Search Results (350)

Epigenetic regulation of gene expression is studied at three physical scales: micro: DNA sequence-level methylation/demethylation; meso: nucleosome occupancy and remodeling; and macro: chromosomal domain silencing by Polycomb complexes, heterochromatin, and topologically associating domain (TAD) boundaries. The challenge to fully understand epigenetic gene regulation patterns is that these scales are not independent. Their influence overlaps and they share a recurring architectural theme across scales of a targeted molecular pattern followed by cooperative, feedback-driven, spatially bounded spreading. We argue here that disruption of this shared architecture at any one scale is independently sufficient to tip a bistable silencing domain into an oncogenic state. This paper discusses how such a cross-scale architectural rule set has concrete implications (yet underexploited) for computational cancer epigenomics, e.g., functional enrichment analyses generally focus on epigenetic features at one scale as an independent line of evidence, ignoring corroborating signals that could be reinforced by underlying hierarchical levels. This paper outlines options for functional enrichment statistics that combine multiple corroborating molecular features within a scale and corroborating evidence across scales into composite confidence scores calibrated against an empirical null that preserves correlations between assays. We propose benchmarking this approach against conventional single-feature enrichment in matched multi-omic cancer datasets as a direct test of the model. Full article

Cutaneous leishmaniasis (CL) is a chronic infectious disease characterized by extensive tissue destruction and profound extracellular matrix (ECM) remodeling. This study provides the first evidence of O-glycosylated oncofetal fibronectin (onf-FN) expression in human CL lesions. Immunohistochemical analysis revealed increased onf-FN expression throughout the inflammatory lesions, displaying a distribution pattern closely resembling that observed in human tumors and overlapping with total fibronectin expression. The detection of onf-FN in an infectious disease caused by protozoan parasites broadens the current understanding of ECM remodeling beyond cancer and developmental processes, suggesting that onf-FN may also participate in the host tissue response to chronic infection. Given the well-established biological functions of onf-FN in regulating cell adhesion, tissue remodeling, and repair, its expression in CL lesions raises important questions regarding its potential role in disease pathogenesis and parasite persistence. These findings identify onf-FN as a previously unrecognized component of the CL microenvironment, providing a foundation for future studies investigating its biological and clinical significance in parasitic diseases. Full article

Background/Objectives: Immune checkpoint inhibitors have revolutionized the treatment of advanced melanoma, yet primary and acquired resistance remain major barriers to durable disease control. This narrative review examines the clinical patterns, biological mechanisms, biomarker limitations, and therapeutic implications of immunotherapy failure. Methods: A structured search of PubMed, Web of Science, and ClinicalTrials.gov identified relevant studies published from January 2010 to May 2026, supplemented by landmark earlier reports. Results: Immunotherapy resistance encompasses heterogeneous patterns, including early progression, oligoprogression, dissociated response, brain-dominant progression, relapse after response, and progression after treatment discontinuation. These clinical phenotypes arise from overlapping mechanisms such as loss of antigen presentation, impaired interferon signaling, oncogenic immune exclusion, melanoma dedifferentiation, suppressive myeloid and regulatory T-cell programs, stromal and vascular barriers, metabolic restriction, and deterioration of tumor-reactive T-cell clones. Conventional response criteria and static biomarkers, including PD-L1 expression and tumor mutational burden, do not adequately capture this complexity because resistance varies across lesions and evolves under treatment pressure. Negative trials of IDO1 inhibition, cytokine intensification, vaccines, and intratumoral immune stimulation further show that biological plausibility and early activity do not guarantee clinical benefit when target engagement, patient enrichment, and endpoint selection are inadequate. Conclusions: Immunotherapy resistance in melanoma should be viewed as a variety of biologically distinct clinical states rather than a single endpoint. Future progress will require resistance-matched treatment, longitudinal tissue and circulating tumor DNA assessment, adaptive trial designs, and endpoints aligned with treatment kinetics. This framework may improve salvage selection and interpretation of post-PD-1 studies in clinical practice. Full article

