Search Results (13,659)

Osteoporosis (OP) and osteoarthritis (OA) are two common degenerative musculoskeletal disorders associated with aging and are traditionally classified and managed as distinct disease entities. Emerging evidence suggests that OP and OA may share bidirectional associations and common biological mechanisms, and that under specific pathological conditions they may develop into a mutually reinforcing comorbid state. The comorbidity of osteoporosis and osteoarthritis (OP–OA) is not a simple superimposition of bone loss and cartilage degeneration; rather, it represents a disorder of the osteochondral unit centered on disruption of the subchondral bone microenvironment. Alterations in the structural strength, remodeling dynamics, vascular and neural status, and bone marrow lesions of subchondral bone collectively reshape the local microenvironment, thereby directly affecting mechanical signal transmission and cellular behavior within the joint. Focusing on the subchondral bone microenvironment as the central pathological nexus, this review systematically summarizes how mechanical imbalance, aberrant bone remodeling, inflammatory activation, metabolic dysregulation, and cellular senescence jointly remodel the local niche in OP–OA comorbidity. These microenvironmental changes further induce phenotypic remodeling and fate deviation of bone marrow mesenchymal stem cells, bone remodeling-related cells, osteoimmune cells, and chondrocytes. On this basis, we integrate the regulatory roles of developmental signaling, mechanotransduction pathways, and inflammatory–immune signaling networks, and propose that microenvironment-driven cell fate plasticity may serve as a key mechanistic hub promoting the initiation and progression of OP–OA comorbidity as well as the persistent destabilization of the osteochondral unit. This perspective may help overcome the limitations of current studies that address OP and OA separately, and may provide a theoretical framework for early identification and stratification, biomarker discovery, and combined precision-targeted interventions for this comorbid condition. Full article

FOXP3 is the master transcriptional regulator of regulatory T cells (Tregs) and is expressed in humans as two main alternatively spliced isoforms: full-length FOXP3 (FOXP3-FL) and the exon 2-deficient variant (FOXP3-Δ2). While the role of these isoforms has been mainly studied in CD4⁺ T cells, their distribution across peripheral blood leukocyte populations and their relationship with immune checkpoint expression remain incompletely defined. In this study, we used a multiparametric flow cytometry panel allowing isoform-specific detection of FOXP3-FL and FOXP3-Δ2, together with PD-1 and CTLA-4, to analyze peripheral blood samples from six healthy donors under basal conditions. Major leukocyte populations, including CD4⁺CD25⁺ and CD4⁺CD25⁻ T cells, CD8⁺ T cells, monocytes, and neutrophils, were evaluated. FOXP3-FL predominated in CD4⁺CD25⁺ T cells, whereas FOXP3-Δ2 was more frequently detected in CD8⁺ T cells, monocytes, and neutrophils. However, the absolute frequencies of these FOXP3-Δ2-positive populations were low, consistent with the overall low levels of FOXP3 expression observed in these cell types. In CD4⁺ T-cell subsets, PD-1 expression was generally higher than CTLA-4, regardless of FOXP3 isoform, and FOXP3-Δ2⁺ cells showed relatively higher PD-1 expression compared to FOXP3-FL⁺ cells. In contrast, checkpoint expression in non-CD4⁺ populations was limited. The observed FOXP3-FL⁺/FOXP3-Δ2⁺ ratios across immune cell populations were consistent with a predominant role of FOXP3-FL in maintaining immune tolerance under basal conditions; whether these patterns are preserved or altered in pathological settings warrants further investigation. These results provide a descriptive overview of FOXP3 isoform distribution and checkpoint expression across peripheral blood immune cell subsets in healthy individuals, which may serve as a reference for future studies in immune-mediated diseases. Full article

