Search Results (17,740)

Metabolic reprogramming is a defining feature of breast cancer, enabling tumor cells to sustain rapid proliferation, survive under stress, and resist therapy. Key pathways including glycolysis, glutaminolysis, lipid metabolism, and one-carbon metabolism, play central roles in meeting the energetic and biosynthetic demands of malignant cells. Enhanced glycolytic flux supports ATP generation and lactate production, while glutamine metabolism fuels the tricarboxylic acid cycle and provides nitrogen for nucleotide synthesis. Lipid metabolic pathways, particularly fatty acid synthesis, contribute to membrane biogenesis and signaling, and one-carbon metabolism driven by serine and glycine supplies methyl groups for epigenetic regulation and nucleotide production. These metabolic adaptations not only promote tumor growth but also create vulnerabilities that can be exploited therapeutically. Inhibiting these pathways has shown promise in preclinical models; however, challenges such as metabolic plasticity, tumor heterogeneity, and potential toxicity in normal tissues underscore the need for biomarker-driven strategies and rational combination therapies. Herein, we describe current knowledge of the role of these pathways in breast cancer progression, highlighting the role of key enzymes in promoting breast cancer tumor cell growth and in breast cancer prognoses. Full article

Background/Objectives: Aggressive behaviour is commonly associated with neurodevelopmental disorders, such as autism spectrum disorder (ASD), and could be understood as a response to daily stress routines, which negatively impacts patients’ quality of life. Oxytocin (OT), a neuropeptide involved in social bonding and socio-affective regulation, has emerged as a promising candidate to enrich, rather than replace, current pharmacological approaches in managing ASD-associated aggressive behaviour. In this study, we examined the potential of OT to modulate aggressive behaviour frequency in a VPA-based animal model of ASD. Methods: Sixty adult zebrafish (1:1 sex ratio) were divided into six groups (n = 10/group) and received the following treatment for 7 consecutive days: CTR—control (no treatment); VPA (28.8 mg/L valproic acid); OT (33.2 ng/mL oxytocin); RIS (170 μg/L risperidone); VPA + OT (28.8 mg/L valproic acid and 33.2 ng/mL oxytocin); and VPA + RIS (28.8 mg/L valproic acid and 170 μg/L risperidone). The locomotor performance, and socio-affective and aggressive behaviours, were measured in the Novel Tank and Mirror Biting tests at the end of the treatments. Results: We observed that the VPA treatment led to locomotion and socio-affective impairments, as well as aggressive behaviour. Also, we found that OT and RIS had comparable potential to modulate the frequency of aggressive and anxiety-like behaviours. Conclusions: Our preliminary data showed that OT has the potential to modulate the frequency of anxiety-like and aggressive behaviours, similarly to the atypical antipsychotic, RIS, in our VPA zebrafish model. However, further studies are needed to investigate the mechanisms of action and their potential synergistic effects. Full article

Adolescence represents a critical window of metabolic plasticity, during which profound hormonal, neurobiological, and physiological remodelling increases susceptibility to nutritional exposures. In parallel with the rising prevalence of obesity, insulin resistance, metabolic syndrome, and non-alcoholic fatty liver disease among young people, there is growing interest in the potential for functional food components to modulate epigenetic pathways that govern metabolic programming. This narrative review synthesises current evidence (2015–2025) from PubMed, Scopus, Web of Science, and Embase to elucidate how diet-derived bioactive compounds influence epigenetic regulation relevant to adipogenesis, appetite control, insulin signalling, and lipid homeostasis during adolescence. Particular emphasis is placed on molecular mechanisms, including DNA methylation changes in genes regulating adipocyte differentiation, hypothalamic neuropeptide expression, and pancreatic β-cell function; histone modifications, such as acetylation and methylation events that remodel chromatin accessibility in metabolic tissues; and modulation of microRNA networks implicated in lipid metabolism, inflammatory signalling, and insulin secretion. Furthermore, the review examines the interplay between diet, the gut microbiota, and the epigenome, highlighting the role of microbially derived short-chain fatty acids (SCFAs) as endogenous histone deacetylase inhibitors and mediators of epigenetic remodelling in adipose tissue. By linking these mechanisms to specific functional food components, including polyphenols, long-chain omega-3 fatty acids, fermentable dietary fibre, and other bioactive molecules, we demonstrate how nutritional signals can counteract maladaptive metabolic trajectories and potentially reduce the intergenerational transmission of metabolic risk. A deeper understanding of these epigenetic effects provides the foundation for developing personalised nutrition strategies aimed at preventing metabolic disorders from emerging during adolescence and beyond. Full article

