Search Results (5,217)

Background/Objectives: Circadian disruption resulting from factors such as jet lag, shift work, or aging leads to exaggerated inflammatory responses and increased disease susceptibility. However, the core dynamical mechanism by which circadian disruption exacerbates innate immune responses remains poorly understood. Methods: We develop an integrated mathematical model coupling the mammalian circadian clock with antigen-induced innate immune responses, incorporating key regulatory interactions including glucocorticoid modulation and pro-inflammatory positive feedback loops. Results: The model successfully recapitulates experimental data regarding homeostatic immune circadian oscillations and time-dependent gating of acute inflammatory responses. Dynamic analyses reveal that the circadian clock exerts its gating function by modulating the bistable characteristics within pro-inflammatory positive feedback loops. Circadian disruption, simulated as jet lag or age-related reduction in clock gene amplitude, reshapes this bistable landscape and prolongs residence duration in the pathological hyperinflammatory state. Conclusions: This shift not only amplifies acute cytokine bursts but also sustains exaggerated inflammatory activity, providing a mechanistic explanation for acute tissue injury and chronic low-grade inflammation (inflammaging) under these circadian disruption scenarios. Full article

The carcinogenic liver fluke Opisthorchis viverrini underlies one of the world’s heaviest burdens of bile duct cancer, yet for decades it was treated as a single, genetically uniform parasite whose transmission was shaped mainly by environment and human behavior. However, advances in molecular biology have fundamentally reshaped this conceptual model. Evidence accumulated over the past three decades demonstrates that O. viverrini comprises geographically structured populations linked to hydrological connectivity, host distribution, and long-term evolutionary processes across interconnected river systems of mainland Southeast Asia, particularly within the Lower Mekong Basin. This review synthesizes research on the systematics and population structure of O. viverrini and its Bithynia snail hosts, tracing the transition from early allozyme studies to contemporary DNA-based and genomic approaches. Collectively, mitochondrial, nuclear, microsatellite, and intron markers reveal strong spatial structuring among parasite populations, while genetic patterns observed in snail hosts show partial geographic concordance with parasite population structure, suggesting that both may be influenced by shared hydrological organization, ecological isolation, and host connectivity across endemic aquatic systems. Population structure is strongly scale-dependent, with local panmixia often occurring within connected aquatic systems but pronounced differentiation emerging across broader geographic regions. Together, these findings indicate that transmission dynamics are shaped not only by environmental and behavioral factors, but also by evolutionary and landscape-level processes influencing host and parasite connectivity. Finally, we emphasize the increasing significance of population genomics and landscape genetics in understanding how transmission systems persist, disperse, reconnect, and respond to environmental change across endemic landscapes. Full article

Progressive bladder fibrosis and impaired detrusor function represent converging pathological endpoints across diverse bladder disorders, including bladder outlet obstruction (BOO) associated with benign prostatic hyperplasia, spinal cord injury (SCI)-induced neurogenic bladder, radiation cystitis, and interstitial cystitis/bladder pain syndrome. Conventional therapies primarily manage symptoms and rarely reverse established fibrosis or restore durable bladder homeostasis. Mesenchymal stem/stromal cells (MSCs) have attracted considerable interest as therapeutic agents owing to their antifibrotic, immunomodulatory, angiogenic, and trophic paracrine activities. This review synthesises six key studies from our group and places them within the broader international literature on bladder regenerative medicine: (i) feasibility of superparamagnetic iron oxide (SPIO)-based molecular MRI tracking of transplanted human MSCs (hMSCs) in the bladder; (ii) SPIO-hMSC therapy for BOO-associated fibrosis with concurrent MRI monitoring; (iii) hepatocyte growth factor (HGF)-overexpressing engineered hMSC (B10.HGF) therapy in BOO; (iv) hMSC transplantation into the SCI-injured bladder wall monitored by MRI; (v) systematic review and meta-analysis of stem cell therapy effects on urodynamic outcomes in SCI models; and (vi) HGF-overexpressing hMSC therapy for BOO-induced underactive bladder. These six key studies are contextualised within the broader literature addressing cell sources, biomaterial-assisted delivery platforms, mechanistic pathways, emerging clinical evidence, and the evolving regulatory landscape for cell-based advanced therapy medicinal products. Key translational challenges include product standardisation, long-term durability, and mechanism-linked potency assay development. Full article

