Search Results (1,477)

WRKY (WRKY domain-containing) transcription factors represent one of the largest families of plant-specific transcription regulators and play pivotal roles in plant growth, development, nutrient acquisition, and responses to biotic and abiotic stresses. In this study, the coding sequence of TaWRKY65-3B was cloned from the hexaploid wheat cultivar Hanxuan 10. Domain analysis revealed that TaWRKY65-3B contains a conserved WRKY domain and a typical C₂H₂-type zinc finger motif. The gene spans 1478 bp and comprises two exons and one intron. Promoter analysis identified multiple cis-acting regulatory elements, including those responsive to abscisic acid, methyl jasmonate, drought, and low temperature. Quantitative real-time PCR (qRT-PCR) demonstrated that TaWRKY65-3B was significantly upregulated under polyethylene glycol (PEG)-simulated-drought stress in wheat. Overexpression of TaWRKY65-3B in rice resulted in marked growth inhibition, characterized by reduced plant height, shortened grains, and decreased grain width, perimeter, and surface area. These morphological changes led to a significant reduction in thousand-grain weight and overall grain yield. Mechanistically, TaWRKY65-3B activated the expression of OsCPS2, OsCPS4, and OsKS4, which encode key enzymes in the diterpenoid phytoalexin biosynthetic pathway. Subsequent oxidative modifications catalyzed by the cytochrome P450 monooxygenase OsCYP76M7 facilitated the accumulation of the defensive diterpenoid neoabietic acid. Integrated transcriptomic and metabolomic analyses revealed that constitutive TaWRKY65-3B overexpression reprograms simulated-drought-responsive metabolism in rice, with a diterpenoid metabolite annotated as neoabietic acid as a key correlative feature—though definitive structural confirmation requires authentic standards. These findings identify a WRKY-mediated regulatory module connecting diterpenoid phytoalexin metabolism to simulated-drought stress responses, although the precise molecular cascades governing the growth-defence trade-off between stress adaptation and yield warrant further investigation. Full article

Age-related macular degeneration (AMD) is a leading cause of visual impairment. Beyond the classical pathogenetic pathways, increasing evidence suggests that epigenetic regulation and the gut–retina axis may substantially contribute to AMD development and progression. This review synthesizes current evidence on two increasingly recognized and interconnected domains of AMD pathogenesis: epigenetic regulation and gut microbiota dysbiosis. Epigenetic processes, such as DNA methylation, histone modifications, and non-coding RNAs, can influence gene function involved in oxidative stress responses, complement regulation, angiogenesis, and inflammation, while several related markers have emerged as potential diagnostic and prognostic biomarkers. Moreover, growing evidence suggests a functional gut–retina axis, in which alterations in the gut microbiota impair intestinal barrier function and facilitate the systemic passage of bacteria and microbial metabolites, potentially affecting retinal inflammation and immune responses. Furthermore, several microbial metabolites, including short-chain fatty acids, lipopolysaccharide, bile acids, tryptophan derivatives, and trimethylamine-N-oxide, may have either protective or harmful effects on retinal and choroidal homeostasis, with altered circulating and fecal concentrations reported in patients with AMD compared with controls. These findings support AMD as a systemically and molecularly interconnected disorder, while further longitudinal, mechanistic, and multi-omics studies are required to establish causality, define interactions between epigenetic and microbiome-related pathways, and clarify their potential utility as biomarkers and therapeutic targets. Full article

