 1 × 10−30), and enriched synaptic pathways were identified across brain and blood. Conclusions: Olfactory behavior, shaped by genetic and environmental factors, may serve as a sensitive, translatable biomarker of AD risk. Integrative systems-level approaches reveal brain and blood signatures of early sensory–cognitive vulnerability, supporting new avenues for early detection and intervention in AD. Full article
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18 pages, 6039 KiB  
Article
Neutrophil Gelatinase-Associated Lipocalin: A Shared Early Biomarker of Remote Organ Dysfunction in Blast-Induced Extremity Trauma
by Cassie J. Rowe, Uloma Nwaolu, Philip J. Spreadborough and Thomas A. Davis
Int. J. Mol. Sci. 2025, 26(16), 7794; https://doi.org/10.3390/ijms26167794 - 12 Aug 2025
Viewed by 307
Abstract
Polytrauma is a critical global health concern characterized by immune dysregulation and a high risk of multiple organ dysfunction syndrome (MODS). Early molecular mechanisms linking trauma severity to organ injury are poorly understood. We used two rat blast-polytrauma models: a tourniquet-induced ischemia/reperfusion injury [...] Read more.
Polytrauma is a critical global health concern characterized by immune dysregulation and a high risk of multiple organ dysfunction syndrome (MODS). Early molecular mechanisms linking trauma severity to organ injury are poorly understood. We used two rat blast-polytrauma models: a tourniquet-induced ischemia/reperfusion injury (tIRI) model and a non-ischemia/reperfusion injury (non-IRI) model. Naïve animals served as controls. RT-qPCR of 120 inflammatory genes in the lung, kidney, and liver, combined with STRING protein–protein interaction analysis, revealed distinct yet overlapping inflammatory gene signatures across all the organs. A core set of genes (Il6, Lbp, Nos2, and Lcn2) was consistently upregulated, indicating shared inflammatory pathways. Transcriptomic responses were most pronounced in the tIRI group, with greater magnitude and altered temporal dynamics, uniquely amplifying pro-inflammatory cytokines, immune cell activators, chemokines, and tissue damage markers. Lipocalin-2 (Lcn2/NGAL) emerged as a shared hub gene across all the organs within 24 h post-injury. Its expression significantly correlated with MODS activity and adverse outcomes, independent of the injury model. At 168 h, Lcn2 expression correlated with increased liver damage and NGAL levels correlated with tissue trauma severity. These findings elucidate distinct pro-inflammatory mediators and networks underlying secondary organ dysfunction, highlighting NGAL as a potential universal biomarker of trauma-induced inflammation and MODS activity, suggesting it as a therapeutic target. Full article
(This article belongs to the Section Molecular Biology)
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16 pages, 11917 KiB  
Article
Untargeted Metabolomics Uncovers Food Safety Risks: Polystyrene Nanoplastics Induce Metabolic Disorders in Chicken Liver
by Xuan Hu, Yinyin Liu, Yinpeng Ma, Jing Zhang, Lina Ma, Wanqiang Chen, Xiujun Tang, Junxian Lu, Lingzhi Chen, Guodong Cai, Jianchun Bian and Yushi Gao
Foods 2025, 14(16), 2781; https://doi.org/10.3390/foods14162781 - 10 Aug 2025
Viewed by 292
Abstract
Polystyrene nanoplastics (NPs) threaten agricultural ecosystems and the food chain; however, their hepatotoxicity in chickens, a key poultry species, remains unclear. This study investigated the effects of chronic NP exposure on hepatic metabolism to evaluate food safety risks in poultry products. Chickens were [...] Read more.
