Search Results (1,413)

Ilex rotunda Thunb. is a prestigious ornamental tree renowned for its vibrant red fruits, yet the molecular mechanisms governing its fruit color variation remain poorly understood. The discovery of a rare yellow-fruited natural bud sport cultivar, ‘Peace Time’, provides an ideal model to investigate these processes compared to the wild-type red fruit. In this study, we integrated physiological evaluations, untargeted metabolomics, and de novo transcriptomics across multiple fruit developmental stages to elucidate the basis of this color transition. Our results demonstrated that the yellow phenotype is characterized by high lightness and yellowness values, driven by the profound suppression of anthocyanin biosynthesis. Biochemical and transcriptomic profiling revealed that DFR (dihydroflavonol 4-reductase), a critical “gatekeeper” gene, experiences severe transcriptional silencing in the yellow-fruited cultivar. This enzymatic bottleneck triggers a “passive substrate overflow,” redirecting shared precursors toward the parallel flavonol branch, resulting in the substantial accumulation of specific flavonols, including rutin and isoquercitrin. Furthermore, correlation network analysis highlighted a putative dual regulatory module associated with this metabolic reprogramming: the down-regulation of the putative activator bHLH30 coupled with the robust up-regulation of the putative repressor bHLH51, together likely contributing to the silencing of DFR transcription. These findings provide a comprehensive “dual-module” and “passive overflow” framework for fruit coloration in I. rotunda, highlighting a remarkable metabolic plasticity that reshapes this cultivar’s phytochemical profile and offers vital insights for future ornamental breeding. Full article

Background: Long noncoding RNAs (lncRNAs) have emerged as critical regulators of hepatic metabolism and disease progression. The hepatocyte nuclear factor 1 alpha antisense 1 (HNF1A-AS1) lncRNA modulates liver-specific transcription factors; however, its physiological role in diet-dependent lipid homeostasis remains poorly defined. Methods: In this study, we investigated the mouse ortholog, Hnf1a opposite strand 1 (Hnf1aos1), using AAV-mediated knockdown in C57BL/6J mice fed either a chow diet (10% kcal from fat) or a high-fat diet (HFD; 60% kcal from fat) for 12 weeks. Metabolic phenotyping included hepatic lipid quantification, histological analysis, serum biochemistry, and quantitative gene expression profiling. Results: Loss of Hnf1aos1 produced distinct, diet-dependent alterations in hepatic lipid handling. Under chow conditions, knockdown mice exhibited selective hepatic cholesterol accumulation (6.10 ± 2.9 mg/g tissue vs. 3.51 ± 1.1 mg/g in controls), accompanied by dysregulation of cholesterol clearance pathways. In contrast, under HFD conditions, knockdown precipitated severe macrovesicular degeneration, with hepatic triglyceride levels approximately doubled relative to HFD-fed controls (51.72 ± 19.8 mg/g vs. 26.34 ± 11.9 mg/g) and a numerically elevated triglyceride-to-cholesterol ratio (TG:TC ≈ 6.1:1; p = 0.0621, trend). Chow/Kd mice gained significantly less weight than chow-fed controls, whereas HFD/Kd mice exhibited weight gain comparable to HFD controls despite severe hepatic steatosis. This paradoxical phenotype suggests impaired metabolic feedback at the post-transcriptional level, in which compensatory upregulation of Hnf1a mRNA is insufficient to suppress lipid-associated genes such as Cd36, despite profound lipid overload; however, HNF1A protein levels were not directly measured in this study. Conclusion: Collectively, these findings identify Hnf1aos1 as a regulator of hepatic lipid homeostasis whose loss produces a phenotype consistent with inappropriate lipid accumulation during nutrient excess, without defining the underlying molecular mechanism. Our results support a role for Hnf1aos1 in shaping hepatic metabolic plasticity and provide insight into lncRNA-associated MASLD phenotypes. Full article