Background/Objectives: Palliative care (PC) is an integral component of ischemic stroke management, yet contemporary nationwide data on its utilization, recent utilization rates, and associated disparities are lacking. This study examined PC utilization rates, demographic disparities, and clinical factors associated with receipt of PC (PC) across ischemic stroke hospitalizations in the United States (US) from 2016 to 2022. Methods: This retrospective cross-sectional study used data extracted from the National Inpatient Sample (NIS) to identify adult hospitalizations primary for ischemic stroke, identified via validated International Classification of Disease—10th Clinical Modification (ICD-10-CM) codes. PC use was identified using the code Z51.5. Multivariable logistic regression was performed to identify factors independently associated with PC, adjusting for demographics, hospital characteristics, clinical severity (National Institutes of Health Stroke Scale [NIHSS] category, Charlson Comorbidity Index), complications, and receipt of thrombolysis/thrombectomy. Results: Among 4350,924 weighted ischemic stroke hospitalizations, 253,555 (5.83%) received PC, ranging from 5.34% in 2016 to 6.40% in 2022. Hospitalizations involving Black (adjusted odds ratio [aOR], 0.71; 95% CI, 0.69–0.74) and Hispanic (aOR, 0.73; 95% CI, 0.70–0.77) individuals had significantly lower odds of PC receipt compared with those involving White individuals. Lower-income quartiles, rural hospitals, and non-teaching hospitals were independently associated with reduced odds of PC receipt. Compared with NIHSS scores of 0–9, higher NIHSS scores demonstrated a graded association with PC use (NIHSS 20–29: aOR, 8.53; NIHSS 30–39: aOR, 12.22). Malignant neoplasm (aOR, 3.83), respiratory failure (aOR, 3.04), and cerebral edema (aOR, 2.82) showed clinically large statistically significant associations with PC. Receipt of reperfusion therapies were inversely associated with PC use (aOR, 0.85 for thrombolysis; aOR, 0.71 for thrombectomy). Conclusions: PC utilization among ischemic stroke hospitalizations remains low, with persistent racial/ethnic, socioeconomic, and institutional disparities. System-level interventions are needed to expand equitable PC access across all stages of ischemic stroke care, including patients who receive reperfusion therapies. Full article

Osteoarthritis (OA) is now widely discussed as a whole-joint immunometabolic disease involving cartilage, synovium, and subchondral bone, rather than as cartilage degeneration driven only by mechanical stress. Tissue injury, cell death, mitochondrial dysfunction, and extracellular matrix degradation can lead to the persistent release of damage-associated molecular patterns (DAMPs), which activate innate immune responses through pattern recognition receptors (PRRs). A key unresolved issue is why inflammation can persist or recur when there is no continuous external stimulus. Trained immunity provides an emerging framework for approaching this problem, with initial direct evidence now available in circulating monocytes from knee OA but broader validation still lacking. Following an initial stimulus and a subsequent resting interval, monocytes and macrophages may retain epigenetic and metabolic alterations that modify their responses to later homologous or heterologous challenges. This review summarizes the sources of DAMPs and their recognition mechanisms in the OA microenvironment, with particular attention to their potential links with trained immunity in monocyte–macrophage populations. We discuss PRR-mediated changes in chromatin accessibility, histone modifications, DNA methylation, and non-coding RNA regulation, as well as immunometabolic events such as enhanced glycolysis, tricarboxylic acid cycle remodeling, mitochondrial dysfunction, and accumulation of key metabolites. We also examine how monocyte–macrophage populations with persistent hyperresponsiveness after stimulus withdrawal and restimulation may contribute to persistent synovitis, cartilage matrix degradation, and abnormal subchondral bone remodeling. Finally, we summarize therapeutic opportunities potentially relevant to the proposed links between DAMP signaling and trained immunity. Recent evidence that high-mobility group box 1 (HMGB1) primes a trained phenotype in circulating monocytes provides initial direct support for DAMP-associated trained immunity in knee OA. However, its generalizability across independent cohorts, other DAMP classes, myeloid-cell compartments, disease stages, and OA phenotypes remains to be established. Full article

Over the past decades, male reproductive health has markedly declined, as evidenced by reduced sperm concentration, impaired motility, increased morphological abnormalities, and a higher incidence of testicular disorders. Environmental factors, particularly endocrine disruptors (EDs), are increasingly recognized as important contributors due to their ability to interfere with hormonal signaling and cellular homeostasis. Mechanistically, EDs induce oxidative stress, mitochondrial dysfunction, DNA damage, endocrine imbalance, and epigenetic reprogramming. These alterations include changes in DNA methylation, histone modifications, and non-coding RNA expression that may persist beyond the period of direct exposure and potentially affect subsequent generations. In parallel, EDs disrupt the hypothalamic–pituitary–gonadal axis, impair steroidogenesis, and compromise Sertoli cell function and blood–testis barrier integrity. This part of review also discusses emerging strategies to mitigate ED-induced reproductive toxicity, including antioxidants, natural bioactive compounds, probiotics, and other interventions targeting oxidative stress, apoptosis, and endocrine dysfunction. Collectively, these findings highlight the complex molecular, epigenetic, and endocrine mechanisms underlying ED-induced male reproductive dysfunction and its potential long-term consequences. Full article