Industrial contamination can influence the transfer of toxic and essential elements through soil–plant–animal systems and may pose risks to food safety. This study aimed to determine whether contamination patterns in soil are reflected in forage vegetation and meat products and to evaluate trace-element behavior across interconnected components of the soil–plant–animal system. This study assessed the distribution and transfer of 12 elements (As, Be, Cd, Co, Cr, Cu, Hg, Mn, Ni, Pb, V, and Zn) in soil, forage vegetation, and meat products from five industrially affected areas of Central Kazakhstan. Element concentrations were determined by inductively coupled plasma mass spectrometry. Soil contained the highest concentrations of most elements, confirming its role as the primary reservoir of contamination, whereas forage vegetation reflected local pollution patterns. The highest levels of contamination were generally observed in the industrial centers of Temirtau and Zhezkazgan, with Zhezkazgan exhibiting the most distinct element profile. Soil-to-forage transfer was most pronounced for Cd, Cu, Pb, and Zn, with significant positive relationships between soil and forage concentrations (p < 0.001). Meat products generally contained lower element concentrations than soil and forage; however, Cd, Hg, and As exceeded regulatory limits in 23 of 279 samples (8.2%). By integrating environmental and animal-derived matrices within a single framework, this study provides new insight into trace-element transfer pathways and facilitates the identification of priority contaminants, high-risk areas, and livestock products requiring enhanced environmental and food safety monitoring in industrial regions. Full article

c-Jun N-terminal kinase (JNK) is a highly conserved, stress-activated protein kinase that plays key roles in cellular development and cell fate. An extensive study over more than 30 years has identified roughly 100 substrates for this kinase including the transcription factor c-Jun and other cell fate effectors. These studies have shown that JNK activation is tightly regulated both spatially through recruitment to subcellular locations and temporally through specific activation dynamics. Ultimately, these two regulatory mechanisms contribute to JNK’s function as a major driver of cell fate and function. A growing field of live-cell imaging, biosensor development, and other novel approaches to manipulate kinase function and localization are now providing novel insights into JNK function at the single-cell level. The purpose of this review is to illustrate our historical understanding of the spatiotemporal functions of JNK signaling within cells as well as emerging studies within the field. Ultimately, we aim to provide insight into remaining knowledge gaps within the field and how emerging technologies may help address these questions. Full article

Circadian clocks are endogenous timing systems that coordinate plant physiology, metabolism, development, and stress responses with daily and seasonal environmental cycles. In crops, circadian and photoperiodic pathways influence agronomically important traits including photosynthesis, carbon allocation, flowering time, growth, stress resilience, and nutritional quality. Although flowering time and photoperiod response pathways have long been indirectly exploited during domestication and breeding, the broader potential of circadian regulation for crop improvement and time-sensitive management remains only partially developed. This review examines the role of plant circadian clocks in crop productivity, with emphasis on molecular mechanisms, crop-specific clock-associated loci, breeding strategies, and chrono-agricultural applications. We summarize conserved and divergent features of the plant clock, including transcriptional repression and activation modules, environmental entrainment, and post-transcriptional regulatory layers. We then discuss how circadian regulation shapes productivity traits and highlight examples from rice, wheat, barley, maize, soybean, sorghum, tomato, and other crops. These examples show that agricultural adaptation often involves fine-tuning or rewiring circadian and photoperiodic outputs rather than maintaining a universal optimal clock state. Finally, we evaluate chrono-agriculture as an emerging framework for aligning management practices with biological timing. While controlled-environment agriculture and high-value horticultural systems are currently the most practical settings for testing chrono-agricultural strategies, open-field applications require careful consideration of environmental variability, sensor limitations, labour, machinery logistics, economic feasibility, and multi-environment validation. Integrating circadian biology with crop genetics, phenotyping, modelling, and agronomy may provide new opportunities to improve productivity, resilience, resource-use efficiency, and quality traits in sustainable agricultural systems. Full article

Keratoconus, a progressive corneal ectasia, remains a major cause of irreversible visual impairment worldwide. Conventional corneal cross-linking (CXL) with riboflavin/ultraviolet A (UVA) has revolutionized clinical management, yet its efficacy is still constrained by epithelial barriers, oxygen dependence, and safety concerns in thin corneas. Emerging nanotechnology provides a transformative opportunity to overcome these bottlenecks. This review highlights the enhancement of riboflavin delivery efficiency by nanocarriers, the photodynamic optimization of nano-enhanced cross-linking agents, and the synergistic strengthening effect of nanocomposites on corneal mechanical strength. We emphasize not only their potential to enhance drug penetration, improve cross-linking efficiency, and extend clinical indications, but also their role in advancing toward a new generation of personalized, intelligent, and minimally invasive corneal therapy. Finally, we discuss translational challenges, including manufacturing, long-term biosafety, and regulatory frameworks, and present a theoretical roadmap that integrates nanotechnology, real-time imaging, and artificial intelligence (AI)-assisted decision-making to achieve a closed-loop “sense–decide–act” therapeutic system. By situating nanomaterial-enhanced CXL within precision ophthalmology, this review highlights its capacity to redefine the standard of care for keratoconus and related ectatic disorders. Full article