Introduction: Traditional instruments for measuring lifelong learning of health professionals fail to capture digital-age learning, creating a critical measurement disconnect. To address this gap, we developed a 16-item Self-Pursuits, Aspirations, and Knowledge Endeavors in the Digital Era (SPArKED) instrument. Methods: To gather validity evidence for SPArKED, a cross-sectional survey was deployed to health professional students (n = 558). The survey questionnaire included: SPArKED, Jefferson scale of lifelong learning for students in health professions, basic psychological needs satisfaction scale, and human–computer trust scale assessing students’ trust in generative technology to support lifelong learning. Exploratory factor analysis (EFA) and correlation analysis were performed. Results: The EFA of the SPArKED revealed a three-component structure: networked learning, i-learning (individual mastery), and AI-powered learning, together explaining 55% of the total variance. The SPArKED demonstrated good internal consistency (α = 0.86) and convergent validity with the Jefferson scale of lifelong learning (r = 0.75). The correlations between SPArKED and psychological needs satisfaction scores were moderately high: autonomy (r = 0.50), competence (r = 0.48), and relatedness (r = 0.51). SPArKED had a higher correlation with students’ trust in generative technology to support lifelong learning than the Jefferson scale (r = 0.52 and r = 0.32, respectively). Conclusions: Compared to the Jefferson scale, the SPArKED instrument appears to better capture digital-age learning behaviors among students in health professions. By assessing these evolving behaviors in learners, education programs can better guide future health practitioners in developing desired lifelong learning competencies and digital literacies. Future research should gather validity evidence for SPArKED across diverse learner samples and educational stages, informing a critical re-assessment of established instruments in the rapidly evolving learning landscape. Full article

Expert assessments of the ecological impacts of road construction in natural ecosystems were examined through a cross-disciplinary comparative perspective. Data were collected from experts in civil engineering, urban and regional planning, forest engineering, and landscape architecture. Responses to the Ecological Impacts of Road Construction in Natural Ecosystems (EIRCNE) scale were analyzed using exploratory factor analysis and comparative statistical tests. Five hypotheses (H1–H5) were developed to examine disciplinary differences in expert evaluations. Results indicated broad agreement on the overall ecological impacts of road construction, although discipline-specific differences emerged in perceptions of direct ecological damage and construction priorities. Factor analysis confirmed a multidimensional structure of expert assessments (KMO = 0.810; χ² = 1665.219; df = 435; p < 0.001). Hypotheses concerning direct ecological damage (H2) and construction priorities (H5) were supported, whereas no significant disciplinary differences were detected for indirect effects or managerial processes (H3 and H4). These findings suggest that evaluating road planning and construction solely from a technical perspective may overlook important ecological dimensions. The study provides empirical evidence from Türkiye regarding how experts from different professional disciplines perceive and prioritize the ecological impacts of road construction and highlights the importance of incorporating diverse disciplinary perspectives into environmental decision-making processes. Full article

To study the soil moisture dynamics and rainfall infiltration characteristics of karst sloping farmland and their driving factors, an abandoned farmland was selected for this study, and five monitoring points (from the foot, S1, of the slope to the top, S5) were set along the terrain gradient. The volumetric water content data of the 0–40 cm soil layer was obtained through in situ monitoring for one year. The infiltration characteristics were quantified in combination with a staining tracer test, and the soil properties were determined. The results showed that the soil moisture content increased with the deepening of the soil layer, and there was significant slope differentiation. The moisture content in the downhill slopes (S1, S2) was significantly higher than that in the uphill slopes (S4, S5), and the annual average value of S5 was 27.4% lower than that of S1. The moisture difference (Δθ, the difference in moisture content between hillslope and flatland) changed from positive to negative from the foot of the slope to the top, indicating that moisture was transported downward along the slope surface. A dye tracer showed that from S1 to S5, the water transport pathway gradually shifted from exhibiting deeper vertical penetration and narrower lateral spread to showing shallower vertical penetration and wider lateral spread. The preferential flow index decreased from 46.6 ± 2.3% to 34.7 ± 2.1%, indicating a progressive reduction in rapid vertical channeling, while the lateral flow index reached its peak (21.4 ± 2.7%) in the middle of the slope (S3), suggesting enhanced horizontal water redistribution at this position. Correlation analysis indicated that soil bulk density was extremely significantly negatively associated with infiltration capacity, while capillary porosity, non-capillary porosity, total porosity, organic matter, and high aggregate content were extremely significantly positively associated with infiltration capacity. These results revealed that the topographic gradient affected soil moisture and water infiltration paths by regulating soil physical properties in this karst forest ecosystem. It should be noted that the research results are only applicable to one slope and should not be directly extended to all karst slope agricultural landscapes. Full article