This systematic review synthesizes theoretical, meta-analytic, and empirical evidence from 85 studies to clarify the conceptual boundaries and overlaps among five core job performance dimensions: task performance (TP), contextual performance (CP), adaptive performance (AP), creative and innovative performance (CIP), and counterproductive work behavior (CWB). In doing so, it addresses two gaps in the literature. To our knowledge, no prior study has: (1) systematically examined the distinctions and overlaps among all five dimensions simultaneously, across a broad range of occupations, rather than in isolated pairs, or (2) synthesized their antecedents into a single integrative framework. The synthesized evidence indicates that these dimensions are empirically and conceptually distinct yet correlated, and that multivariate, dimension-specific models can account for both shared and unique variance across dimensions, consistent with more targeted performance management. As the review’s central contribution, we propose a two-stage conceptual model. In the expression stage, the degree to which the work role prescribes a behavior (prescribed, discretionary, proscribed, or unscripted) determines which determinant class (ability, motivation, or opportunity) remains free to vary and hence to predict each dimension, with proximal states (e.g., task knowledge and skill, engagement, psychological capital) carrying these effects into behavior. In the evaluation stage, behavior is converted into dimension scores against standards that are themselves prescription-dependent, explaining why rater and measurement effects pattern differently across dimensions. The model yields testable propositions, most distinctively that formalizing a previously discretionary behavior should shift both which antecedents predict it and how it is scored. Full article

Background: Chronic obstructive pulmonary disease (COPD) is associated with systemic inflammation and increased cardiovascular comorbidity, yet peripheral blood molecular markers for cardiovascular comorbidity-related stratification in COPD remain poorly defined. Methods: In this study, PBMC transcriptomic datasets from a COPD cohort (GSE42057) and a CAD cohort (GSE113079) were analyzed using weighted gene co-expression network analysis (WGCNA) to identify disease-associated modules, followed by overlapping gene screening. Machine-learning models were then applied to prioritize the shared genes. External validation was performed in an independent COPD cohort (GSE54837) and an independent CAD cohort (GSE250283). Immune-cell deconvolution and single-cell transcriptomic analysis of a CAD dataset (GSE269269) were further used to characterize the immune and cellular context of the leading candidate. Finally, RT–qPCR was performed in an institutional PBMC cohort for experimental validation. Results: A total of 169 shared genes were identified, with enrichment in immune, mitochondrial, oxidative phosphorylation, and metabolic pathways. RTN4 was the most consistently validated candidate across COPD and CAD cohorts and was associated with poorer lung function, advanced GOLD stages, and monocyte-related immune patterns. In CAD single-cell data, RTN4-associated signals were mainly localized to monocytes, particularly intermediate monocytes under plaque rupture conditions, with enrichment of immune, antigen-presentation, oxidative-stress, and metabolic pathways. RT–qPCR confirmed increased RTN4 mRNA expression in COPD and a further increase in patients with COPD and comorbid CAD despite comparable FEV1% predicted between the two COPD groups. Conclusions: These findings suggest that elevated RTN4 expression may serve as a PBMC-derived, monocyte-associated candidate molecular feature related to COPD–CAD comorbidity. Full article

Background: Domain of Unknown Function 1645 (DUF1645) is a conserved but poorly characterized plant gene family whose evolutionary history and roles in stress adaptation remain unclear. We performed an integrated genomic, evolutionary, transcriptomic, and Quantitative Trait Locus (QTL) characterization of the DUF1645 family in rice (Oryza sativa). Methods and Results: We identified 14 intronless, non-redundant OsDUF1645 genes distributed across eight chromosomes. Phylogenetic and collinearity analyses suggested that family expansion within Poaceae involved ancestral segmental and localized tandem duplication events. Promoter analysis identified stress- and phytohormone-responsive cis-acting elements, including ABRE, MBS, and MeJA-associated motifs. Public transcriptome datasets revealed diverse OsDUF1645 expression patterns under abiotic and hormonal treatments. Integration with the Quantitative Trait Loci Annotation Rice Online (Q-TARO) QTLome identified physical co-localization of multiple OsDUF1645 loci with stress- and agronomic-trait QTLs, including salinity-, drought-, root architecture-, and water-deficit-associated regions. On Chromosome 1, OsDUF1645.1, OsDUF1645.2, OsDUF1645.3, and OsDUF1645.4 overlapped QTL intervals associated with salinity-related physiological traits, including Na⁺ uptake and Na⁺ balance, and drought-related root traits. On Chromosome 5, the tandemly arranged OsDUF1645.8, OsDUF1645.9, and OsDUF1645.10 co-localized with QTLs related to root architecture and water-deficit responses. qRT-PCR validation under salinity, osmotic stress, and cadmium exposure confirmed distinct stress-responsive expression profiles; OsDUF1645.6 exhibited broad multi-stress responsiveness, whereas OsDUF1645.3 was downregulated under several conditions. Conclusions: The OsDUF1645 family exhibits substantial functional diversification, supported by distinct regulatory architectures, expression profiles, and QTL associations. These findings provide a framework for prioritizing OsDUF1645 candidates for functional validation and their potential application in molecular breeding and development of climate-resilient rice cultivars. Full article