Background: Cell division plays a crucial role in plant growth and development. Cyclin-dependent kinase inhibitors (ICK/KRP) negatively regulate the cell cycle, thereby affecting cell elongation and organ development. This study aimed to systematically identify and characterize the ICK/KRP gene family in pepper, and to explore their roles in growth, development, and stress responses. Methods: Bioinformatics approaches were used for genome-wide identification, chromosomal localization, collinearity analysis, sequence characterization, promoter element prediction, and tissue-specific expression profiling of pepper ICK genes. Phylogenetic analysis was performed with homologs from Arabidopsis, tomato, maize, and rice. Quantitative real-time PCR and virus-induced gene silencing (VIGS) were applied to validate gene expression patterns and gene function, respectively. Subcellular localization assays were also conducted. Results: A total of six ICK genes were identified in pepper. They were classified into three subfamilies and distributed on different chromosomes, with one pair showing evidence of duplication. All ICK/KRPs contain the conserved Motif 1 (amino acid sequence: KIPTTREIEEFFATAEKQQQRRFIEKYNFDPVNEKPL) and were predicted to localize to the nucleus. Promoter analysis revealed cis-acting elements associated with plant development, stress responses, and hormone signaling. Expression pattern analysis indicated tissue-specific divergence and significant induction/repression under temperature stress. qRT-PCR results were consistent with transcriptome data, and expression differences were observed in materials with different stigma lengths. Subcellular localization confirmed that Caz03g38750.1 and Caz12g03790.1 proteins localize to both the nucleus and plasma membrane. Silencing of CazICK1 significantly repressed stigma elongation and altered stigma morphogenesis. Conclusions: The six pepper ICK/KRP genes display distinct diversity in distribution, structure and expression, and function in plant growth, development and stress adaptation. This work not only lays a solid basis for exploring the cell cycle regulatory network of pepper and contributes to relevant theoretical research, but it also identifies key gene resources for improving stigma traits. It has great potential for application in molecular breeding to promote high yield and efficient hybrid seed production in pepper. Full article

The molecular mechanisms governing the efficient packaging of the large SARS-CoV-2 RNA genome into progeny virions remain incompletely understood, with the role of untranslated regions (UTRs) being particularly enigmatic. Leveraging proximity ligation sequencing data, we identified direct, high-frequency interactions between the viral packaging signal PS9 and both the 5′ and 3′ UTRs during intracellular replication stages. Functional validation using an infectious virus-like particle (iVLP) system demonstrated that genomes incorporating SARS-CoV-2 UTRs exhibited significantly enhanced packaging efficiency, yielding an increase in both packaged RNA copies and reporter gene expression post-infection. Competitive packaging assays confirmed the UTRs confer a selective advantage during particle assembly. Mechanistically, Western blot and digital Western analysis revealed that UTR-containing iVLPs incorporated approximately 2-fold more nucleocapsid (N) proteins, suggesting enhanced N recruitment or retention. The deletion of specific core sequences within the UTRs predicted to form a base pair with PS9 abrogated this enhancement, suggesting the functional significance of the UTR-PS9 interaction interface. Collectively, these results establish that the 5′ and 3′ UTRs act synergistically through direct RNA-RNA interactions with PS9 to promote N protein recruitment and enhance packaging efficiency in a PS9-dependent iVLPs system. This UTR-PS9 regulatory axis presents a novel target for therapeutic intervention against SARS-CoV-2 and related coronaviruses. Full article