Polystyrene nanoplastics (NPs) threaten agricultural ecosystems and the food chain; however, their hepatotoxicity in chickens, a key poultry species, remains unclear. This study investigated the effects of chronic NP exposure on hepatic metabolism to evaluate food safety risks in poultry products. Chickens were orally exposed to 100 nm polystyrene NPs via feed for 120 days. Histopathological evaluation, serum biochemical analysis revealed hepatotoxicity in NP-exposed poultry, characterized by histopathological liver injury, elevated lipid droplet accumulation, significantly increased alanine aminotransferase (ALT) activity, and elevated triglyceride (TG) levels (p < 0.05). Untargeted LC-MS/MS Metabolomics profiling identified 193 differentially abundant metabolites—predominantly organic acids and lipids—with L-leucine and NADH emerging as pivotal metabolic hubs. A KEGG pathway analysis demonstrated significant enrichment in purine metabolism and oxidative phosphorylation, while a gene set enrichment analysis (GSEA) confirmed the suppression of ABC transporters. Notably, the key biomarkers 9-cis-retinal and phenylalanyl phenylalanine were significantly altered, reflecting metabolic disturbances linked to NPs exposure. Overall, this study characterized exposure-associated metabolic signatures and established NP-induced hepatic injury phenotypes in poultry production systems. Full article
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22 pages, 11006 KiB  
Article
Supervised Machine-Based Learning and Computational Analysis to Reveal Unique Molecular Signatures Associated with Wound Healing and Fibrotic Outcomes to Lens Injury
by Catherine Lalman, Kylie R. Stabler, Yimin Yang and Janice L. Walker
Int. J. Mol. Sci. 2025, 26(15), 7422; https://doi.org/10.3390/ijms26157422 - 1 Aug 2025
Viewed by 258
Abstract
Posterior capsule opacification (PCO), a frequent complication of cataract surgery, arises from dysregulated wound healing and fibrotic transformation of residual lens epithelial cells. While transcriptomic and machine learning (ML) approaches have elucidated fibrosis-related pathways in other tissues, the molecular divergence between regenerative and [...] Read more.
Posterior capsule opacification (PCO), a frequent complication of cataract surgery, arises from dysregulated wound healing and fibrotic transformation of residual lens epithelial cells. While transcriptomic and machine learning (ML) approaches have elucidated fibrosis-related pathways in other tissues, the molecular divergence between regenerative and fibrotic outcomes in the lens remains unclear. Here, we used an ex vivo chick lens injury model to simulate post-surgical conditions, collecting RNA from lenses undergoing either regenerative wound healing or fibrosis between days 1–3 post-injury. Bulk RNA sequencing data were normalized, log-transformed, and subjected to univariate filtering prior to training LASSO, SVM, and RF ML models to identify discriminatory gene signatures. Each model was independently validated using a held-out test set. Distinct gene sets were identified, including fibrosis-associated genes (VGLL3, CEBPD, MXRA7, LMNA, gga-miR-143, RF00072) and wound-healing-associated genes (HS3ST2, ID1), with several achieving perfect classification. Gene Set Enrichment Analysis revealed divergent pathway activation, including extracellular matrix remodeling, DNA replication, and spliceosome associated with fibrosis. RT-PCR in independent explants confirmed key differential expression levels. These findings demonstrate the utility of supervised ML for discovering lens-specific fibrotic and regenerative gene features and nominate biomarkers for targeted intervention to mitigate PCO. Full article
(This article belongs to the Section Molecular Informatics)
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17 pages, 4219 KiB  
Article
Identification of Differentially Expressed Genes and Pathways in Non-Diabetic CKD and Diabetic CKD by Integrated Human Transcriptomic Bioinformatics Analysis
by Clara Barrios, Marta Riera, Eva Rodríguez, Eva Márquez, Jimena del Risco, Melissa Pilco, Jorge Huesca, Ariadna González, Claudia Martyn, Jordi Pujol, Anna Buxeda and Marta Crespo
Int. J. Mol. Sci. 2025, 26(15), 7421; https://doi.org/10.3390/ijms26157421 - 1 Aug 2025
Viewed by 313
Abstract
Chronic kidney disease (CKD) is a heterogeneous condition with various etiologies, including type 2 diabetes mellitus (T2D), hypertension, and autoimmune disorders. Both diabetic CKD (CKD_T2D) and non-diabetic CKD (CKD_nonT2D) share overlapping clinical features, but understanding the molecular mechanisms underlying each subtype and distinguishing [...] Read more.
