Search Results (8,452)

The increasing complexity of contemporary urban systems necessitates decision-making frameworks capable of systematically integrating multidimensional sustainability considerations into policy evaluation processes. While existing urban sustainability assessment approaches predominantly focus on isolated environmental or socio-economic indicators, they often lack methodological coherence and direct applicability to operational decision-making. This study proposes a multi-layer sustainability indicator framework explicitly designed to support evidence-based urban decision-making under conditions of uncertainty, institutional constraints, and competing policy objectives. The framework integrates environmental, economic, social, and institutional dimensions of sustainability into a structured decision-support architecture. Methodologically, the study employs a two-stage approach combining expert-based weighting techniques (Analytic Hierarchy Process and Best–Worst Method) with multi-criteria decision-making methods (TOPSIS and VIKOR) to evaluate and rank alternative urban policy scenarios. The proposed framework is empirically validated through an urban case study, demonstrating its capacity to translate abstract sustainability indicators into comparable decision outcomes and policy priorities. The results indicate that the integration of multi-layer indicator systems with formal decision-analysis tools enhances transparency, internal consistency, and strategic coherence in urban governance processes. By bridging the gap between sustainability measurement and decision implementation, the study contributes to the advancement of urban governance scholarship and provides a replicable analytical model applicable to cities facing complex sustainability trade-offs. Full article

Type 2 diabetes mellitus (T2DM) is characterized not only by chronic hyperglycemia but also by profound adipose tissue dysfunction, including impaired lipid handling, low-grade inflammation, mitochondrial dysfunction, and extracellular matrix (ECM) remodeling. These adipose tissue alterations play a central role in the development of systemic insulin resistance, ectopic lipid accumulation, and cardiometabolic complications. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), particularly semaglutide, have emerged as highly effective therapies for T2DM and obesity. While their glucose-lowering and appetite-suppressive effects are well established, accumulating evidence indicates that semaglutide exerts pleiotropic metabolic actions that extend beyond glycemic control, with adipose tissue representing a key target organ. This review synthesizes current preclinical and clinical evidence on the molecular and cellular mechanisms through which semaglutide modulates adipose tissue biology in T2DM. We discuss depot-specific effects on visceral and subcutaneous adipose tissue, regulation of adipocyte lipid metabolism and lipolysis, enhancement of mitochondrial biogenesis and oxidative capacity, induction of beige adipocyte programming, modulation of adipokine and cytokine secretion, immunometabolic remodeling, and attenuation of adipose tissue fibrosis and ECM stiffness. Collectively, available data indicate that semaglutide promotes a functional shift in adipose tissue from a pro-inflammatory, lipid-storing phenotype toward a more oxidative, insulin-sensitive, and metabolically flexible state. These adipose-centered adaptations likely contribute to improvements in systemic insulin sensitivity, reduction in ectopic fat deposition, and attenuation of cardiometabolic risk observed in patients with T2DM. Despite compelling mechanistic insights, much of the current evidence derives from animal models or in vitro systems. Human adipose tissue-focused studies integrating molecular profiling, advanced imaging, and longitudinal clinical data are therefore needed to fully elucidate the extra-glycemic actions of semaglutide and to translate these findings into adipose-targeted therapeutic strategies. Full article

Background/Objectives: Triple negative breast cancer (TNBC) is an aggressive subtype treated primarily with chemotherapy, which often leads to drug resistance (DR) and reduced effectiveness. Phytochemicals, including anthocyanins from dark sweet cherry (ACN), have emerged as potential adjuvants to overcome DR, though mechanisms remain unclear. This study examines ACN effects on canonical and non-canonical antioxidant pathways (Nrf2-Keap1 and p62) as a mechanism to overcome DR in 4T1 TNBC cells with acquired DR. Methods: Two conditions were tested: ACN with basal doxorubicin (DOX) as resistance-maintaining conditions and ACN with DOX at IC₅₀ to induce oxidative stress (OS). Results: Under resistance-maintaining conditions, ACNs activated the canonical Nrf2-Keap1 pathway at high doses, which can potentially contribute to DR development due to its cellular protection effects. However, at a low dose, ACN did not trigger an antioxidant response linked to GST and GGT enzyme activities and instead impaired autophagy, increasing OS. Under OS, ACN activated the non-canonical antioxidant pathway mediated by p62 while deactivating Nrf2, leading to autophagy-induced cell death and further impairing autophagy at a low dose. Notably, inflammation persisted at both treatment levels without being relieved, keeping stress signaling active. At both conditions, ACN at doses likely attainable under physiological conditions effectively impaired autophagy and elevated OS, resulting in cell death. Conclusions: These results underscore the context-dependent dual function of polyphenols in cancer therapy, demonstrating their potential to enhance cellular sensitivity to chemotherapy and providing guidance for their strategic use as adjuvants in treating TNBC and overcoming DR. However, this study was limited to a single cell line derived from a murine model. Future research should include comparative studies using human TNBC cell lines to validate these findings and better assess their translational relevance. Full article