Epitranscriptomic modifications, particularly RNA methylations, have emerged as regulators of gene expression, with their dysregulation acting as a key factor in tumorigenesis and metastatic progression. This review evaluates the therapeutic landscapes of N⁶-methyladenosine (m⁶A) and N¹-methyladenosine (m¹A) modifications in cancer. While the m⁶A machinery predominantly dictates mRNA turnover and stability, the m¹A network is uniquely positioned to drive translational reprogramming, allowing malignant cells to endure severe microenvironmental stress and evade cell death. Despite positional and chemical differences, these modifications exhibit profound epitranscriptomic crosstalk through shared regulatory proteins. Here, we comprehensively analyze current pharmacological strategies targeting the m⁶A axis, highlighting the transition from classical small-molecule inhibitors of regulatory proteins of these methylations, such as methyltransferase-like 3 (METTL3), fat mass and obesity-associated protein (FTO), and AlkB homolog 5 (ALKBH5), to the novel event-driven approach of proteolysis-targeting chimeras (PROTACs). Furthermore, we assess the emerging therapeutic potential of the m¹A regulatory machinery, positioning tRNA methyltransferase 6/61A (TRMT6/61A) writers and AlkB homolog 1 to 3 (ALKBH1-3) erasers as promising therapeutic targets. Finally, we discuss clinical successes and current translational obstacles, including off-target toxicity, pharmacokinetic limitations, and epitranscriptomic escape, emphasizing that site-specific modulation and smart precision therapies will dictate the future of oncology. Full article

Cassava is a critical staple crop for food security and rural livelihoods in Sub-Saharan Africa, yet high-resolution maps of its distribution remain scarce, particularly for smallholder systems. In this study, we generated a 10 m resolution cassava presence map for Uganda (CM24) by fine-tuning a Random Forest classifier on TESSERA foundation model embeddings derived from Sentinel-1 and Sentinel-2 time series. Using field survey data from the Copernicus4GEOGLAM campaign for training and validation, the model achieved excellent discriminative ability (validation AUC = 0.9532, test AUC = 0.9524). Visual validation against high-resolution satellite imagery confirmed good spatial agreement, capturing both large contiguous fields and small fragmented plots. Comparison with two existing global products (CassavaMap and SPAM2020) and two seasons of national survey data conducted by the Uganda Bureau of Statistics showed that CM24 produced national harvested area estimates that fell between the two survey totals, whereas CassavaMap and SPAM2020 systematically overestimated harvested area by factors of two to three. Our results demonstrate that foundation-model embeddings offer a robust and scalable approach for mapping cassava in heterogeneous smallholder landscapes. The resulting CM24 map provides a spatially explicit tool to support disease surveillance, agricultural monitoring, and food security planning in Uganda and beyond. Full article

Traditional Chinese villages are important carriers of rural heritage, collective memory, vernacular landscapes, and living cultural traditions. However, rapid urbanization, agricultural modernization, climate change, and tourism development have increasingly threatened their spatial integrity and cultural continuity, highlighting the need for evidence-based conservation and adaptive management. This study examines the spatial distribution patterns and associated factors of 8155 national-level traditional villages in China. An integrated spatial analytical framework was developed by combining kernel density estimation, spatial autocorrelation analysis, Geodetector, and multiscale geographically weighted regression (MGWR). The results show that: (1) traditional villages are unevenly distributed across China and form a distinct “three-core and multi-node” spatial pattern, with major high-density clusters concentrated in several cross-provincial regions and secondary clusters distributed in other heritage-rich areas; (2) the spatial differentiation of traditional village density is statistically associated with natural, cultural, and socioeconomic factors, among which temperature and precipitation show the strongest explanatory power, while cultural endowment, ecological quality, and socioeconomic variables show more context-dependent associations; and (3) compared with OLS and conventional GWR, MGWR improves model performance by capturing spatially heterogeneous and scale-dependent relationships through variable-specific bandwidths. These findings provide national-scale empirical evidence for differentiated conservation planning and support the integration of traditional village protection with rural revitalization, cultural heritage conservation, and sustainable regional development. Full article