The spread of Bursaphelenchus xylophilus has caused a critical shortage of traditional Poria cocos cultivation materials, making bag-based substrates an urgent alternative. Yet, how substrate stoichiometry shapes nutritional quality remains unclear. Using non-targeted metabolomics combined with redundancy analysis (RDA) and weighted gene co-expression network analysis (WGCNA), we profiled P. cocos cultivated on four substrates: healthy pine logs, pine wilt wood bags, oak bags, and pine needle/branch bags. Bag-cultivated P. cocos showed significantly elevated total amino acids, poria cocos acid, and total triterpenoids, with pine wilt wood bags (P1) performing best overall. Nitrogen, phosphorus, and the N/P ratio independently drove metabolomic variation (pairwise overlap < 5%). Nitrogen-line hub metabolites were negatively correlated with amino acid content, suggesting that suppressed lipid metabolism may free carbon skeletons for the accumulation of nitrogenous nutrients. Phosphorus-line hub metabolites were positively associated with polysaccharide indices, whereas the N/P ratio in line lipid amides showed strong negative correlations with polysaccharides under phosphorus limitation. These correlational patterns are consistent with a stoichiometric resource allocation model, although direct validation through controlled-element experiments is required. These findings provide quantitative guidance for optimizing bag-substrate formulations in P. cocos cultivation. Full article

Exposure to ambient particulate matter (PM) has been linked to renal dysfunction, particularly in diabetic populations, but the underlying mechanisms remain unclear. We performed bidirectional Mendelian randomization to assess causal relationships between PM exposure and estimated glomerular filtration rate (eGFR), integrated transcriptomic datasets to identify PM-related genes overlapping with diabetic kidney disease (DKD) differentially expressed genes, and applied machine learning approaches to select key feature genes and construct diagnostic models. Single-cell and spatial transcriptomic analyses were used to characterize cell-type and region-specific expression patterns, while in silico knockout analysis explored potential functional associations. PM2.5–10 exposure was causally associated with decreased eGFR, particularly among individuals with diabetes, with no evidence of reverse causality. Transcriptomic integration identified 168 shared PM-DKD genes enriched in inflammatory, immune, and metabolic pathways, including AGE-RAGE, IL-17, TNF, and PI3K-Akt signaling. Seven feature genes (AVPI1, DUSP1, FOSB, JUNB, PDK2, TPPP3, and VIM) showed good diagnostic performance across training and external validation cohorts, and machine learning models and nomogram analyses demonstrated consistent predictive performance. Single-cell and spatial transcriptomic analyses revealed distinct cell-type and region-specific expression patterns, with VIM enriched in interstitial and fibrotic regions, TPPP3 mainly detected in podocytes, and other genes distributed across tubular or immune cell populations. In silico knockout analysis suggested potential associations of these genes with mitochondrial metabolism, oxidative stress, tubular function, and inflammatory processes. Database-based therapeutic exploration identified VIM as a potential candidate target, with sanguinarine showing favorable predicted binding affinity. Collectively, these findings suggest that PM2.5–10 exposure may contribute to DKD susceptibility through inflammatory, metabolic, and oxidative stress-related mechanisms, and provide candidate molecular markers for further investigation. Full article