Agricultural production remains highly susceptible to water-related risks, such as drought and flooding. Although hydrologic forecasting systems, such as the National Water Model (NWM), have advanced considerably, their outputs are rarely used for real-time agricultural decision-making. This study developed the Agricultural Water Risk Indicator (AWRI), a framework that translates NWM streamflow forecasts into crop-specific risk assessment indicators. The AWRI framework has three key components: (1) the hydrological threat and exposure characterization based on NWM streamflow forecasts (B1); (2) crop sensitivity by growth stage and water needs (B2); and (3) adaptive capacity reflecting the presence of irrigation or drainage infrastructure (B3). The AWRI was evaluated across three NWM reach IDs covering five farm sites in the Black Belt region of Alabama, USA. The results show that the AWRI captured variations in hydrologic conditions, risk, and crop tolerance across the research sites within the one- to four-week forecast range. Crops in the reproductive stage were especially sensitive. Without resilience measures, up to 55% of the crops simulated at some sites had high-risk AWRI categories. Including irrigation or drainage decreased risk scores by one to two levels. The AWRI tool provides farmers and stakeholders with critical information to support proactive agricultural water management. Full article

Background: Ovarian granulosa cells (GCs) play a pivotal role in folliculogenesis, and their dysfunction is central to disorders such as polycystic ovary syndrome (PCOS) and premature ovarian failure (POF). MicroRNAs (miRNAs) have emerged as crucial post-transcriptional regulators of GC homeostasis. Method: This review synthesizes current evidence by systematically analyzing relevant studies, integrating data from in vitro GC models, animal experiments, human cell lines, and clinical samples to elucidate the specific mechanisms by which miRNAs regulate GCs. Results: miRNAs precisely modulate GC proliferation, apoptosis, steroidogenesis, and oxidative stress responses by targeting key signaling pathways (e.g., PI3K/AKT/mTOR, TGF-β/SMAD) and functional genes (e.g., TP53, CYP19A1). Exosomal miRNAs serve as vital mediators of communication within the follicular microenvironment. To date, nearly 200 miRNAs have been associated with PCOS. Conclusions: miRNAs constitute a decisive regulatory network governing GC fate, offering promising therapeutic targets for PCOS and POF. However, significant challenges remain, primarily miRNA pleiotropy and the lack of follicle-specific delivery systems. Future clinical translation requires rigorous validation in human-relevant models. Full article

Background: The profound heterogeneity of glioblastoma and the often-limited efficacy of conventional treatments, including arsenic trioxide (ATO), underscore the urgent and critical demand for innovative combination strategies specifically designed to overcome treatment resistance. Methods: We evaluated the therapeutic effects of ATO as a single agent and in combination with the MNK1 inhibitor AUM001 across patient-derived xenograft (PDX) models and investigated molecular determinants of sensitivity and synergy. Our results demonstrated that GBM models resistant to ATO, particularly those of the mesenchymal subtype, are more likely to show synergistic cytotoxicity when AUM001 is added. The combination significantly reduces the frequency of glioblastoma stem cells (GSCs) compared to either drug alone, especially in ATO-resistant models. Results: These observations suggest that targeting the MNK1 pathway in conjunction with ATO is a promising strategy to specifically eradicate GSCs, which are major drivers of GBM recurrence and therapeutic failure. Transcriptomic analyses revealed that ATO sensitivity correlated with activated translation-related pathways and cell cycle processes, while synergistic responses to the combination were driven by distinct molecular signatures in different GBM subtypes. Overall, synergistic response to the combination therapy is more associated with cellular organization, amino acid transmembrane transporter activity, ion channels, extracellular matrix organization and collagen formation. Conclusions: Our findings highlight that specific molecular pathways and their activities, including those involving translation, cell cycle and ion transport, appear to modulate the synergistic efficacy of the ATO and AUM001 combination, thereby offering potential biomarkers for improved patient stratification in future GBM clinical trials of such ATO-based treatments. Full article