Encoding genetic information involves both structure and sequence. Non-protein-coding (NCR) RNAs modulate host immune responses by guiding and assembling stress-specific protein effectors, with flipons enabling dynamic transitions between states. Small NCRs transcribed by both RNA Polymerases 2 and 3 normally modulate these pathways. The miRNAs, tRNA fragments, mitrons, piRNAs, and endo-small-interfering RNA products target the guide effector complexes to their targets. These NCRs filter the subset of RNAs that are translated, a process modulated by other NCRs that fine-tune RNA stability, localization, and kinetics through the modifications they direct. When these RNAs, or their targets, are dysregulated, host interferon responses are activated through the accumulation of uncapped triphosphorylated RNAs, dsRNAs, or flipon-encoded Z-RNAs. These responses are initially suppressed to avoid attacks on self-RNAs, but above a threshold, highly immunogenic pathways are unleashed. These same responses resist viral and other infections without pathogen-specific effectors or prior exposure. They also eliminate dysfunctional cells. These universal responses, when unresolved, contribute to a range of pathologies, increasing cancer, inflammatory diseases, and senescence. The review focuses on recent findings showing how these integrated host responses are driven by, and exploit, the retrotransposon invasion of animal genomes. Full article

Epigenetic regulation has emerged as a fundamental mechanism governing immune function in poultry by integrating genetic, environmental, nutritional, and microbial signals without altering the DNA sequence. Recent advances in epigenomics have revealed that DNA methylation, histone modifications, chromatin remodeling, and non-coding RNAs are associated with regulation of immune and inflammatory responses, inflammatory signaling, immune-cell differentiation, and host–pathogen interactions. Poultry-specific studies, predominantly conducted in chickens, have identified infection- and challenge-associated epigenetic changes in models including avian influenza, Marek’s disease, and bacterial inflammatory stimulation, with the strongest current evidence relating to innate and inflammatory immune regulation. Environmental factors such as nutrition, gut microbiota, heat stress, and developmental conditions further shape immune competence through epigenetic programming, while emerging evidence suggests that some epigenetic modifications may contribute to transgenerational disease resistance. Emerging evidence suggests that some epigenetic signatures may persist across generations; however, robust evidence for stable transgenerational inheritance of immune-related epigenetic traits in poultry remains limited. Advances in whole-genome bisulfite sequencing, ATAC-seq, ChIP-seq, and single-cell multi-omics are improving characterization of the avian epigenome, whereas CRISPR-based epigenome editing, artificial intelligence-assisted prediction, epigenetic selection, and epigenome-informed vaccine optimization remain prospective applications requiring substantial functional and field validation. This review synthesizes current knowledge of epigenetic mechanisms regulating poultry immunity, evaluates their roles in host–pathogen interactions and environmental adaptation, and highlights emerging genomic technologies that may facilitate translation of immunoepigenetic discoveries into practical strategies for improving poultry health, disease resilience, and sustainable production. Full article