Chronic kidney disease (CKD) is a heterogeneous condition with various etiologies, including type 2 diabetes mellitus (T2D), hypertension, and autoimmune disorders. Both diabetic CKD (CKD_T2D) and non-diabetic CKD (CKD_nonT2D) share overlapping clinical features, but understanding the molecular mechanisms underlying each subtype and distinguishing diabetic from non-diabetic forms remain poorly defined. To identify differentially expressed genes (DEGs) and enriched biological pathways between CKD_T2D and CKD_nonT2D cohorts, including autoimmune (CKD_nonT2D_AI) and hypertensive (CKD_nonT2D_HT) subtypes, through integrative transcriptomic analysis. Publicly available gene expression datasets from human glomerular and tubulointerstitial kidney tissues were curated and analyzed from GEO and ArrayExpress. Differential expression analysis and Gene Set Enrichment Analysis (GSEA) were conducted to assess cohort-specific molecular signatures. A considerable overlap in DEGs was observed between CKD_T2D and CKD_nonT2D, with CKD_T2D exhibiting more extensive gene expression changes. Hypertensive-CKD shared greater transcriptomic similarity with CKD_T2D than autoimmune-CKD. Key DEGs involved in fibrosis, inflammation, and complement activation—including Tgfb1, Timp1, Cxcl6, and C1qa/B—were differentially regulated in diabetic samples, where GSEA revealed immune pathway enrichment in glomeruli and metabolic pathway enrichment in tubulointerstitium. The transcriptomic landscape of CKD_T2D reveals stronger immune and metabolic dysregulation compared to non-diabetic CKD. These findings suggest divergent pathological mechanisms and support the need for tailored therapeutic approaches. Full article
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14 pages, 1813 KiB  
Article
Elevated Antigen-Presenting-Cell Signature Genes Predict Stemness and Metabolic Reprogramming States in Glioblastoma
by Ji-Yong Sung and Kihwan Hwang
Int. J. Mol. Sci. 2025, 26(15), 7411; https://doi.org/10.3390/ijms26157411 - 1 Aug 2025
Viewed by 443
Abstract
Glioblastoma (GBM) is a highly aggressive and heterogeneous brain tumor. Glioma stem-like cells (GSCs) play a central role in tumor progression, therapeutic resistance, and recurrence. Although immune cells are known to shape the GBM microenvironment, the impact of antigen-presenting-cell (APC) signature genes on [...] Read more.
Glioblastoma (GBM) is a highly aggressive and heterogeneous brain tumor. Glioma stem-like cells (GSCs) play a central role in tumor progression, therapeutic resistance, and recurrence. Although immune cells are known to shape the GBM microenvironment, the impact of antigen-presenting-cell (APC) signature genes on tumor-intrinsic phenotypes remains underexplored. We analyzed both bulk- and single-cell RNA sequencing datasets of GBM to investigate the association between APC gene expression and tumor-cell states, including stemness and metabolic reprogramming. Signature scores were computed using curated gene sets related to APC activity, KEGG metabolic pathways, and cancer hallmark pathways. Protein–protein interaction (PPI) networks were constructed to examine the links between immune regulators and metabolic programs. The high expression of APC-related genes, such as HLA-DRA, CD74, CD80, CD86, and CIITA, was associated with lower stemness signatures and enhanced inflammatory signaling. These APC-high states (mean difference = –0.43, adjusted p < 0.001) also showed a shift in metabolic activity, with decreased oxidative phosphorylation and increased lipid and steroid metabolism. This pattern suggests coordinated changes in immune activity and metabolic status. Furthermore, TNF-α and other inflammatory markers were more highly expressed in the less stem-like tumor cells, indicating a possible role of inflammation in promoting differentiation. Our findings revealed that elevated APC gene signatures are associated with more differentiated and metabolically specialized GBM cell states. These transcriptional features may also reflect greater immunogenicity and inflammation sensitivity. The APC metabolic signature may serve as a useful biomarker to identify GBM subpopulations with reduced stemness and increased immune engagement, offering potential therapeutic implications. Full article
(This article belongs to the Special Issue Advanced Research on Cancer Stem Cells)
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30 pages, 5307 KiB  
Article
Self-Normalizing Multi-Omics Neural Network for Pan-Cancer Prognostication
by Asim Waqas, Aakash Tripathi, Sabeen Ahmed, Ashwin Mukund, Hamza Farooq, Joseph O. Johnson, Paul A. Stewart, Mia Naeini, Matthew B. Schabath and Ghulam Rasool
Int. J. Mol. Sci. 2025, 26(15), 7358; https://doi.org/10.3390/ijms26157358 - 30 Jul 2025
Viewed by 525
Abstract
Prognostic markers such as overall survival (OS) and tertiary lymphoid structure (TLS) ratios, alongside diagnostic signatures like primary cancer-type classification, provide critical information for treatment selection, risk stratification, and longitudinal care planning across the oncology continuum. However, extracting these signals solely from sparse, [...] Read more.