Background/Objectives: Pediatric solid tumors (PST) are a biologically distinct group of malignancies whose developmental origins and molecular drivers differ substantially from those of adult cancers, with direct implications for therapeutic strategy and clinical outcome. This review synthesizes current evidence on molecular pathogenesis, tumor microenvironment biology, and the structural conditions that shape access to care across select PST. Methods: A narrative review of peer-reviewed literature was conducted primarily using PubMed, supplemented by Google Scholar, covering publications from 2000 to 2025. Tumor types were selected based on their prevalence in the pediatric population and the availability of evidence addressing both molecular features and health disparities. Body: Across eight tumor types (neuroblastoma, Ewing sarcoma, pediatric brain tumors, rhabdomyosarcoma, Wilms tumor, retinoblastoma, osteosarcoma, and chondrosarcoma), recurrent molecular alterations including MYCN amplification, EWS-FLI1 fusions, PAX-FOXO1 rearrangements and IDH 1/2 mutations emerge as central determinants of disease behavior and eligibility for treatment. The tumor microenvironment manifests as a shared mediator of immune exclusion and therapeutic resistance across tumor types, with, but not limited to, tumor-associated macrophages, myeloid-derived suppressor cells, and checkpoint molecule expression, identified as recurrent features influencing treatment response. Immunotherapeutic strategies have shown variable efficacy across PST, with the most consistent clinical benefit established in neuroblastoma. A critical and underappreciated pattern stands out across tumor types: children carrying the most aggressive molecular subtypes are disproportionately those with the least access to therapies those subtypes demand, emphasizing an overlap of biological and structural disadvantage that is also amplified in low- and middle-income countries, where late-stage presentation, treatment abandonment and limited access to molecular diagnostics compound the biological disadvantage. Conclusions: Within the eight PST reviewed, the most aggressive molecular subtypes and the greatest structural disadvantages converge in the same children; those carrying MYCN amplification, PAX-FOXO1 fusions, or EWS-FLI1 fusions are disproportionately those with the least access to the therapies their biology demands. Genomic and immunologic advances will only reach their full clinical potential when paired with inclusive trial data, diversified genomic databases, and most importantly, equitable access to biomarker-specialized therapies across all populations. Full article

Background: Systemic autoinflammatory phenotypes can clinically overlap with Familial Mediterranean Fever and other monogenic autoinflammatory diseases, yet some cases remain unclassified in the absence of pathogenic variants in MEFV or other related genes. In this study, we aimed to investigate the genetic and molecular basis of an unclassified autoinflammatory phenotype in a two-generation family comprising four affected members and one unaffected member. Methods: We performed whole-exome sequencing in all family members and prioritized variants according to rarity, predicted functional impact, segregation pattern, and biological relevance to inflammatory pathways. Downstream molecular analyses were performed using PBMCs from affected individuals and the unaffected family member. Results: Whole-exome sequencing identified a novel splice-site variant in PSMB10 (NM_002801; c.56+1G>A) affecting the canonical splice donor site. The variant segregated with the autoinflammatory phenotype and was associated with reduced full-length PSMB10 transcript levels in patient-derived PBMCs, supporting a predicted loss-of-function effect. Although pathogenic variants in PSMB10 have previously been implicated in proteasome-associated autoinflammatory syndrome (PRAAS), the clinical presentation in this family differed from the classical PRAAS phenotype. Molecular analyses showed altered immunoproteasome-related gene expression and a severity-associated interferon-related response. Severely affected individuals showed increased expression of interferon-related genes, including ISG15, IFI35, and SIGLEC1, whereas mildly affected individuals showed lower or reduced expression patterns. Notably, the extent of these molecular alterations differed among family members and broadly reflected the observed clinical heterogeneity. Conclusions: We report a novel PSMB10 splice-site variant as a strong potential contributor to an unclassified autoinflammatory disease, with a predicted disruption of canonical splicing and loss of protein function. Our findings expand the clinical spectrum of immunoproteasome-associated disorders and suggest that immunoproteasome-related dysregulation and variable interferon responses may contribute to disease severity. The intrafamilial variability observed in this family suggests that additional genetic or immunogenetic factors may modify disease expression, even in autoinflammatory disorders that appear to follow a monogenic inheritance pattern. Full article