The cystic fibrosis transmembrane conductance regulator (CFTR) is a member of the atypical ATP-binding cassette (ABC) family that functions as a phosphorylation-regulated epithelial anion channel. Cystic fibrosis (CF) is characterised by variants in the CFTR gene that lead to impaired epithelial chloride–ion transport and increased mucus viscosity. Although CFTR modulators such as Trikafta^® have transformed the care of many CF patients, individuals harbouring rare CFTR variants still have no effective treatment options. In this study, we used primary air–liquid interface (ALI) airway cultures obtained from 21 CF patients (pwCF) and 21 healthy controls (HC) to evaluate the therapeutic efficacy of CFTR restoration based on chitosan-mediated CFTR mRNA and modulators. While modulators restored CFTR channel function in most cultures derived from CF patients, those with class I or other rare variants showed no improvement. Chitosan-mediated CFTR mRNA delivery successfully restored CFTR function in ALI cultures of patients carrying rare CFTR variants with limited or no observed clinical response to modulator therapy, assessed by electrophysiology using our newly developed Multi Transepithelial Current Clamp (MTECC) Ussing chamber. This was then confirmed by morphological visualisation of CFTR protein expression in modulator-responsive patient samples using immunofluorescence (IF) staining. IF revealed an increase in CFTR signal and the restoration of epithelial barrier integrity following chitosan-mRNA and modulator treatment as a secondary outcome alongside CFTR functional measurements. Notably, MUC5AC expression, a major gel-forming mucin expressed by airway goblet cells and mucus viscosity were elevated in CF cultures, but were markedly reduced following successful intervention, approaching the levels seen in HCs. These findings establish the potential of chitosan-mRNA delivery as a therapeutic approach for CF patients, particularly those who do not respond to modulators. They also provide a practical, comparative evaluation of advanced mRNA-based treatments in patient-derived airway models. Full article

Sleep banking, i.e., preemptively obtaining extra sleep prior to anticipated sleep loss, has been proposed as a strategy to reduce the cognitive and physiological consequences of sleep deprivation. However, our understanding remains incomplete regarding the effectiveness of preemptive sleep extension in enhancing resilience to sleep loss. A comprehensive literature search was conducted using PubMed, MEDLINE, and Embase for studies published between 2004 and 2025. Following a comprehensive literature search, we identified 12 studies meeting the inclusion criteria—seven primary experimental trials comprising approximately 140 participants, predominantly healthy young adults aged 18–39 years. We evaluated the effects of sleep banking on cognitive performance, mood, physiological parameters, and real-world outcomes. Included studies encompassed experimental laboratory trials, observational research, and field studies in occupational and athletic settings. Although the number of studies on sleep banking remains limited, experimental evidence demonstrates that preemptive sleep extension improves objective alertness and vigilance during subsequent sleep restriction or total sleep deprivation. Individuals who obtained additional sleep exhibited fewer attentional lapses, faster reaction times, and improved mood, although subjective sleepiness often remained high. Preliminary field evidence suggests that preemptive sleep extension enhances workplace safety, reduces errors, and improves sustained attention in shift workers. In athletic contexts, sleep banking has been associated with improved physical endurance and reaction speed. Importantly, this review primarily addresses the homeostatic dimension of sleep regulation (Process S); circadian factors (Process C), including chronotype, social jetlag, and circadian timing of sleep extension and testing, were not systematically addressed in the included studies and represent important limitations of the current evidence base. Overall, sleep banking appears to be a viable strategy for enhancing resilience to acute sleep loss. It confers measurable benefits in performance, cognitive function, and physiological markers, supporting its application in high-demand occupations and competitive environments. Although it does not fully eliminate subjective fatigue, sleep banking may serve as a valuable complement to other fatigue mitigation strategies for anticipated short-term sleep loss. Full article