Prognostic markers such as overall survival (OS) and tertiary lymphoid structure (TLS) ratios, alongside diagnostic signatures like primary cancer-type classification, provide critical information for treatment selection, risk stratification, and longitudinal care planning across the oncology continuum. However, extracting these signals solely from sparse, high-dimensional multi-omics data remains a major challenge due to heterogeneity and frequent missingness in patient profiles. To address this challenge, we present SeNMo, a self-normalizing deep neural network trained on five heterogeneous omics layers—gene expression, DNA methylation, miRNA abundance, somatic mutations, and protein expression—along with the clinical variables, that learns a unified representation robust to missing modalities. Trained on more than 10,000 patient profiles across 32 tumor types from The Cancer Genome Atlas (TCGA), SeNMo provides a baseline that can be readily fine-tuned for diverse downstream tasks. On a held-out TCGA test set, the model achieved a concordance index of 0.758 for OS prediction, while external evaluation yielded 0.73 on the CPTAC lung squamous cell carcinoma cohort and 0.66 on an independent 108-patient Moffitt Cancer Center cohort. Furthermore, on Moffitt’s cohort, baseline SeNMo fine-tuned for TLS ratio prediction aligned with expert annotations (p < 0.05) and sharply separated high- versus low-TLS groups, reflecting distinct survival outcomes. Without altering the backbone, a single linear head classified primary cancer type with 99.8% accuracy across the 33 classes. By unifying diagnostic and prognostic predictions in a modality-robust architecture, SeNMo demonstrated strong performance across multiple clinically relevant tasks, including survival estimation, cancer classification, and TLS ratio prediction, highlighting its translational potential for multi-omics oncology applications. Full article
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)
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18 pages, 392 KiB  
Article
Semantic Restoration of Snake-Slaying in Chan Buddhist Koan
by Yun Wang and Yulu Lv
Religions 2025, 16(8), 973; https://doi.org/10.3390/rel16080973 - 27 Jul 2025
Viewed by 432
Abstract
In the Chan Buddhism koan (gong’an 公案) tradition, the act of “slaying the snake” functions as a signature gesture imbued with complex, historically layered cultural meanings. Rather than merely examining its motivations, this paper emphasizes tracing the semantic transformations that this motif has [...] Read more.