Background: Triple-negative breast cancer (TNBC) represents the most aggressive breast cancer subtype, characterized by high genomic instability, metabolic stress, and limited therapeutic options. Ferroptosis, an iron-dependent form of regulated cell death, has emerged as a promising vulnerability in TNBC, yet its subtype-specific regulatory landscape remains insufficiently defined. Methods: Using transcriptomic (METABRIC, TCGA, GEO) and proteomic (CPTAC) datasets, ferroptosis-related genes were profiled across PAM50 breast cancer subtypes. Differential expression, univariate Cox regression, LASSO modeling, survival analyses, GSEA, and dimensionality reduction (PCA, t-SNE) were applied. A Ferroptosis Index (FI) was calculated using β-coefficients from the Cox/LASSO regression model. Single-cell RNA-seq data was used to map ferroptosis-associated signature across tumor and microenvironmental compartments. Results: Basal-like tumors exhibited the strongest ferroptosis-associated transcriptional shift, characterized by upregulation of ACSL4 and EZH2 and downregulation of AR, GPX4, and CIRBP. Sixteen ferroptosis-related genes were associated with overall survival, forming a ferroptosis-associated signature. The FI was significantly higher in Basal-like tumors, indicating elevated ferroptosis-associated transcriptional state. GSEA revealed enrichment of cell cycle, mitotic, cytoskeletal, and metabolic stress pathways. Single-cell analysis demonstrated expression of ferroptosis markers across cancer epithelial, stromal, and myeloid populations. Conclusions: Basal-like tumors harbor a distinct ferroptosis-associated transcriptional state linked to tumor aggressiveness and poor prognosis. These findings provide a biologically grounded framework for ferroptosis-related stratification and support future functional and translational studies targeting ferroptosis vulnerabilities in aggressive breast cancer. Full article

This study investigated the influence of awareness, knowledge, and risk perceptions on environmental attitudes and behaviours in Türkiye, specifically in the context of climate change, using structural equation modelling (SEM). Data were collected from all 81 provinces covering the seven geographical regions of the country. The results revealed that awareness and risk perception have the strongest direct impact on pro-environmental behaviour. Environmental attitudes also demonstrated a significant positive effect, though the findings suggest that high awareness and risk perception can directly drive action even independently of attitude. Uniquely, this study fills a critical gap in the developing country literature by demonstrating that in Türkiye, perceiving the risk translates directly into action, contrasting with the ‘value-action gap’ often observed in Western contexts. Practically, the findings suggest that policymakers should prioritize risk-communication strategies and disaster-preparedness drills over passive information campaigns to effectively stimulate pro-environmental behaviours. Full article

Advances in kidney organoid technologies have expanded opportunities to model human renal development, disease, and therapeutic response. Yet pluripotent stem cell-derived organoids remain limited by cellular heterogeneity, incomplete tubular maturation and low scalability, restricting their translational relevance. Tubular-specific organoids, derived from adult kidney epithelium, address many of these constraints by providing stable, reproducible cultures enriched for functional proximal and distal tubular cells. Their polarized transport, metabolic activity and patient-specific phenotypes enable high-fidelity modeling of acute and chronic tubular disorders, nephrotoxicity, and inherited tubulopathies—areas where conventional animal and cell-line models often fall short. In this Perspective, we outline recent advances that position tubuloids as a versatile platform for drug screening, toxicity testing and personalized disease modeling. We highlight emerging integration with microfluidics, biomaterials, and gene-editing strategies that promise greater physiological realism and precision therapeutics. We also discuss persistent barriers that impede broader adoption and clinical translation. We propose a roadmap for advancing tubuloid technologies toward precision nephrology and their future incorporation into diagnostic, pharmacological and regenerative pipelines. Full article