Current research on the participation of inverter-based air conditioners in demand response often prioritizes system performance during regulation periods yet frequently overlooks the prolonged high indoor temperatures that follow. Furthermore, oversimplified user comfort constraints limit the accurate evaluation of peak-shaving potential. To address these limitations, this paper proposes a novel control framework. First, a differential user comfort evaluation model is established to quantify the adjustable temperature range under varying scenarios. Second, an analog duty cycle grouped rotation control model is developed. By leveraging the variable-frequency characteristics of inverter ACs, this method optimized peak-shaving potential while preventing indoor temperatures from remaining at their upper limits for extended durations. Third, to ensure fairness, a user selection model incorporating a User Impact Factor is introduced as a dynamic ranking criterion for participation priority. Finally, to address the inevitable parameter mismatch in practical engineering, the control strategy is upgraded to a feedforward–feedback closed-loop framework. Simulation results demonstrate the superiority of the proposed ADC strategy over existing methods. Specifically, compared to existing methods, it achieved a 45–50% reduction in the high-temperature influence factor and a 67% decrease in the standard deviation of user impact, indicating significantly improved thermal comfort and fairness. Furthermore, the framework exhibits strong robustness; even under 20% parameter uncertainty, it restricted the duration of temperature exceedance to within 0.8%, strictly outperforming traditional open-loop approaches in preventing user discomfort. These improvements ensure a more uniform distribution of comfort impacts among users, thereby enhancing both the precision and sustainability of demand-side peak shaving. Full article

Reproductive efficiency in female cattle is significantly influenced by micronutrient status, particularly the availability and balance of essential trace minerals. Selenium, copper, zinc, cobalt, and iron serve as critical components of enzymatic systems, antioxidant defense networks, hormone synthesis, and cellular metabolism, collectively sustaining reproductive health. This review integrates current research evidence on the physiological functions and molecular mechanisms through which these five trace minerals regulate reproductive performance in female cattle, with a specific focus on iron—an often overlooked element—highlighting the novelty of this synthesis. Both deficiency and excess of these minerals impair key reproductive outcomes such as estrous cyclicity, conception rate, and embryonic survival. Furthermore, complex interactions among minerals influence their bioavailability and physiological responses. Advances in mineral supplementation strategies, particularly the application of organic minerals and precision feeding technologies, offer promising solutions to improve reproductive performance. Elucidating these interrelationships provides a theoretical foundation for optimizing trace mineral nutrition, thereby enhancing female cattle fertility, reducing metabolic disorders and promoting the sustainable development of beef and dairy industries. Full article

Numerous scientific studies highlight the crucial role of common genetic and epigenetic factors in the development and progression of cancer. To deepen our understanding of how different VEGFR and epigenetic pathways interact in carcinogenesis, the current review examines novel therapeutic agents that target various molecular mechanisms involved in this complex disease. Growing evidence from scientific studies suggests that VEGFR and epigenetic signaling pathways contribute to complex pathophysiological changes in cancer. Therefore, simultaneously targeting VEGFR and epigenetic factors, such as sirtuins, by developing dual inhibitors could provide more individualized therapeutic approaches with safer and more effective outcomes. In this context, Computer-Aided Drug Design (CADD) offers a comprehensive suite of bioinformatic, chemoinformatic, and chemometric approaches to design novel chemotypes of epigenetic dual-target inhibitors. This facilitates the efficient discovery of new drug candidates, enabling innovative treatments for these multifactorial diseases. The review also explores the detailed anticancer mechanisms by which VEGFR, SIRT, and dual-target inhibitors modify metastatic and tumorigenic properties, affect the tumor microenvironment, and regulate the immune response. Full article

The transition towards climate neutrality requires the development of spatially explicit planning approaches that account for territorial differences and land-use dynamics. Within this conceptual framework, this study has the objective of identifying and discussing spatially explicit planning approaches that can support the transition to climate neutrality in different regional spatial contexts. With reference to this research question, a methodological framework is introduced and applied that is designed to support climate neutrality through spatial planning strategies. Carbon sequestration (CS) serves as a key metric to evaluate both the current state and the temporal evolution of this process, examined in connection with the provision of specific ecosystem services (ESs) within the relevant spatial setting. The work is structured as follows. An approach is developed to define the provision of ESs. Drawing on previous research and detailed assessments of environmental, landscape, and socio-cultural features, the study considers the following ESs: maintaining or improving habitat quality to sustain the life cycles of wild species valuable to humans; regulating climate by mitigating land surface temperature; agricultural and forestry production; and nature-based recreational opportunities. Moreover, spatial relationships between CS capacity and ES provision are examined through geographically weighted regressions, allowing comparisons across Basilicata, Campania, and Sardinia, three Regions in southern Italy forming the Italian Mezzogiorno. The multifunctional characteristics of ES supply contributes to optimizing CS capacity and advancing climate neutrality goals. In particular, in all three regional contexts, high values of CS capacity elasticity are recognized in relation to habitat quality and ground temperature mitigation, and very low elasticity conditions as regards the supply of recreational ESs and agricultural and forestry production. Full article