In the Chan Buddhism koan (gong’an 公案) tradition, the act of “slaying the snake” functions as a signature gesture imbued with complex, historically layered cultural meanings. Rather than merely examining its motivations, this paper emphasizes tracing the semantic transformations that this motif has undergone across different historical contexts. It argues that “snake-slaying” operated variously as an imperial narrative strategy reinforcing ruling class ideology; as a form of popular resistance by commoners against flood-related disasters; as a dietary practice among aristocrats and literati seeking danyao (elixirs) 丹藥 for reclusion and transcendence; and ultimately, within the Chan tradition, as a method of spiritual cultivation whereby masters sever desires rooted in attachment to both selfhood and the Dharma. More specifically, first, as an imperial narrative logic, snake-slaying embodied exemplary power: both Liu Bang 劉邦 and Guizong 歸宗 enacted this discursive strategy, with Guizong’s legitimacy in slaying the snake deriving from the precedent set by Liu Bang. Second, as a folk strategy of demystification, snake-slaying acquired a moral aura—since the snake was perceived as malevolent force, their slaying appeared righteous and heroic. Finally, as a mode of self-cultivation among the aristocracy, snake-slaying laid the groundwork for its later internalization. In Daoism, slaying the snake was a means of cultivating the body; in Chan Buddhism, the act is elevated to a higher plane—becoming a way of cultivating the mind. This transformation unfolded naturally, as if predestined. In all cases, the internalization of the snake-slaying motif was not an overnight development: the cultural genes that preceded its appearance in the Chan tradition provided the fertile ground for its karmic maturation and discursive proliferation. Full article
36 pages, 3579 KiB  
Article
RNA Sequencing Reveals Inflammatory and Metabolic Changes in the Lung and Brain After Carbon Black and Naphthalene Whole Body Inhalation Exposure in a Rodent Model of Military Burn Pit Exposures
by Allison M. Haaning, Brian J. Sandri, Henry L. Wyneken, William T. Goldsmith, Joshua P. Nixon, Timothy R. Nurkiewicz, Chris H. Wendt, Paul Barach, Janeen H. Trembley and Tammy A. Butterick
Int. J. Mol. Sci. 2025, 26(15), 7238; https://doi.org/10.3390/ijms26157238 - 26 Jul 2025
Viewed by 766
Abstract
Military personnel deployed to Iraq and Afghanistan were exposed to emissions from open-air burn pits, where plastics, metals, and medical waste were incinerated. These exposures have been linked to deployment-related respiratory diseases (DRRD) and may also impact neurological health via the lung–brain axis. [...] Read more.
Military personnel deployed to Iraq and Afghanistan were exposed to emissions from open-air burn pits, where plastics, metals, and medical waste were incinerated. These exposures have been linked to deployment-related respiratory diseases (DRRD) and may also impact neurological health via the lung–brain axis. To investigate molecular mechanisms, adult male rats were exposed to filtered air, naphthalene (a representative volatile organic compound), or a combination of naphthalene and carbon black (surrogate for particulate matter; CBN) via whole-body inhalation (six hours/day, three consecutive days). Lung, brain, and plasma samples were collected 24 h after the final exposure. Pro-inflammatory biomarkers were assessed using multiplex electrochemiluminescence and western blot. Differentially expressed genes (DEGs) were identified by RNA sequencing, and elastic net modeling was used to define exposure-predictive gene signatures. CBN exposure altered inflammatory biomarkers across tissues, with activation of nuclear factor kappa B (NF-κB) signaling. In the lung, gene set enrichment revealed activated pathways related to proliferation and inflammation, while epithelial–mesenchymal transition (EMT) and oxidative phosphorylation were suppressed. In the brain, EMT, inflammation, and senescence pathways were activated, while ribosomal function and oxidative metabolism were downregulated. Elastic net modeling identified a lung gene signature predictive of CBN exposure, including Kcnq3, Tgfbr1, and Tm4sf19. These findings demonstrate that inhalation of a surrogate burn pit mixture induces inflammatory and metabolic gene expression changes in both lung and brain tissues, supporting the utility of this animal model for understanding systemic effects of airborne military toxicants and for identifying potential biomarkers relevant to DRRD and Veteran health. Full article
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)
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28 pages, 2549 KiB  
Article
A 25K Wheat SNP Array Revealed the Genetic Diversity and Population Structure of Durum Wheat (Triticum turgidum subsp. durum) Landraces and Cultivars
by Lalise Ararsa, Behailu Mulugeta, Endashaw Bekele, Negash Geleta, Kibrom B. Abreha and Mulatu Geleta
Int. J. Mol. Sci. 2025, 26(15), 7220; https://doi.org/10.3390/ijms26157220 - 25 Jul 2025
Viewed by 1390
Abstract
Durum wheat, the world’s second most cultivated wheat species, is a staple crop, critical for global food security, including in Ethiopia where it serves as a center of diversity. However, climate change and genetic erosion threaten its genetic resources, necessitating genomic studies to [...] Read more.