Background/Objectives: MicroRNAs (miRNAs) are small non-coding RNAs (20–24 nucleotides) that regulate post-transcriptional gene expression and are involved in key biological processes, including proliferation and apoptosis. Dysregulation of miRNA expression is associated with numerous diseases, particularly cancer, making them attractive biomarkers and therapeutic targets for precision medicine. Antisense miRNA oligonucleotides (AMOs) have emerged as promising agents for selectively inhibiting miRNA activity. This review examines the development of radiolabelled AMOs targeting miRNAs for diagnostic and imaging applications, with particular attention to their radiolabelling, biological performance, delivery strategies, and potential therapeutic extension. Methods: The literature was examined with a focus on studies describing the synthesis of radiolabelled AMOs targeting miRNAs. Other oligonucleotide-based molecules, such as antisense oligonucleotides (ASOs) and peptide nucleic acids (PNAs), were not considered. Results: Current evidence demonstrates that AMOs can be efficiently radiolabelled with clinically relevant radionuclides, including ^99mTc and ⁶⁸Ga, using bifunctional chelating agents (BFCA) such as MAG3, DOTA, and NOTA while preserving their biological properties. These probes enable noninvasive imaging of their in vivo localization in regions of interest, supporting their potential for precision diagnostics. However, available studies remain limited, and significant challenges persist, particularly regarding targeted delivery, pharmacokinetics, and nonspecific uptake in excretory organs. Therapeutic applications remain at an early preclinical stage, with radioiodinated AMO-21 providing preliminary evidence for therapeutic use. Conclusions: Radiolabelled AMOs represent a potential approach for miRNA targeted molecular imaging, but their clinical translation remains challenging. Future studies should integrate optimized chemical modifications and delivery systems with rigorous in vivo validation and appropriate controls. Full article

Cancer development is influenced not only by genetic alterations but also by epigenetic dysregulation driven by environmental and lifestyle factors, particularly diet. Nutrigenomics investigates how dietary components interact with the genome to influence gene expression, while nutritional epigenetics focuses on diet-induced modifications such as DNA methylation, histone modifications and non-coding RNA regulation. Increasing evidence indicates that bioactive dietary compounds can modulate epigenetic mechanisms involved in carcinogenesis, highlighting their potential role in cancer prevention. This narrative review synthesizes recent evidence, with emphasis on literature published between 2015 and 2025 and an updated search through September 2026 on the molecular interplay between diet, epigenetic regulation and cancer risk. We examine how key dietary factors—including methyl donors involved in one-carbon metabolism, polyphenols, short-chain fatty acids and omega-3 fatty acids—modulate epigenetic regulators such as DNA methyltransferases and histone deacetylases. Particular emphasis is placed on the emerging Nutrigenomics–Microbiome–Epigenome Axis, whereby microbiota-derived metabolites influence host chromatin architecture and gene expression pathways relevant to tumor suppression and inflammation. In addition, we discuss current evidence linking dietary patterns, including Mediterranean and Western diets, with distinct epigenomic signatures associated with cancer susceptibility. The review further explores the potential of epigenetic biomarkers and epigenome-wide association studies to support precision nutrition strategies for cancer prevention. Collectively, accumulating evidence suggests that diet-driven epigenetic plasticity may contribute to cancer prevention. However, the human evidence remains heterogeneous, and large, well-designed intervention studies with standardized epigenetic endpoints are required before mechanistic findings can be translated into clinically actionable precision nutrition strategies. Full article

Zygotic genome activation (ZGA) is a pivotal event during early mammalian embryonic development and is regulated by multiple molecular factors. In mice, previous studies have demonstrated that long non-coding RNAs (lncRNAs) and transposable elements (TEs) participate in the regulation of this process. However, the functional roles of TEs-associated lncRNAs in porcine ZGA remain largely unknown. In this study, we identified a previously unannotated lncRNA associated with a SINE transposable element sequence in porcine parthenogenetically activated embryos, which we named LincSAKP. LincSAKP exhibited peak expression at the 8-cell stage, coinciding with ZGA, was predominantly localized in the nucleus, and lacked protein-coding potential. Functional analyses demonstrated that depletion of LincSAKP resulted in developmental arrest at the 8-cell stage, accompanied by reduced chromatin accessibility, impaired nascent transcription, and aberrant expression of multiple ZGA marker genes and transcription factors. Transcriptomic analysis combined with rescue experiments identified EP300 as a critical downstream target of LincSAKP. Notably, Depletion of either LincSAKP or EP300 impairs histone H3K27ac modification. EP300 overexpression effectively alleviated the developmental defects caused by LincSAKP depletion. Collectively, our findings identify EP300 as a downstream mediator of LincSAKP in regulating zygotic genome activation, providing insights into the functional network of SINE-associated lncRNAs during parthenogenetically activated early embryonic development. This study expands our understanding of the functional roles of TE-associated non-coding RNAs in early embryonic development and provides a potential theoretical basis for improving the efficiency of in vitro culture of porcine embryos. Full article