Objectives Breast cancer remains a major cause of female cancer-related deaths, with current therapies limited by poor tumor targeting and an immunosuppressive microenvironment. This study designed CA/ZYII-siP-c-L—an asymmetric lipid bilayer-coated calcium/aluminum (CA)-core nanoparticle—to co-deliver PD-L1 siRNA (siP) and ziyuglycoside II (ZYII) to boost therapeutic efficacy. Methods CA/ZYII-siP-c-L was fabricated through modified microemulsification to first construct the CA cores, followed by thin-film hydration for encapsulation of ZYII within the hydrophobic domain, and via hybridization of the outer lipid layer with DSPE-PEG1000-PAMAM to finally enable specific adsorption of siP. The characterization of CA/ZYII-siP-c-L was performed to get size distribution, zeta potential and in vitro release behavior. In vitro cytotoxicity of the nanoparticles to NIH3T3 and 4T1 cells was detected by the CCK-8 method. The uptake capacity to 4T1 breast cancer cells was determined using inductively coupled plasma optical emission spectrometry and high-performance liquid chromatography. Pharmacokinetic studies and tissue distribution experiments were performed. In BALB/c mice bearing orthotopic 4T1 tumors, efficacy evaluations were conducted with the detection of tumor immune microenvironment; meanwhile, organ damage was evaluated by hematoxylin-eosin staining of major organs and detection of routine biochemical indicators. Results CA/ZYII-siP-c-L was characterized by dynamic light scattering (mean size ~185.7 nm) and zeta potential analysis (~9.35 mV). In vitro, the nanoparticle exhibited low cytotoxicity in NIH3T3 normal cells, high uptake by 4T1 breast cancer cells, and pH-responsive release. For the pharmacokinetic study, CA nanoparticle system could significantly enhance the systemic exposure of ZYII, compared to free ZYII suspension. In BALB/c mice with orthotopic 4T1 tumors, CA/ZYII-siP-c-L accumulation in tumors was 3.5-fold higher than that of free drugs, significantly enriching helper T cells and cytotoxic T lymphocytes while reducing regulatory T cells and suppressive dendritic cells in the tumor immune microenvironment; this immunomodulatory effect, combined with PD-L1 silencing at protein levels, contributed to ~62% inhibition of tumor growth with no organ damage (confirmed by hematoxylin and eosin staining of major organs and normal biochemical indices). Conclusions CA/ZYII-siP-c-L integrates safety, targeting, and codelivery capabilities, offering a promising strategy for breast cancer treatment by combining siP-mediated immunity regulation and the antitumor effects of ZYII. Full article