CD19-directed chimeric antigen receptor (CAR) T-cell therapy has fundamentally transformed the treatment landscape for relapsed and refractory B-cell malignancies, yet antigen escape remains a persistent therapeutic challenge that limits long-term remission durability. While antigen loss is typically considered a somatic event acquired during tumor evolution under therapeutic selective pressure, germline CD19 polymorphisms could theoretically influence CAR-binding kinetics, alter epitope presentation, and modulate therapeutic outcomes in ways that remain largely not characterized. Unfortunately, Middle Eastern populations are underrepresented in pharmacogenomic databases and CAR-T clinical trials, creating a knowledge gap that may perpetuate global health disparities in access to precision immunotherapy. We analyzed publicly available whole-exome sequencing data from 1196 individuals of Arab origin to comprehensively characterize CD19 variants with potential relevance to CAR T-cell immunotherapy. The L174V (rs2904880) variant stood out, and showed the Valine/Valine (V/V) genotype frequency was 65.3%, corresponding to a V174 allelic frequency of 76.6%, while the minor allele, L174, has a frequency of 23.4%. The missense mutation (c.520C > G) responsible for this variant results in a leucine-to-valine (L174V) substitution at position 174 of the CD19 protein, relative to the reference genome. The cohort genotypes (CC, CG, and GG) exhibited a significant deviation from Hardy–Weinberg equilibrium (p < 0.00001). While this deviation is consistent with the high consanguinity rates (25–60%) amongst Arab populations, it remains not fully explained, and may be attributed to population structure, relatedness, or technical factors. We further emphasize that our computational analysis cannot establish any direct clinical or functional impact due to this variant, and therefore we refrain from suggesting any specific actions at the current time. In light of these findings, we hypothesize that the distinctive genetic architecture of consanguineous populations should not be viewed as a confounding variable. Instead, it presents a unique opportunity to investigate the clinical relevance of germline variation in the context of precision oncology, particularly at therapy-relevant loci, pending functional validation. Full article

Every year, respiratory syncytial virus (RSV) causes an estimated 33 million lower respiratory tract infections in children under five years of age, driving millions of hospitalizations worldwide and substantial mortality in developing countries. For 28 years, the monoclonal antibody (mAb) palivizumab has been the principal agent for RSV immunoprophylaxis, reducing hospitalization in defined high-risk groups through monthly intramuscular dosing. The recent approval of two second-generation long-acting mAbs, nirsevimab and clesrovimab, and maternal preF vaccine has fundamentally changed the RSV prevention landscape. In contrast to palivizumab, the long-acting mAbs offer single-dose seasonal protection across a broader infant population, enabling universal immunization programmes for the first time. In this review, we conjointly examine nirsevimab and clesrovimab across their mechanisms of action, pharmacokinetics, efficacy, safety and cost-effectiveness, using palivizumab as the reference standard. Cross-trial efficacy comparisons are complicated by differences in study populations and endpoint definitions; however, when these factors are considered, the available evidence suggests that all three agents offer broadly comparable protection against severe RSV disease. All three agents also demonstrate favourable and comparable tolerability profiles. Nirsevimab is now supported by a substantial body of real-world evidence confirming effectiveness in routine immunization programmes that closely align with registrational studies. Clesrovimab, as the newest agent, currently lacks real-world effectiveness, and both long-acting monoclonals require further confirmatory evidence in high-risk groups. Overall, existing data support that both monoclonals have equivalent efficacy and safety profiles as palivizumab, and choice should be based on cost-effectiveness and local availability, with consideration given to optimal integration of infant immunoprophylaxis alongside maternal RSV vaccination programmes. Full article