The purpose of this study is to explore how Zimbabwean firms use Environmental Management Accounting (EMA) and climate risk disclosure amid climate policy uncertainty and how managers perceive these practices as relevant to organisational resilience and long-term sustainability within a volatile institutional and macroeconomic context. The study was couched in the interpretivist research philosophy and adopted the inductive research approach. A case study research design, which aligns with a qualitative research design, was chosen for the study. The study employed in-depth interviews with management accountants, finance executives, and industry leaders across firms in Harare. The study adopted the cross-sectional time horizon and analysed data using thematic analysis to develop insights into the role of EMA and climate risk disclosure in times of policy uncertainty. The findings suggest that participants perceived climate policy uncertainty as influencing organisational efforts to reconfigure management accounting practices through greater environmental performance monitoring, adaptive budgeting, and scenario-based planning. The findings of this study suggest that organisational actors interpreted climate policy uncertainty as a condition requiring greater flexibility in budgeting, environmental monitoring, and strategic planning. Participants in this study associated EMA with improved environmental cost visibility and more adaptive approaches to investment appraisal and risk management under uncertain policy conditions. Similarly, participants perceived climate risk disclosure as increasingly crucial for strengthening organisational legitimacy, stakeholder confidence, and institutional credibility. While respondents linked sustainability-oriented accounting adaptation to broader organisational resilience and long-term sustainable growth aspirations, these relationships were understood through managerial perceptions and organisational experiences rather than as directly measurable macroeconomic outcomes. The study contributes to the sustainability accounting literature by providing qualitative, context-sensitive insights into how managers in an emerging economy interpret climate policy uncertainty and adapt EMA and climate risk disclosure practices within volatile institutional conditions. The study further contributes by integrating sensemaking theory and institutional theory to explain how organisational interpretations of uncertainty shape sustainability-oriented accounting adaptation and perceptions of organisational resilience. It is therefore recommended that the regulatory institutional pillar be strengthened to reduce uncertainty and enhance the EMA’s strategic adaptation. Full article

Background/Aims: While pathogenic germline variants play a critical role in pediatric cancer susceptibility, traditional clinical genetics primarily focuses on single-gene interpretations. Transitioning to a systems-level analysis of inherited variation can uncover shared biological vulnerabilities, informing genetic counseling, surveillance, and targeted therapeutics. This study aims to implement an unsupervised machine learning framework to identify and characterize Germline Mutation Signatures (GMS) across diverse pediatric malignancies, elucidating latent genomic patterns that reveal shared oncogenic mechanisms. Methods: We analyzed germline whole-exome and whole-genome sequencing (WES/WGS) data from a retrospective cohort of 420 pediatric cancer patients and matched non-cancer controls. Variants were deeply annotated to capture multi-dimensional features, including predicted pathogenicity, splice-site disruption, regulatory impact, population frequency, and sequence context. To enable robust modeling, we integrated an augmented feature set encompassing evolutionary constraint, loss-of-function intolerance, and compositionally normalized substitution spectra. These high-dimensional annotations were processed using a deep autoencoder for non-linear representation learning, followed by Gaussian Mixture Modeling (GMM) of the latent space. Results: The framework delineated 13 signatures (GMS1–GMS13), yielding an optimal Davies–Bouldin index of 1.051. These signatures map to fundamental biological processes, including DNA repair deficiencies, transcription-coupled damage, replication stress, and aberrant RNA regulation. Crucially, these GMSs transcend traditional tissue-of-origin classifications, manifesting across multiple distinct cancer types. This observation indicates convergent germline etiologies and suggests potential shared susceptibilities to pathway-directed therapies. Conclusions: The discovery of these cross-cancer signatures provides a scalable, biologically interpretable framework for decoding inherited pediatric cancer risk. While the therapeutic mapping networks identified are currently exploratory and serve as a hypothesis-generating foundation, this deep learning-driven paradigm establishes a robust basis for stratified precision medicine. Pending prospective clinical validation, this approach holds significant translational potential to move beyond single-gene paradigms toward unified, systems-level precision oncology strategies. Full article