River regulation creates reservoir shorelines with hydrological regimes that differ from those of adjacent riparian wetlands, but it remains unclear whether wetland setting and geomorphic region are reflected similarly in aggregate community attributes and species composition. We examined plant community attributes, species composition, dominant-species patterns, and their associations with soil and topographic conditions across 20 wetlands in the Han River basin, China. No community attribute differed significantly between riparian and reservoir shoreline wetlands, whereas lowland wetlands had greater plant cover than mountain wetlands. Of the 28 species recorded on reservoir shorelines, 24 also occurred in riparian wetlands. Species composition showed modest differentiation between mountain and lowland wetlands but not between wetland settings, and the ordination showed considerable overlap among groups. Cynodon dactylon dominated all groups, while the frequency and cover of other common species varied spatially. Slope, fine substrate, and distance to water were significantly associated with species composition, but explained a limited proportion of the variation. Slope contributed most within the explained component. These findings indicate that spatial and seasonal variation may be expressed differently across aggregate community attributes and species patterns. Reservoir shoreline assessment may therefore benefit from considering species composition and dominant-species structure alongside vegetation cover and richness. Full article

This study evaluated dietary sterol-rich yeast hydrolysate (SYH) at 0, 0.2, 0.5, and 0.8 g/kg in 720 yellow-feathered broiler breeder hens for 6 weeks. The tested SYH, supplied as a powder, contained 9.24% mannan, 3.1% total sterols, 2.0% amino nitrogen, and 3.64 g/kg nucleotides. Serum lipoproteins, intestinal morphology, digestive enzyme activities, barrier-related gene expression, and cecal microbiota were assessed. Low-density lipoprotein cholesterol was higher in J-C than in Control, J-A, and J-B, whereas high-density lipoprotein cholesterol did not differ among treatments. Duodenal lipase showed a significant overall treatment effect, but no Dunn–Holm pairwise comparison remained significant; ileal lipase was higher in J-C than in J-A. For barrier-related transcripts, J-A had higher ZO-1 than the Control and J-B and higher occludin and claudin-1 than all other groups, whereas MUC2 was higher in J-A and J-C than in the Control. These transcript changes are consistent with the modulation of molecular components associated with intestinal barrier integrity, but they do not by themselves demonstrate improved barrier function. Intestinal morphology showed selective, segment-specific differences rather than a consistent dose-related pattern. Alpha diversity did not differ, whereas Bray–Curtis PERMANOVA detected an overall difference among treatments (p = 0.017) despite overlapping PCoA distributions. Pairwise differential-abundance analysis using metagenomeSeq identified six family- or genus-level differences after false-discovery-rate correction, but these were specific to individual pairwise comparisons and showed no monotonic dose pattern. No exploratory microbiota–phenotype correlation remained significant after multiple-testing correction. Overall, SYH elicited inclusion-level- and trait-specific responses rather than a coordinated improvement across endpoints; therefore, the present data do not identify a single optimal inclusion level. Full article

The recent introduction of “molecularly defined renal cell carcinomas” in the World Health Organization classification has significantly expanded the diagnostic spectrum of renal neoplasia, highlighting entities characterized by specific genetic alterations with potential clinical and therapeutic relevance. However, the recognition of these tumors in routine practice remains challenging due to overlapping morphological features and variable access to molecular testing. In this context, immunohistochemistry (IHC) has emerged as a practical and widely available tool that can act as a surrogate for underlying molecular alterations. Depending on the biological context, IHC may reflect genetic events either through protein overexpression, as in fusion-driven tumors, or through loss of expression associated with gene inactivation in metabolically or chromatin remodeling-deficient neoplasms. Accordingly, IHC plays a central role as a screening and triage method within the diagnostic workflow of these entities. Overall, IHC remains an indispensable component in the evaluation of molecularly defined renal cell carcinomas, but its optimal use requires integration with morphological assessment and, in most cases, confirmatory molecular testing. The aim of this review is to provide a comprehensive and evidence-based overview of the main immunohistochemical surrogates used in molecularly defined renal cell carcinomas, including TFE3-, TFEB-, and ALK-rearranged tumors, as well as SDH-, FH-, and SMARCB1-deficient neoplasms, highlighting their diagnostic applications, strengths, pitfalls, and role within an integrated diagnostic workflow. For each marker, the biological rationale, expected staining patterns, diagnostic applications, and major pitfalls are discussed, with particular emphasis on variability across studies and technical limitations. Full article