To clarify the genetic background and biological characteristics of grape germplasm resources and provide theoretical support for germplasm innovation and new-variety breeding, we conducted systematic morphological identification and SSR molecular-marker analysis on 38 core grape germplasms (29 fresh-eating cultivars, 1 local cultivar, and 8 wild germplasms) from the National Southeast Mountainous Crop Germplasm Repository (Jiangxi·Yichun) and other regions. For morphological identification, 14 quantitative traits and 5 descriptive traits of leaves, floral organs and fruits were determined in strict accordance with the NY/T 2932-2016 Descriptors for Grape Germplasm Resources. For SSR molecular-marker analysis, eight pairs of internationally universal core primers were used for PCR amplification and fluorescence detection referring to the NY/T 3640-2020 Identification of Grape Cultivars Using SSR Markers, and genetic diversity analysis was conducted on 11 local and wild grape germplasms. The results revealed abundant phenotypic diversity among the tested germplasms: the functional leaves of cultivars were predominantly pentagonal and cuneate, while those of wild germplasms were mostly reniform and cordate, with 3–5 lobes for most germplasms; all germplasms were hermaphroditic, except for two wild accessions with unisexual flowers. Significant variations were observed in fruit traits, with the coefficient of variation (CV) of cluster weight and berry weight reaching 67.64% and 50.53%, respectively. The genetic plasticity of weight-related traits was much higher than that of shape- and length-related traits, and the average Shannon–Wiener index (H′) of 19 morphological traits was 3.47, indicating a high level of overall phenotypic diversity. SSR analysis showed that the eight primer pairs amplified a total of 42 genotypes (5.25 per primer pair on average). The population had a mean observed number of alleles (Na) of 5.28, a mean effective number of alleles (Ne) of 7.25, and a mean polymorphism information content (PIC) of 0.74, demonstrating rich genetic diversity and high polymorphism of the tested loci. Cluster analysis divided the 11 local germplasms into four groups, which clearly reflected the genetic relationships among them, and genetic admixture was found in some germplasms due to unclear introduction traceability. In this study, fresh-eating grape cultivars suitable for the climatic conditions of Jiangxi Province were screened, the utilization value of local germplasm resources was clarified, and a two-dimensional evaluation system based on phenotypic traits and SSR molecular markers was constructed. The findings provide basic data and a scientific basis for the precise evaluation, elite gene mining, and new-variety breeding of grape germplasm resources in Jiangxi Province. Full article

Depression is a highly heterogeneous psychiatric disorder with its pathogenesis increasingly linked to dysregulated neuroinflammation. Microglia, as the resident immune cells of the central nervous system (CNS), play a pivotal role in the initiation and progression of the neuroinflammation and the pathophysiology of depression. These cells exhibit a dual role in pro- and anti-inflammatory processes, dynamically regulating immune responses through immunometabolic reprogramming in response to environmental cues. This review elaborates how metabolic remodeling in microglia, particularly within glucose, lipid, and amino acid pathways, drives their polarization toward a pro-inflammatory phenotype. This shift promotes depression pathogenesis via the release of inflammatory factors, disruption of synaptic plasticity, and mediation of neurotoxicity. We further discuss the impact of existing antidepressants on cellular metabolism and highlight the promise and challenges of targeting specific microglial metabolic pathways as a novel therapeutic strategy. This synthesis provides new insights into the immunometabolic mechanisms of depression and outlines directions for developing targeted treatments. Full article

Infectious diseases remain a major global health challenge, driven by antimicrobial resistance, pathogen persistence, and the limited integration of mechanistically innovative therapeutic approaches. Emerging evidence indicates that epigenetic regulation is fundamental to host–pathogen interactions, influencing transcriptional programmes associated with virulence, immune evasion, stress adaptation, and phenotypic plasticity. In organisms such as bacteria, parasites, and intracellular pathogens, including Mycobacterium tuberculosis and Plasmodium falciparum, chromatin-associated regulators and DNA-modifying enzymes have been identified as dosage-sensitive determinants of infection outcomes. Traditional strategies focus primarily on occupancy-driven enzymatic inhibition. In contrast, targeted protein degradation (TPD) introduces an event-driven pharmacological paradigm in which transient ligand engagement triggers sustained depletion of regulatory proteins. Platforms such as proteolysis-targeting chimeras (PROTACs) and BacPROTACs exemplify the ability to exploit host and pathogen proteolytic systems, thereby expanding the druggable proteome beyond conventional small-molecule targets. This review examines the relationship between epigenetic regulation and pathogen survival, highlights recent advances in degradation technologies, and discusses conceptual and translational challenges in implementing TPD in antimicrobial and antiparasitic drug discovery. Full article