Microglia are central regulators of Alzheimer’s disease pathogenesis, but their roles cannot be reduced to a simple protective-versus-harmful dichotomy. Genetic, single-cell, and spatial studies have shown that Alzheimer ’s-associated microglia occupy diverse disease-linked states shaped by amyloid plaques, tau pathology, lipid stress, complement activation, astrocyte signaling, aging, and immune genetic risk. Among the regulatory nodes controlling these states, SPI1, which encodes the myeloid transcription factor PU.1, has emerged as a key determinant of microglial identity and disease responsiveness. Human genetic studies suggest that reduced SPI1 expression may be protective, whereas experimental data indicate that excessive PU.1 suppression can impair essential microglial functions. This review examines the emerging concept that partial, plaque-associated reduction in PU.1 may enable a distinct lymphoid-like immunoregulatory microglial program marked by CD28 expression. Recent evidence suggests that PU.1-low CD28-positive microglia may restrain neuroinflammation and amyloid pathology, raising the possibility that Alzheimer’s plaques induce not only inflammatory and phagocytic microglial responses, but also endogenous suppressive programs that limit tissue damage. We discuss this proposed PU.1/CD28 regulatory axis in relation to disease-associated microglia, TREM2–APOE signaling, complement-mediated synapse loss, antigen-presentation pathways, plaque-niche biology, and therapeutic microglial reprogramming. We also highlight major unresolved questions, including whether PU.1-low CD28-positive microglia are present and functional in human Alzheimer’s disease, whether they are specific to amyloid-rich niches or extend to tau and mixed pathologies, and how such states could be safely manipulated without disrupting essential immune surveillance. We propose that lymphoid-like suppressive microglia represent a promising but still unproven framework for understanding protective neuroimmune regulation in Alzheimer’s disease and for developing state-specific microglial therapies. Full article

Melatonin occupies a paradoxical position in contemporary sleep medicine: despite its physiological role as a regulator of circadian timing, it is frequently used and perceived as a nonspecific “natural” hypnotic. Although melatonin demonstrates modest benefits for sleep initiation and clearer efficacy in circadian rhythm sleep–wake disorders, its clinical use is often undermined by diagnostic imprecision, inappropriate dosing, mistimed administration, inconsistent formulations, and inadequate patient counseling. Circadian disorders can be misclassified as primary insomnia, leading to symptomatic treatment approaches that fail to address the underlying phase misalignment. At the same time, supraphysiological doses and reflexive bedtime administration have become normalized despite evidence that melatonin acts primarily as a chronobiotic whose effects depend more on timing than dose. Regulatory inconsistencies and substantial variability in over-the-counter preparations further complicate safe and reproducible use. These factors contribute to avoidable treatment failure, inaccurate labeling of nonresponse, and persistent misconceptions regarding melatonin’s mechanism of action. Therefore, melatonin should be approached as a pharmacological intervention requiring the same diagnostic rigor, individualized dosing, and longitudinal assessment expected of other sleep therapeutics, particularly when integrated with behavioral and circadian interventions. Full article

Understanding the spatiotemporal evolution of runoff and its driving mechanisms is of great significance for water resources development, utilization, and sustainable management in mid- to high-latitude river basins under climate change. However, runoff variability is jointly influenced by multiple meteorological factors, and a comprehensive understanding of its multi-scale response characteristics and the relative contributions of different drivers remains limited. In this study, runoff data from three hydrological stations in the Songhua River Basin during 1980–2022 were analyzed. A set of statistical and time-series methods, including the Mann–Kendall test, Pettitt change-point test, Hurst exponent, wavelet analysis, and wavelet coherence, was applied, and a random forest model was used to quantify the influence of key climatic factors such as precipitation, air temperature, and evapotranspiration. The results show that air temperature exhibits significant increasing trends in all four seasons, with the strongest warming occurring in spring (Sen’s slope ≈ 0.06 °C a⁻¹). Precipitation displays pronounced spatial heterogeneity and interannual variability, while evapotranspiration shows an overall increasing trend. Both runoff and major meteorological variables exhibit significant spatial heterogeneity across the basin. Hydro-meteorological variables also show distinct periodic variations among seasons, with temperature, precipitation, and evapotranspiration exhibiting stronger seasonal fluctuations during summer. Wavelet coherence analysis indicates that short-term runoff variability is mainly driven by temperature and precipitation. Temperature exhibits significant coherence with runoff across multiple time scales ranging from approximately 2 to 20 years, whereas precipitation shows stronger coherence at medium- to long-term scales (approximately 10–35 years), with evident seasonal differences. Random forest results indicate that evapotranspiration is the most important contributor to runoff variability at all three stations, accounting for 33.5%, 28.6%, and 26.2% of the total importance at Jiamusi, Fuyu, and Jiangqiao stations, respectively. Temperature and sunshine duration rank second, while precipitation and relative humidity contribute comparatively less. These findings indicate that evapotranspiration plays a key regulatory role in long-term water balance. In addition, runoff exhibits multi-scale variability and a transition from gradual changes to stage-like abrupt shifts. The findings provide a scientific basis for water resources management, flood mitigation, and climate change adaptation in the Songhua River Basin. Full article