The rapid adoption of artificial intelligence (AI) programming assistants has raised questions about the actual benefits they provide in professional software development. This exploratory longitudinal case study compares configurations of three AI programming assistants (GitHub Copilot, ChatGPT, and Cursor)—specific combinations of tool, underlying model, interaction interface, and period of use—by reimplementing a full-stack thesis management application (a .NET Core 8.0 representational state transfer (REST) application programming interface (API) and a React.js client with 25 functionalities) that was first developed manually to establish a baseline. Each tool was evaluated using a seven-criteria framework covering code correctness, prompt complexity, context awareness, number of prompts, bug count, bug severity, and recorded implementation time. All three configurations significantly reduced the total recorded implementation time relative to manual implementation (by 66%, 63%, and 83% for Copilot, ChatGPT, and Cursor, respectively; p < 0.001). The Cursor configuration ranked best on four of the five evaluation criteria, with significantly higher context awareness and significantly fewer bugs than Copilot; because the tools were applied in a fixed order between January and November 2025, a period during which the underlying models were upgraded, and Cursor was both applied last and received the largest such upgrade, these results reflect tool–model–interface–time configurations rather than the tools in isolation. All tools performed significantly worse on the multi-layer API than on the client application. All 336 recorded bugs were organized into a fourteen-category taxonomy, in which hallucinated code elements and incomplete multi-file modifications were the most frequent failure modes, a pattern consistent with the tools’ limited ability to track context across files and architectural layers. The results indicate that AI programming assistants are most effective as pair programming tools whose output requires systematic human review before integration. Full article

Background: Sjögren’s disease (SjD) causes severe ocular surface desiccation, progressing from aqueous-deficient dry eye (ADDE) to vision-threatening corneal ulceration, stromal melting, and perforation. Recent consensus guidelines and therapeutic innovations have transformed ophthalmic diagnosis and management. Methods: A comprehensive narrative overview of PubMed and Google Scholar (July 2016–July2026) was conducted to evaluate updates in SjD diagnostics, ocular surface mechanics, topical/biological pharmacotherapies, neurostimulation, and meibomian gland interventions. Results: Diagnostic parameters have shifted towards non-invasive salivary metabolomics (lactate, alanine, malate), regulatory non-coding RNAs (H19 ICR hypomethylation), tear point-of-care MMP-9 testing, and salivary gland ultrasonography (SGUS). Large-diameter scleral lenses provide continuous corneal fluid shielding, though edge design and surface modification are required to mitigate midday fogging. Additionally, emerging therapeutics are shifting care from palliative lubrication to targeted secretomotor and biological reactivation, including cold thermosensory TRPM8 agonists (acoltremon 0.003%), water-free formulations (0.1% cyclosporine, perfluorohexyloctane), reactive aldehyde species (RASP) modulators (reproxalap), syndecan-1 receptor agonists (Lacripep), systemic B-cell depleting biotherapy (ianalumab), trigeminal neurostimulation, and combined intense pulsed light with meibomian gland expression (IPL + MGX). Conclusions: Ophthalmic SjD management has evolved from palliative lubrication toward a stepwise, mechanism-directed paradigm integrating novel diagnostics, secretomotor stimulation, mechanical protection, and biologic disease modification; dedicated SjD-specific trials remain essential to validate these emerging interventions. Full article

Stress can reshape the epigenome through changes in DNA methylation, histone modifications, chromatin accessibility, and non-coding RNA regulation. Much is known about how these changes arise during stress, yet their fate once the initiating stimulus has subsided is less clear. Some alterations are rapidly reversed, whereas others recover only partially or at selected loci, and a subset persists long after the acute response has ended. This review examines the mechanisms and contextual factors that shape post-stress recovery and persistence. We consider how stress interacts with cell identity, chromatin context, metabolic state, DNA damage and repair, and the machinery responsible for rebuilding epigenetic organization. We use epigenetic recovery capacity as a conceptual framework describing the extent and rate at which altered epigenetic features return toward a defined pre-stress or homeostatic state. We propose that this capacity, together with stress burden and locus susceptibility, may shape post-stress fate. Persistence itself does not necessarily constitute epigenetic memory. Some persistent states may remain functionally neutral, whereas others may be engaged during adaptive or maladaptive responses. We further outline an evidence framework that distinguishes epigenetic persistence from functional and causal epigenetic memory and discuss the potential for redirecting maladaptive post-stress trajectories. Full article