Psychological stress is increasingly investigated as a potentially modifiable factor in male infertility, in part through oxidative stress. This narrative review synthesizes mechanistic and translational evidence linking stress-related neuroendocrine activation and coping behaviors with redox imbalance in the male reproductive tract. Chronic activation of the hypothalamic–pituitary–adrenal axis and sympathetic outflow elevates glucocorticoids and catecholamines. In controlled animal stress paradigms, this is accompanied by suppression of the hypothalamic–pituitary–gonadal axis and by immune and metabolic changes that favor reactive oxygen species generation. The resulting oxidative stress may reduce Leydig cell steroidogenesis, impair testicular and epididymal function, and induce lipid peroxidation, mitochondrial dysfunction, and sperm DNA fragmentation. In such models, these lesions, together with apoptosis of germ and supporting cells, are associated with lower sperm concentration, reduced motility, compromised viability, and diminished fertilizing potential. Overall, preclinical animal studies using defined stress paradigms provide experimental evidence consistent with causal effects of stress on oxidative injury and reproductive impairment in preclinical settings. Human studies linking perceived stress, anxiety/depression, and disturbed sleep to adverse semen parameters and oxidative biomarkers are summarized. However, the human evidence is predominantly associative, and the available studies are cross sectional and remain vulnerable to residual confounding and reverse causality. Potential effect modifiers, including smoking, alcohol use, and circadian disruption, are also discussed as contributors to heterogeneity across clinical studies. Standardized assessment of stress biology and redox status, longitudinal designs aligned with spermatogenic timing, and well-powered intervention trials are needed to define dose–response relationships and support individualized prevention and care. Full article

In the era of digital transformation, organizations increasingly invest in Artificial Intelligence (AI) to enhance competitiveness, yet persistent evidence shows that AI investment does not automatically translate into superior firm performance. Drawing on the Resource-Based View (RBV) and Dynamic Capabilities Theory (DCT), this study aims to explain this paradox by examining how AI-enabled dynamic capability (AIDC) is converted into performance outcomes through organizational mechanisms. Specifically, the study investigates the mediating roles of organizational data-driven culture (DDC) and organizational learning (OL). Data were collected from 254 senior managers and executives in U.S. firms actively employing AI technologies and analyzed using partial least squares structural equation modeling (PLS-SEM). The results indicate that AIDC exerts a significant direct effect on firm performance as well as indirect effects through both DDC and OL. Serial mediation analysis reveals that AIDC enhances performance by first fostering a data-driven mindset and subsequently institutionalizing learning processes that translate AI-generated insights into actionable organizational routines. Moreover, DDC plays a contingent moderating role in the AIDC–performance relationship, revealing a nonlinear effect whereby excessive reliance on data weakens the marginal performance benefits of AIDC. Taken together, these findings demonstrate the dual role of data-driven culture: while DDC functions as an enabling mediator that facilitates AI value creation, beyond a threshold it constrains dynamic reconfiguration by limiting managerial discretion and strategic flexibility. This insight exposes the “dark side” of data-driven culture and extends the RBV and DCT by introducing a boundary condition to the performance effects of AI-enabled capabilities. From a managerial perspective, the study highlights the importance of balancing analytical discipline with adaptive learning to sustain digital efficiency and strategic agility. Full article

Skin cancer (SC) is the most prevalent malignancy worldwide, with subtypes varying in aggressiveness: basal cell carcinoma tends to be locally invasive, squamous cell carcinoma has a higher metastatic risk, and melanoma remains the deadliest form. Current treatments such as surgery, radiotherapy, and systemic chemotherapy are associated with aesthetic and functional morbidity, recurrence, and/or systemic toxicity. Although targeted therapies and immunotherapies offer clinical benefits, their high cost and limited accessibility underscore the need for innovative, affordable alternatives. Metal-based compounds (metallopharmaceuticals) are promising anticancer agents due to their ability to induce oxidative stress, modulate redox pathways, and interact with DNA. However, clinical translation has been limited by poor aqueous solubility, rapid degradation, and low skin permeability. This review discusses the most recent preclinical findings on gold, silver, platinum, palladium, ruthenium, vanadium, and copper complexes, mainly in topical and systemic treatments of SC. Advances in chemical and physical enhancers, such as hydrogels and microneedles, and in drug delivery systems, including bacterial nanocellulose membranes and nanoparticles, as well as liposomes and micelles, for enhancing skin permeation and protecting the integrity of metal complexes are also discussed. Additionally, we examine the contribution of photodynamic therapy to SC treatment and the use of mathematical and computational modeling to simulate skin drug transport, predict biodistribution, and support rational nanocarrier design. Altogether, these strategies aim to bridge the gap between physicochemical innovation and clinical applicability, paving the way for more selective, stable, and cost-effective SC treatments. Full article