Improvement in the in vitro maturation (IVM) of oocyte quality is a gateway to enhancing the efficiency of in vitro embryo production. The anti-Müllerian hormone (AMH) is a crucial hormone secreted by granulosa cells that effectively suppresses primordial follicle recruitment and regulates follicular growth and development. This study was designed to investigate the role of AMH on the IVM of sheep oocytes. In this current study, oocytes in vitro were cultured in media supplemented with AMH. We comprehensively analyzed the impact of AMH on various developmental parameters of sheep oocytes, such as cellular activity, cortical granules (CGs) migration, cytoskeleton and mitochondrial function of oocytes. Furthermore, Smart-seq2 single-cell RNA sequencing (scRNA-seq) was employed to elucidate the oocytes’ development. The results showed that treatment with 100 ng/mL improved the maturation rate of the oocytes, the normal distribution rate of cortical granules and mitochondrial function, while reducing the rate of spindle abnormalities in oocytes. A total of 741 differentially expressed genes (DEGs) were observed between the FSH_12 h and AMH_12 h groups, and 746 DEGs were observed between the FSH_24 h and A+F groups. KEGG pathway analysis revealed that the FSH_12 h and AMH_12 h groups significant enrichment in DEGs were associated with p53, MAPK, PI3K-Akt and TGF-beta signaling pathways, and the FSH_12 h and AMH_24 h groups significant enrichment in DEGs were associated with cAMP, AMPK, Hedgehog and estrogen signaling pathways. These findings suggest that AMH may regulates oocytes IVM via several candidate signaling pathways. Our results provide preliminary clues for exploring the regulatory mechanism of sheep oocyte maturation and optimizing relevant culture systems. Full article

Palmatine chloride (berbericinine, C₂₁H₂₂ClNO₄) is a protoberberine alkaloid found in several plants, including Rhizoma Coptidis, Cortex Phellodendri, Rhizoma Corydalis, Guduchi (Tinospora cordifolia), and Tinospora sagittata roots. Palmatine chloride (PA) is known as an inhibitor of dopamine generation. However, its effect on endoplasmic reticulum (ER) stress-related macrophage activation caused by endotoxin (lipopolysaccharide) is not yet well known. In this study, the effects of PA on pyroptotic responses of mouse macrophages (RAW 264.7) activated by endotoxin were investigated using Griess reagent assay for nitric oxide (NO) production, fluo-4 assay for cytosolic calcium release, dihydrorhodamine 123 assay for hydrogen peroxide production, multiple cytokine assay for cytokine production, real-time PCR for inflammatory gene transcriptions, and flow cytometry assay for p38 MAPK activation. Preliminary experiments using THP-1 human monocytic cells demonstrated that PA was not cytotoxic and significantly reduced basal NO production. Results revealed that PA significantly reduced excessive production levels of NO, hydrogen peroxide, pro-inflammatory cytokines (such as interleukin (IL)-6, CCL3 (MIP-1α), and CSF2 (GM-CSF)), and cytosolic calcium release in endotoxin-stimulated RAW 264.7, but significantly increased the production of anti-inflammatory cytokine IL-10. PA inhibited endotoxin-induced transcripts of Chop, Stat1, Fas, and c-Fos in activated RAW 264.7. It also decreased p38 MAPK phosphorylation and level of Fas in RAW 264.7 stimulated by endotoxin. To further interpret these findings, a network pharmacology-informed analysis based on large-scale literature mining was performed, supporting the multi-target regulatory role of PA in ER stress-related pathways. Briefly, PA exerts anti-inflammatory effects on endotoxin-stimulated RAW 264.7 via the calcium-CHOP pathway, consequently reducing endotoxin-induced production of pro-inflammatory mediators (NO, cytokines, etc.) and relieving ER stress-related pyroptotic cascade. Full article