Durum wheat, the world’s second most cultivated wheat species, is a staple crop, critical for global food security, including in Ethiopia where it serves as a center of diversity. However, climate change and genetic erosion threaten its genetic resources, necessitating genomic studies to support conservation and breeding efforts. This study characterized genome-wide diversity, population structure (STRUCTURE, principal coordinate analysis (PCoA), neighbor-joining trees, analysis of molecular variance (AMOVA)), and selection signatures (FST, Hardy–Weinberg deviations) in Ethiopian durum wheat by analyzing 376 genotypes (148 accessions) using an Illumina Infinium 25K single nucleotide polymorphism (SNP) array. A set of 7842 high-quality SNPs enabled the assessments, comparing landraces with cultivars and breeding populations. Results revealed moderate genetic diversity (mean polymorphism information content (PIC) = 0.17; gene diversity = 0.20) and identified 26 loci under selection, associated with key traits like grain yield, stress tolerance, and disease resistance. AMOVA revealed 80.1% variation among accessions, with no significant differentiation by altitude, region, or spike density. Landraces formed distinct clusters, harboring unique alleles, while admixture suggested gene flow via informal seed exchange. The findings highlight Ethiopia’s rich durum wheat diversity, emphasizing landraces as reservoirs of adaptive alleles for breeding. This study provides genomic insights to guide conservation and the development of climate-resilient cultivars, supporting sustainable wheat production globally. Full article
(This article belongs to the Special Issue Latest Research on Plant Genomics and Genome Editing, 2nd Edition)
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21 pages, 13833 KiB  
Article
Machine Learning-Based Prognostic Signature in Breast Cancer: Regulatory T Cells, Stemness, and Deep Learning for Synergistic Drug Discovery
by Samina Gul, Jianyu Pang, Yongzhi Chen, Qi Qi, Yuheng Tang, Yingjie Sun, Hui Wang, Wenru Tang and Xuhong Zhou
Int. J. Mol. Sci. 2025, 26(14), 6995; https://doi.org/10.3390/ijms26146995 - 21 Jul 2025
Viewed by 501
Abstract
Regulatory T cells (Tregs) have multiple roles in the tumor microenvironment (TME), which maintain a balance between autoimmunity and immunosuppression. This research aimed to investigate the interaction between cancer stemness and Regulatory T cells (Tregs) in the breast cancer tumor immune microenvironment. Breast [...] Read more.
Regulatory T cells (Tregs) have multiple roles in the tumor microenvironment (TME), which maintain a balance between autoimmunity and immunosuppression. This research aimed to investigate the interaction between cancer stemness and Regulatory T cells (Tregs) in the breast cancer tumor immune microenvironment. Breast cancer stemness was calculated using one-class logistic regression. Twelve main cell clusters were identified, and the subsequent three subsets of Regulatory T cells with different differentiation states were identified as being closely related to immune regulation and metabolic pathways. A prognostic risk model including MEA1, MTFP1, PASK, PSENEN, PSME2, RCC2, and SH2D2A was generated through the intersection between Regulatory T cell differentiation-related genes and stemness-related genes using LASSO and univariate Cox regression. The patient’s total survival times were predicted and validated with AUC of 0.96 and 0.831 in both training and validation sets, respectively; the immunotherapeutic predication efficacy of prognostic signature was confirmed in four ICI RNA-Seq cohorts. Seven drugs, including Ethinyl Estradiol, Epigallocatechin gallate, Cyclosporine, Gentamicin, Doxorubicin, Ivermectin, and Dronabinol for prognostic signature, were screened through molecular docking and found a synergistic effect among drugs with deep learning. Our prognostic signature potentially paves the way for overcoming immune resistance, and blocking the interaction between cancer stemness and Tregs may be a new approach in the treatment of breast cancer. Full article
(This article belongs to the Section Molecular Informatics)
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27 pages, 3379 KiB  
Article
Cutaneous T-Cell Lymphoma: Yin-Yang Effects of Transcription Factors HLF and NFIL3 in Regulation of Malignant T-Cell Markers in the Context of HDAC Inhibitor Romidepsin Treatment
by Andrew V. Kossenkov, Noor Dawany, Sonali Majumdar, Celia Chang, Calen Nichols, Maria Wysocka, Richard Piekarz, Michael K. Showe, Susan E. Bates, Alain H. Rook, Ellen J. Kim and Louise C. Showe
Cancers 2025, 17(14), 2380; https://doi.org/10.3390/cancers17142380 - 17 Jul 2025
Viewed by 497
Abstract
Background/Objectives: We examined the in vivo effects of successive treatments with the histone deacetylase (HDAC) inhibitor romidepsin in patients with cutaneous T-cell lymphoma (CTCL), using changes in gene expression in peripheral blood mononuclear cells (PBMCs). Methods: Exploiting data from a highly responsive CTCL [...] Read more.