This study evaluates how titanium and polymethyl methacrylate (PMMA) Boston Keratoprosthesis backplate substrates influence human corneal fibroblast proliferation, cytotoxicity, morphology, activation phenotype, and mechanotransductive signaling. Human corneal fibroblasts were cultured on titanium and PMMA, with tissue culture plastic or glass as controls. Proliferation was assessed over 7 days using metabolic assays, and cytotoxicity was measured by lactate dehydrogenase release. Cell morphology and surface coverage were examined by scanning electron microscopy, while immunofluorescence quantified fibroblast-specific protein 1 (FSP-1) and α-smooth muscle actin (α-SMA). Gene expression of α-SMA, collagen I, FSP-1, and focal adhesion kinase (FAK) was analyzed by quantitative PCR. Cells cultured on both substrates maintained stable viability with modest increases in estimated cell numbers and comparable proliferation curves, indicating preserved metabolic activity without growth suppression. Cytotoxicity remained low and similar between groups. SEM demonstrated broader and more continuous cell spreading on titanium, whereas cells on PMMA were more sparsely distributed. Immunofluorescence showed higher FSP-1 expression on titanium and increased α-SMA on PMMA. Gene expression analysis revealed higher FAK transcripts on PMMA, with no significant differences in α-SMA, FSP-1, or collagen I. These results confirm the cytocompatibility of both titanium and PMMA backplates with human corneal fibroblasts and support their use with the Boston Keratoprosthesis. Full article

Amblyopia is increasingly conceptualized as a neurodevelopmental visual disorder that often arises from discordant binocular visual experience during early life and is associated with abnormal binocular interactions, interocular suppression, orientation-dependent developmental abnormalities in selected refractive phenotypes, and experience-dependent plasticity, consistent with a distributed-network perspective rather than a purely monocular acuity deficit. We performed a structured state-of-the-art narrative synthesis of peer-reviewed reviews, randomized controlled trials, and key mechanistic human studies indexed in PubMed/MEDLINE, Web of Science, and Scopus (1 January 2016–28 February 2026; last search 28 February 2026), prioritizing recent evidence from 2021–2026. Literature supports consideration of clinically trackable constructs beyond best-corrected visual acuity (BCVA), including quantified suppression/imbalance, binocular function, and functionally meaningful outcomes such as reading-related limitation and broader functional impact. Across established and emerging intervention classes, treatment effects are heterogeneous across ages and etiologies. Evidence is strongest for conventional penalization and selected active training-based approaches, whereas newer protocol-standardized approaches remain investigational and require prospective evaluation with transparent exposure/dose reporting. Based on these findings, we outline a clinically oriented, core outcome set for amblyopia and strabismus (COSAMS)-aligned framework that combines quantified binocular imbalance with multidimensional phenotyping and a hypothesis-driven, prospectively testable therapeutic model intended to structure (not replace) clinical decision-making. Priorities for precision-oriented amblyopia care include standardization of suppression metrics, adoption of core outcome sets, transparent reporting of ‘not measurable’ outcomes and missingness, and prospective validation of phenotype-driven, prediction-ready frameworks. Full article