This study investigates the pedagogical landscape of state language instruction in Hungarian-medium schools in Slovakia. Situated within the wider context of European minority language policies, this study explores the institutional ecosystems, didactic approaches and teaching strategies, and the relationship between teacher- and student-centered methodologies in state language instruction. A questionnaire survey based on a self-developed Multi-Level Diagnostic Model was administered to a representative sample of teachers, accounting for 23% of the total Slovak teacher population working in this distinctive sociolinguistic setting (N = 112). Although the results indicate that the educational process is shaped by various factors and there is an endeavor to promote communicative practice, the competence–use gap persists due to the reliance on conventional teacher-centered teaching approaches. This trend is driven by a methodological vacuum, the absence of specialized L2 teaching materials and the lack of modern digital resources; it also suggests that teachers are forced to prioritize instructional security rather than being resistant to innovation. The findings suggest that the current educational system is ready for change, but it requires systemic investment in resources to promote the balanced development of intercultural communicative competence. Addressing the linguistic distance between Hungarian L1 and Slovak L2 through specialized materials may promote a model of additive bilingualism that ensures professional credibility and the protection of minority cultural identity. Full article

Existing studies have mainly focused on either intangible cultural heritage (ICH) or traditional villages separately, while limited attention has been paid to their coupled spatial relationship and influencing mechanisms at the provincial scale. To address this gap, this study investigates the spatial characteristics and influencing factors of 869 national and provincial intangible cultural heritage (ICH) items and 777 traditional villages in Yunnan Province using Geographic Information Systems (GISs) and geographic detector methods. The results indicate significant differences in their spatial distribution patterns: ICH exhibits a “multi-core clustering” structure, whereas traditional villages present a “dual-core clustering with multiple dispersed patches” pattern. The study further reveals a spatial mismatch as well as a significant positive spatial correlation between ICH and traditional villages. Natural environmental conditions and historical-cultural factors jointly shape their spatial differentiation, while socio-economic factors such as urbanization exert a stronger influence on ICH distribution, and demographic and economic conditions more strongly affect traditional villages. This study contributes to the literature by integrating cultural landscape theory with GIS-based spatial analysis to reveal the spatial interaction mechanisms between ICH and traditional villages in Yunnan Province. The findings provide theoretical support and practical implications for cultural heritage conservation, rural revitalization, and territorial spatial planning in ethnically diverse border regions. Full article

Sustainability transitions confront firms with the following informational paradox: the regulatory pressure to innovate green has intensified, yet the knowledge required to do so is dispersed across agencies, sectors, and jurisdictions that rarely speak to one another. Treating data as a strategic factor of production, this paper asks whether and how opening public data—the systematic release of government-held datasets—reconfigures the conditions under which firms generate green innovation. We model the green-innovation ecosystem as a Complex Adaptive System (CAS) in which heterogeneous, bounded-rational agents co-evolve with a data-mediated selection environment. Within this frame, public data openness (PDO) is not marginal input but an exogenous shock to the fitness landscape that propagates through three coupling channels—supply–demand alignment, recalibration of government intervention, and amplification of green credit. Formal derivations link each channel to a testable proposition, and a multi-period Difference-in-Differences (DIDs) design built on the staggered roll-out of Chinese municipal open-data platforms identifies the causal effects, with Callaway–Sant’Anna estimators and double/debiased machine learning (DDML) addressing recent econometric critiques. The evidence supports each proposition and reveals the following distinctive heterogeneity signature consistent with absorptive-capacity heterogeneity: the policy is most consequential where agents and ecosystems are best able to convert data into knowledge. Reframing PDO as a systemic enabler clarifies why uniform rollouts yield uneven returns and motivates a tiered design that scales with the absorptive capacity of recipient firms and regions. Full article

Scent marking has been discussed as an important component of communication in brown bears (Ursus arctos Linnaeus, 1758). However, the environmental factors influencing the occurrence of rub trees and their value for non-invasive genetic sampling remain poorly understood. This study examined the patterns of rub tree occurrence in the eastern High Tatra Mountains (Slovakia) at two spatial scales. At the tree scale, paired-design generalized linear mixed models showed that rub trees were more frequently recorded on large-diameter coniferous trees, indicating an association with visually prominent and chemically suitable substrates. At the landscape scale, logistic regression models revealed that the probability of rub tree occurrence increased with elevation and distance from human settlements, identifying high-elevation forests as areas of higher predicted rub tree occurrence. The best-supported model was used to produce a predictive map of rub tree occurrence across the study area. We also evaluated whether rub trees are reliable sources of biological material for non-invasive sampling. Hair collected during repeated field visits provided DNA suitable for genotyping and individual identification. Overall, the results show that rub trees exhibit non-random spatial patterns and represent effective focal points for systematic genetic sampling, linking patterns of rub tree occurrence to the spatial targeting of non-invasive genetic sampling in mountain landscapes. Full article