Background/Objectives: We examined the in vivo effects of successive treatments with the histone deacetylase (HDAC) inhibitor romidepsin in patients with cutaneous T-cell lymphoma (CTCL), using changes in gene expression in peripheral blood mononuclear cells (PBMCs). Methods: Exploiting data from a highly responsive CTCL patient through 12 months of treatment, we identified a malignant cell predictor (MCP), a gene signature associated with the diminishing numbers of circulating malignant cells. Results: The MCP was successfully validated in the patient’s relapse sample 9 months after treatment was terminated and via an independent set of CTCL patient samples. Conclusions: The MCP set of genes contained novel CTCL markers, including membrane-associated proteins not normally expressed in lymphocytes. A subclass of those markers was also detectable in residual malignant cells undetected by flow cytometry in remission samples from a patient who relapsed 10 months later. We identified a subset of transcriptional regulators, miRNAs and methylation patterns associated with the effect of progressive treatments revealing potential mechanisms of transcriptional dysregulation and functional effects in the malignant cells. We demonstrate a role for transcriptional activator HLF, over-expressed in malignant cells, and downregulated transcriptional-suppressor and immune-modulator NFIL3, as regulators of CTCL-specific genes. Full article
(This article belongs to the Special Issue Cutaneous Lymphomas: From Pathology to Treatment)
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26 pages, 1016 KiB  
Article
TIM-3/Galectin-9 Immune Axis in Colorectal Cancer in Relation to KRAS, NRAS, BRAF, PIK3CA, AKT1 Mutations, MSI Status, and the Cytokine Milieu
by Błażej Ochman, Anna Kot, Sylwia Mielcarska, Agnieszka Kula, Miriam Dawidowicz, Dorota Hudy, Monika Szrot, Jerzy Piecuch, Dariusz Waniczek, Zenon Czuba and Elżbieta Świętochowska
Int. J. Mol. Sci. 2025, 26(14), 6735; https://doi.org/10.3390/ijms26146735 - 14 Jul 2025
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Abstract
In this study, we investigated the expression of TIM-3 and Galectin-9 (Gal-9) in colorectal cancer (CRC) and their associations with oncogenic mutations, MSI status, cytokine profiles, and transcriptional data. TIM-3 and Gal-9 protein levels were significantly increased in CRC tissues compared to matched [...] Read more.
In this study, we investigated the expression of TIM-3 and Galectin-9 (Gal-9) in colorectal cancer (CRC) and their associations with oncogenic mutations, MSI status, cytokine profiles, and transcriptional data. TIM-3 and Gal-9 protein levels were significantly increased in CRC tissues compared to matched non-tumor margins (p < 0.05 and p < 0.001, respectively). TIM-3 protein concentration was notably higher in PIK3CA-mutated tumors (p < 0.05), while no associations were found with KRAS, NRAS, BRAF, AKT1, or MSI status. Multiplex cytokine profiling revealed strong correlations between TIM-3 and Gal-9 levels and key immunomodulatory pathways, including IL-10, IL-17, and chemokine signaling. We also observed significant associations with cytokine subsets involved in protumor activity and immune regulation. Gene set enrichment analysis (GSEA) demonstrated that high TIM-3 and Gal-9 expression was associated with upregulation of cell cycle-related pathways, and downregulation of immune signatures, such as interferon responses and TNF-α/NFκB signaling. These findings suggest that increased TIM-3 and Gal-9 expression reflects a shift toward proliferative activity and immune suppression in the CRC tumor microenvironment, highlighting their potential as biomarkers of immunoevasive tumor phenotypes, especially in PIK3CA-mutant CRC tumors. Full article
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