Lower-grade gliomas (LGGs) often follow a relatively protracted clinical course; however, a substantial proportion eventually undergo malignant transformation to high-grade, treatment-refractory disease. This process has traditionally been interpreted in the context of stepwise histopathologic progression and recurrent genetic alterations. Increasing evidence, however, suggests that malignant transformation is more accurately understood as an evolutionary process shaped by the interplay among epigenetic constraints, cell-state plasticity, and selective pressures. In this review, we examine current evidence supporting a model in which early LGGs, particularly isocitrate dehydrogenase (IDH)-mutant tumors, are initially maintained in relatively restricted cellular states by metabolically imposed epigenetic programs, but progressively escape these constraints under the cumulative influence of therapy, hypoxia, immune remodeling, and genomic instability. We summarize recent advances demonstrating that progression from lower-grade to high-grade disease is accompanied by cell-state transitions characterized by altered lineage identity, acquisition of stem-like features, increased proliferative capacity, and adaptation to cellular stress. We further discuss how these transitions are reinforced by microenvironmental evolution, including vascular remodeling, extracellular matrix reorganization, and changes in immune composition, thereby creating conditions that favor clonal expansion, invasion, and therapeutic resistance. Particular attention is given to longitudinal, single-cell, and spatially resolved studies, which collectively indicate that malignant transformation is not a discrete event but a continuous process of evolutionary selection and phenotypic reprogramming. Finally, we discuss the translational implications of this framework for early risk stratification, biomarker development, and mechanism-based therapeutic intervention. By reframing malignant transformation in LGGs as a process of cell-state escape under persistent selective pressure, this review aims to provide an integrated view of glioma progression and to highlight new opportunities for precision monitoring and treatment. Full article

Microbial communities inhabiting natural and anthropogenically impacted environments are exposed to diverse abiotic stressors that can influence the distribution of functional traits. However, distinguishing the processes underlying phenotypic patterns remains challenging in microbial systems, where ecological and evolutionary dynamics often overlap. In this study, we experimentally assessed the distribution of biofilm formation and plastic degradation capacity in bacterial isolates across environments characterized by different stress regimes, to evaluate whether these traits are primarily associated with environmental context rather than phylogenetic relatedness, and may therefore reflect environment-dependent phenotypic modulation on a lineage-specific functional background. Taxonomic affiliation was assessed using 16S rRNA gene sequencing, while expressed biochemical profiles were characterized by Fourier-transform infrared (FTIR) spectroscopy. Multivariate ordination and Partial Least Squares analyses were used to explore relationships among taxonomy, biochemical profiles, functional phenotypes, and environment of isolation. Phylogenetic signal analysis confirmed that neither trait was strongly constrained by vertical inheritance, with Blomberg’s K ≈ 0 and Fritz & Purvis’ D = 0.51, consistent with environment-driven rather than phylogenetically conserved trait distributions. Both biofilm production and plastic degradation capacity showed significant environment-dependent differences in their relative frequencies (Fisher’s exact test, biofilm: p = 5.5 × 10⁻⁵; PCL degradation: p = 2.5 × 10⁻⁴) and were not directly associated with each other (Wilcoxon rank-sum test, p = 0.45; linear model, p = 0.68). Overall, these results indicate that microbial functional traits are unevenly distributed across environments and weakly constrained by taxonomy, consistent with the contribution of multiple, non-mutually exclusive processes that remain difficult to disentangle empirically. Full article

Background/Objectives: Major depressive disorder (MDD) remains a leading cause of disability worldwide and exhibits substantial biological heterogeneity that is not adequately captured by current symptom-based diagnostic systems. While the classical monoamine hypothesis has historically guided antidepressant development, it does not fully account for variability in treatment response, delayed therapeutic onset, or the persistence of cognitive and anhedonic symptoms. Converging evidence from molecular, neuroimaging, and translational studies increasingly implicates glutamatergic dysregulation and impaired neuroplasticity as key mechanisms in depressive pathology. This narrative review aims to integrate monoaminergic and glutamatergic perspectives within a dimensional framework that may help explain clinical heterogeneity and inform mechanism-based treatment strategies. Methods: A narrative synthesis of the literature was conducted using major biomedical databases including PubMed, Scopus, and Web of Science. Preclinical studies, neuroimaging investigations, biomarker research, randomized clinical trials, and meta-analyses examining monoaminergic dysfunction, glutamatergic signaling, neuroplasticity pathways, and rapid-acting antidepressants were reviewed and thematically integrated. Results: Evidence indicates that depressive syndromes may reflect varying contributions of monoaminergic dysregulation and glutamatergic–neuroplastic impairment. Monoaminergic disturbances interact with inflammatory and neuroendocrine processes, including cytokine-driven activation of the kynurenine pathway. In parallel, alterations in glutamatergic signaling, glial function, and BDNF–TrkB–mTOR pathways contribute to synaptic atrophy and network dysfunction. Rapid-acting antidepressants such as ketamine, esketamine, and dextromethorphan–bupropion provide clinical proof-of-concept that direct engagement of synaptic plasticity mechanisms can accelerate symptom improvement, particularly in treatment-resistant depression. Conclusions: Integrating monoaminergic and glutamatergic mechanisms within a “monoamine–glutamate continuum” offers a conceptual framework for understanding depressive heterogeneity and treatment response. Multimodal approaches combining clinical phenotyping with inflammatory, neuroimaging, and molecular markers may ultimately support mechanism-informed precision psychiatry strategies in major depressive disorder. Full article