Epigenetic regulation has transformed our understanding of how fish adapt to changing environments by modulating gene expression without altering the underlying DNA sequence. This review explores the “dark mastery” of fish epigenetics by providing mechanistic insights into the principal epigenetic processes, including DNA methylation, histone modifications, chromatin remodeling, and non-coding RNAs, that govern development, immunity, stress responses, and disease susceptibility. These regulatory mechanisms enable fish to respond dynamically to environmental stressors such as temperature fluctuations, salinity shifts, hypoxia, pollutants, ultraviolet radiation, and nutritional changes, thereby influencing physiological resilience, reproductive performance, and survival. Recent advances in next-generation sequencing and multi-omics technologies have substantially expanded our understanding of the fish epigenome, while bioinformatics has become indispensable for integrating and interpreting complex genomic, transcriptomic, and epigenomic datasets. Furthermore, artificial intelligence (AI) and machine learning (ML) are emerging as powerful approaches for biomarker discovery, predictive modeling of disease susceptibility, environmental risk assessment, and precision aquaculture. The integration of epigenetics with bioinformatics and AI provides unprecedented opportunities to decipher complex regulatory networks, identify adaptive epigenetic signatures, and develop data-driven strategies for improving fish health and aquaculture sustainability. Despite these advances, important challenges remain, including limited species-specific epigenomic resources, difficulties in multi-omics integration, model interpretability, and the need for standardized analytical frameworks. This review highlights current knowledge, emerging computational approaches, and future perspectives for translating epigenetic discoveries into sustainable aquaculture practices and aquatic ecosystem conservation under accelerating environmental change. Full article

Background: Metabolic bone diseases represent prevalent global disorders characterized by disrupted bone homeostasis and chronic inflammation. This review utilizes a broad working definition encompassing osteoporosis and other classic metabolic bone disorders, including osteoarthritis, a primarily degenerative joint disease marked by significant metabolic-driven subchondral bone remodeling. Conventional diagnostic modalities prove inadequate for early-stage disease screening, while classical pharmacological interventions face limitations due to unsatisfactory targeting performance and severe long-term adverse reactions. An urgent clinical need persists for innovative diagnostic biomarkers and targeted therapeutic strategies. Exosomes, a sub-population of small extracellular vesicles (sEVs), are natural nanoscale intercellular vesicles derived from multivesicular bodies, playing critical regulatory roles in bone metabolism and offering substantial clinical translational potential. This review systematically elaborates the regulatory networks associated with exosomes, the biomarker potential of exosomal non-coding RNAs, and advanced engineering modifications for bone-targeted delivery in metabolic bone diseases. Methods: This narrative review involved a literature search conducted across PubMed, Web of Science, Scopus, and Embase from inception to December 2025, focusing on exosome biology, metabolic bone disorders, non-coding RNA biomarkers, and engineered bone-targeted delivery. Inclusion criteria encompassed peer-reviewed English original and review articles, while conference abstracts, case reports, editorials, and non-English literature were excluded. Eighty-two eligible studies underwent thematic analysis without a formal systematic search protocol or preregistration. Results: Exosomes orchestrate osteogenic and osteoclastogenic processes through established bone-metabolic signaling cascades. Exosomal microRNAs and circular RNAs demonstrate promising diagnostic performance in exploratory observational cohorts for early-stage screening and prognostic assessment of metabolic bone diseases; however, large-scale multi-center clinical validation remains insufficient. Engineered exosomes facilitate precise local bone intervention in preclinical animal models, overcoming significant drawbacks of conventional therapies in experimental settings. Nevertheless, clinical translation is obstructed by non-standardized production workflows and unresolved biosafety risks. Conclusions: Exosomes present promising dual diagnostic and therapeutic potential to enhance precision and individualized management of metabolic bone diseases. Further technical refinement in exosome preparation and modification will expedite orthopedic clinical translation and improve patient outcomes in metabolic bone disorders. Full article