Peripheral artery disease (PAD) remains a great threat to the health of older people globally. Nitric oxide (NO), as an important signaling molecule, is integral to processes such as angiogenesis, inflammation, and tissue regeneration, making it a potential candidate for PAD treatment. Nevertheless, NO—based therapies are frequently limited in clinical utility, primarily due to the lack of effective strategies for fine-tuning the release of exogenous NO. In this study, we developed an enzyme—prodrug pair based on endocellulase (Cel5A-h38), which ensured complete bioorthogonality, thus avoiding interference with endogenous enzymes and eliciting an inflammatory response. This delivery system enables localized and controlled NO release, thus preventing side effects induced by systemic exposure. The therapeutic efficacy of the NO delivery system was systematically evaluated in a porcine model of hindlimb ischemia. Our results confirmed the benefits of targeted NO delivery in hindlimb ischemia, which include enhanced neovascularization and tissue perfusion, reduced inflammation, and alleviated muscle fibrosis, demonstrating its optimal translational potential. Full article

Background: Developmental coordination Disorder (DCD) is a prevalent and persistent neurodevelopmental condition characterized by motor learning difficulties that significantly affect daily functioning and participation. Despite growing interest in artificial intelligence (AI) applications within healthcare, the extent and nature of AI use in the evaluation and intervention of DCD remain unclear. Objective: This scoping review aimed to systematically map the existing literature on the use of AI and AI-assisted approaches in the evaluation, screening, monitoring, and intervention of DCD, and to identify current trends, methodological characteristics, and gaps in the evidence base. Methods: A scoping review was conducted in accordance with the PRISMA extension for Scoping Reviews (PRISMA-ScR) guidelines and was registered on the Open Science Framework. Systematic searches were performed in Scopus, PubMed, Web of Science, and IEEE Xplore, supplemented by snowballing. Peer-reviewed studies applying AI methods to DCD-relevant populations were included. Data was extracted and charted to summarize study designs, populations, AI methods, data modalities, clinical purposes, outcomes, and reported limitations. Results: Seven studies published between 2021 and 2025 met the inclusion criteria following a literature search covering the period from January 2010 to 2025. One study listed as 2026 was included based on its early access online publication in 2025. Most studies focused on AI applications for assessment, screening, and classification, using supervised machine learning or deep learning models applied to movement-based data, wearable sensors, video recordings, neurophysiological signals, or electronic health records. Only one randomized controlled trial evaluated an AI-assisted intervention. The evidence base was dominated by early-phase development and validation studies, with limited external validation, heterogeneous diagnostic definitions, and scarce intervention-focused research. Conclusions: Current AI research in DCD is primarily centered on evaluation and early identification, with comparatively limited evidence supporting AI-assisted intervention or rehabilitation. While existing findings suggest that AI has the potential to enhance objectivity and sensitivity in DCD assessment, significant gaps remain in clinical translation, intervention development, and implementation. Future research should prioritize theory-informed, clinician-centered AI applications, including adaptive intervention systems and decision-support tools, to better support occupational therapy and physiotherapy practice in DCD care. Full article

Acne vulgaris is a chronic inflammatory dermatosis where conventional therapies often face limitations in efficacy and safety, necessitating the development of microbiome-targeted interventions. This study investigated the immunomodulatory potential of microbiome-derived tryptophan metabolites as a novel therapeutic strategy for Cutibacterium acnes (C. acnes)-induced inflammation, focusing on the aryl hydrocarbon receptor (AHR) pathway. We evaluated indole-3-lactic acid (ILA), indole-3-acrylic acid (IAA), and indole-3-propionic acid (IPA) in comparison to tapinarof, utilizing C. acnes-stimulated human epidermal keratinocytes and a C. acnes-induced acne mouse model. In vitro, ILA and IPA significantly suppressed C. acnes-driven inflammatory mediators, including Tumor Necrosis Factor-alpha (TNF-α), Interleukin (IL)-1β, and Cyclooxygenase-2 (COX2), whereas IAA demonstrated limited efficacy. In vivo, ILA treatment exhibited superior therapeutic activity, markedly reducing inflammatory cell infiltration, epidermal hyperplasia, and IL-1β expression. Transcriptomic analysis confirmed that ILA attenuates inflammatory signaling (e.g., IL-17 and TNF pathways) while upregulating AHR-responsive genes such as Cytochrome (CYP) 1A1 and CYP1B1. Collectively, these findings establish ILA as a potent postbiotic that mitigates cutaneous inflammation through selective activation of the AHR. Future studies should prioritize the clinical translation of ILA-based topical formulations, with rigorous evaluation of their efficacy and safety in well-designed human trials, to support their development as a non-antibiotic therapeutic alternative for acne management. Full article