The remarkable ecological success of fungi is supported by their capacity for rapid and often reversible molecular responses to fluctuating environments. While conventional evolutionary theory has largely emphasized mutation and selection as central drivers of adaptation, many environmentally responsive fungal traits are also shaped by molecular processes that generate reversible phenotypic variation on ecological or developmental timescales. This review synthesizes current knowledge on reversible genetic and epigenetic mechanisms underlying fungal phenotypic plasticity by integrating insights from programmed genetic rearrangements such as mating-type switching, transposable element activity, variation in tandem repeats and the behavior of accessory chromosomes, together with dynamic epigenetic processes including histone modifications, DNA methylation, chromatin remodeling and RNA mediated regulation. Together, these mechanisms form an interconnected framework that enables rapid and, in many cases, reversible phenotypic diversification, although their consequences range from transient regulatory shifts to partially or fully irreversible sequence-level changes. We highlight the molecular machinery that governs reversibility and its evolutionary implications for fungal pathogenesis, symbiosis, and biotechnology. By uniting genetic and epigenetic perspectives, this review advances a holistic framework in which reversibility is treated as a key property of fungal phenotypic plasticity, helping fungi balance stability with flexibility under environmental challenge. Understanding these mechanisms provides new insights into fungal evolution, and opens new avenues for antifungal intervention and the rational design of industrially valuable fungal strains. Full article

Trained immunity refers to the enduring functional reprogramming of innate immune cells after particular stimuli, driven by epigenetic and metabolic alterations that augment non-specific responses upon subsequent exposure. Neutrophils and monocytes/macrophages, as essential innate effectors, are crucial for the induction and control of trained immunity, which is the primary emphasis of this review. Neutrophils, the predominant circulating leukocytes, were historically considered incapable of memory owing to their brief lifespan. Emerging evidence indicates that trained immunity functions at the bone marrow progenitor level, influencing granulopoiesis to produce neutrophils with lasting functional modifications. This research offers new insights into neutrophil functions in infection, cancer, and inflammation. Monocytes and macrophages, characterized by phenotypic plasticity and tissue residence, function as conventional models of trained immunity. They experience direct peripheral reprogramming or emerge as primed descendants of trained bone marrow precursors, performing pro-inflammatory or reparative roles in malignancies, infections, and ischemia lesions. This study comprehensively outlines the regulatory mechanisms of trained immunity in these cells, clarifies their functions in various clinical situations, and examines therapeutic applications. Comprehending these pathways is crucial for elucidating the cellular foundation of innate immunological memory, uncovering its multiple functions in disease, and guiding innovative therapeutics aimed at granulopoiesis and monocyte-macrophage polarization. Full article