Background: Q&A corpora generated through university student–AI mental health support tools may reveal how physical activity (PA) and psychosocial themes are represented in support-oriented text. However, the absence of individual-level demographic metadata and the pooling of prompt and response fields limit attribution of any expression to a particular speaker, and the corpus describes a specific student population rather than a general or clinical one. Objective: This exploratory study described PA-, sport-, physical education (PE)-, body-, lifestyle-, and emotion-related patterns in a large corpus of university student–AI mental health exchanges collected through an institutional counselling platform. Methods: This study analysed 209,715 paired prompt–response records as combined exchange-level units using a BERTopic-based computational text-mining workflow. The full corpus was used for the main 18-topic model and overlapping dictionary analyses. After secondary data-quality filtering, 178,062 eligible exchanges formed the sampling frame from which a systematic sample of 10,000 exchanges was drawn for a separate complementary BERTopic and scenario-mapping analysis. The workflow used Qdrant/bge-small-zh-v1.5 embeddings, NFKC normalisation, an archived stop-word list, UMAP (n_neighbors = 15, n_components = 5, min_dist = 0.0, cosine metric, seed = 42), HDBSCAN (min_cluster_size = 300, min_samples = 10, Euclidean metric, EOM), c-TF-IDF topic representations, overlapping dictionary screens, and stability testing across seeds 42, 52, and 62. Results: A student/school/family-context lexical screen matched 83,215 exchanges (39.68%), and a broad PA/body/lifestyle screen matched 82,464 exchanges (39.32%). These overlapping indicators describe topical co-occurrence and do not establish PA behaviour or which party to the exchange produced a given term. Eighteen corpus-level themes were retained. In the 10,000-exchange analysis, 13.11% of exchanges matched a narrow movement-related expression screen, with the highest within-topic rate in the sample topic labelled emotional outburst and relaxation regulation (51.09%). Conclusions: The findings describe exchange-level lexical and topic patterns in student–AI interactions rather than actual PA behaviour, intervention delivery, clinical efficacy, or population prevalence, and they do not identify which party introduced the language. The mapping to autonomy, competence, relatedness, and emotional regulation is a post hoc interpretive lens, offered as a hypothesis to inform future, prospectively validated design work in PE and digital mental health support rather than as a demonstrated result. Full article

Sustainable forest governance requires fiscal instruments responsive to community preferences for ecosystem services, yet compensation standards are rarely checked against those preferences. China’s ecological public welfare forest program, which covers 120 million hectares, sets graded provincial compensation rates across internally differentiated communities. Using contingent valuation data from 315 households in Lin’an District, Zhejiang Province (2024), this study compares compensation with community-expressed preferences and asks whether that comparison holds across social groups. The aggregate community willingness to pay (WTP) is CNY 41.07 million per year, with a mean household WTP of CNY 210, and the actual provincial compensation of CNY 41.34 million falls within its confidence interval. Because both quantities carry estimation uncertainty, this interval overlap is not a formal test of equivalence and does not establish that the two are equal. The aggregate correspondence also masks substantial heterogeneity. Income and education generate WTP differentials exceeding 30 percent, and rural residents report valuations 16.6 percent below those of urban residents. This pattern is associated with economic capacity rather than institutional trust or environmental awareness. Lin’an is a most-likely case for such correspondence, since its urban–rural income ratio (1.54:1) lies well below the national average (2.31:1). Preference heterogeneity is therefore plausibly more pronounced elsewhere, although cross-regional replication would be required to confirm this. Graded fiscal instruments for forest resource governance, even where broadly consistent with aggregate preferences, warrant differentiation to sustain community support for conservation across heterogeneous populations. Full article