The progression of chronic bone diseases is intricately linked to dysregulated macrophage polarisation. However, a comprehensive understanding of the complex interplay between macrophage polarisation and metabolic reprogramming in the context of bone disorders remains elusive. Thus, this review conducted a systematic search of major databases, including PubMed, using combinations of keywords such as “macrophage polarisation,” “immunometabolism,” “metabolic reprogramming,” and “chronic bone diseases” (including “osteoporosis,” “osteoarthritis,” and “periodontitis”). Inclusion criteria prioritised original research published within the last five years to capture recent advances. Diverging from previous reviews constrained by the classical M1/M2 dichotomy, this article aims to delineate the heterogeneity and functional plasticity of macrophages within the bone microenvironment, emphasising metabolic reprogramming as a central mechanism driving the dynamic behaviour of macrophages across various skeletal pathologies. Furthermore, this review highlights the pivotal roles of specific metabolites—such as succinate, itaconate, and citrate—within the osseous microenvironment, underscoring their influence on macrophage phenotypic transitions and the regulation of bone metabolic homeostasis. Finally, this article envisages innovative therapeutic strategies targeting the “metabolism–immunity axis,” encompassing the design of nano-delivery systems to modulate macrophage metabolism, the utilisation of engineered extracellular vesicles, the development of immunometabolism-modulating biomaterials, and the exploration of naturally occurring bioactive molecules. Based on these findings, the present work proposes the “metabolism–immunity–skeleton” axis as a theoretical framework, thereby establishing a robust foundation for the development of precision metabolic immunotherapy tailored to a spectrum of chronic bone diseases. Full article

Chimonobambusa utilis is a dominant bamboo species in China, yet its leaves remain an underutilized resource despite their significant bioactive potential. To elucidate the metabolic reprogramming of Ch. utilis leaves across an elevational gradient and its link to antioxidant phenotypes, we integrated widely targeted metabolomics with redox profiling of leaves collected from 1150, 1600, and 2000 m in the Qingba Mountains. The mid-elevation (1600 m) group exhibited the most robust antioxidant capacity and the highest total flavonoid content. Metabolomic analysis identified 3113 metabolites across 13 classes, with flavonoids (604 compounds, 22.7% of total abundance) emerging as the predominant secondary metabolites. Pairwise comparisons revealed 1716 differentially accumulated metabolites (DAMs). KEGG enrichment indicated that while the low-elevation (1150 m) group prioritized primary metabolism and upstream phenylpropanoid branches, the high-elevation (2000 m) group was associated with photoprotection and defense responses. In contrast, the mid-elevation environment optimized the flux toward flavonoid biosynthesis while maintaining steady metabolic supply. HPLC quantification further confirmed that key markers—vitexin, hyperoside, orientin, and luteoloside—peaked at 1600 m. Correlation analysis between 423 differential flavonoids and antioxidant indices demonstrated that distinct radical-scavenging activities are driven by specific flavonoid structural motifs. Overall, altitude-driven metabolic remodeling, characterized by a mid-elevation advantage for flavonoid accumulation, dictates the antioxidant plasticity of Ch. utilis leaves. Full article

Achromobacter spp. are opportunistic pathogens in people with cystic fibrosis (PwCF), yet the role of the upper airways in their persistence and adaptation remains poorly understood. We investigated whether the sinonasal compartment may act as reservoir and evolutionary niche for Achromobacter spp. during airway infection. Twenty-two isolates obtained from paired nasal lavage and sputum samples of seven PwCF were analysed by whole-genome sequencing. Within each PwCF, identical clone types were detected in both airway compartments, supporting bacterial exchange between upper and lower airways. Despite clonal relatedness, substantial genomic diversification was observed between paired isolates. Genomic signatures indicative of elevated mutation rates were detected in a high number of isolates (73%) and in both airway compartments, highlighting widespread genomic diversification across the respiratory tract. Mobilome analysis revealed compartment-specific variations in insertion sequences, prophages, and integrative elements, suggesting genome plasticity. Additionally, mutation in an aspartate kinase gene was consistently associated with loss of biofilm formation in vitro, highlighting a potential link between this pathway and biofilm phenotype. Overall, our findings indicate that upper and lower airways represent interconnected but partially independent ecological niches where Achromobacter populations can diverge during colonization, supporting the view that both compartments contribute to their persistence and evolution in CF airways. Full article