Purpose of Review—sleep disturbance is the main complaint associated with patients who suffer acute postoperative pain. Sleep disturbance may also increase the pain sensitivity and contribute to the development and maintenance of chronic pain. The pathophysiology of pain is complex; management of perioperative pain and preventing chronic pain are challenges in clinical. Use of opioids for pain management are still a therapeutic mainstay and generally safe when taken, in a short time, for severe postoperative pain relief. For long-term use tolerance may be developed, and for their euphoric property, addiction, overdose incidents, and even death may be the social problems. Therefore, the opioid-sparing multimodal analgesia (MMA) for pain management is recommended in current postoperative pain management. The successful MMA for pain management will enhance patient recovery after surgery with less chronic CPSP and long-term opioid use disorder (OUD). The present review discusses all currently used analgesics actions and interactions, and opioid-sparing or opioid-free analgesia in perioperative pain management. Acute pain following major trauma or surgery may originate from both nociceptive and neuropathic mechanisms. Approximately 10–50% of surgical patients develop chronic postoperative pain, which not only causes persistent discomfort but also leads to functional limitations and psychological distress. Growing evidence highlights a close and bidirectional relationship between sleep and pain: pain disrupts sleep architecture, while sleep deprivation intensifies pain sensitivity and impairs recovery. This reciprocal interaction forms a vicious cycle that poses challenges for effective pain management. Melatonin—a neurohormone secreted by the pineal gland—plays a crucial role in regulating circadian rhythm and sleep–wake cycles. Beyond its chronobiotic action, melatonin exhibits anti-nociceptive, anti-inflammatory, and opioid-sparing properties. Recent preclinical studies have demonstrated that exogenous melatonin can attenuate nociceptive responses to noxious stimuli and enhance morphine analgesia while attenuating morphine tolerance. Moreover, environmental light manipulation preserving the circadian rhythm has been shown to synergistically maintain melatonin secretion, improve sleep quality, and modulate neuroimmune responses involved in pain regulation. Together, these findings suggest that circadian alignment and melatonin supplementation may represent a promising integrative approach for improving both pain control and sleep health in perioperative and chronic pain conditions. Chronic pain patients frequently experience opioid tolerance during long-term therapy, resulting in diminished analgesic efficacy and a need for escalating doses. Our recent work revealed that constant light exposure suppresses endogenous melatonin, heightens pro-inflammatory cytokines (TNF-α, IL-1β), reduces IL-10, and accelerates morphine tolerance in a neuropathic pain model. In contrast, maintaining circadian light–dark cycles or supplementing melatonin preserves melatonin rhythm, reduces glial activation, and sustains morphine antinociception. Melatonin’s co-administration not only attenuates morphine tolerance but also enhances morphine efficacy through the modulation of inflammatory and glial pathways. These findings underscore melatonin’s multifaceted role as both a chronotherapeutic and neuroprotective agent, integrating circadian regulation with pain modulation. Clinically, the application of melatonin or circadian-aligned strategies could guide personalized pain and sleep management, offering safer and more effective multimodal analgesic protocols with reduced opioid dependence and improved quality of life. Full article

Nitrogen oxides (NO_x), carbon monoxide (CO), sulfur dioxide (SO₂), and volatile organic compounds (VOCs) in industrial waste gases pose significant threats to environmental quality and human health. Catalytic purification is recognized as a leading abatement technology, crucial for meeting increasingly stringent emission regulations. Rare-earth (RE) catalytic materials, particularly those based on cerium (Ce), lanthanum (La), praseodymium (Pr), and neodymium (Nd) oxides, have attracted intense research due to their unique electronic configurations, high oxygen storage capacity (OSC), facile reversible redox reactions Ce⁴⁺, Ce³⁺, and exceptional thermal stability. This paper provides a comprehensive and methodical overview of RE catalysts used in industrial waste-gas purification. Initially, the physicochemical characteristics of RE elements and their multifaceted roles as active phases, supports, and promoters are explained. Subsequently, the latest developments in RE-based catalysts for NO_x abatement, CO oxidation, VOC degradation, and the removal of sulfur-bearing gas are critically reviewed. The discussion emphasizes structure–activity relationships, reaction mechanisms, and the synergistic interactions between RE elements and transition metals. Comparative analyses are presented through tables focusing on catalyst composition, reaction conditions, performance parameters, and stability. Special attention is given to the enhanced resistance to water vapor and sulfur poisoning afforded by RE materials. Finally, current challenges and future research prospects, including cost reduction, scalability, and long-term durability, are suggested. This review aims to provide practical guidance for the rational design and industrial translation of next-generation RE catalytic materials for air pollution control. Full article

The Albufera of Valencia is a shallow, hypertrophic Mediterranean coastal lagoon. Since the 1970s, the lagoon has undergone substantial ecological deterioration, marked by the decline of macrophyte beds and the predominance of phytoplankton. The objective of this study was to monitor key water quality variables over a 10-year period (2015–2025) to assess the persistence of eutrophication and the current ecological status of the lagoon. For this purpose, a remote sensing approach was applied using the Sentinel-2 constellation, complemented by newly developed algorithms specifically calibrated with ten years of in situ field data (2016–2025). This approach was employed to estimate variables such as the chlorophyll-a (Chl-a) concentration as an indicator of phytoplankton biomass, suspended solids (S.S.), and Secchi disk depth (Z_SD). An analysis of temporal trends from 2017 to 2025 revealed a progressive system deterioration. The concentrations of both chlorophyll-a and suspended solids exhibited a statistically significant increasing trend (p < 0.01). Moreover, in line with these findings, water transparency (Z_SD) decreased significantly (p < 0.001). Thus, there has been a progressive deterioration in the trophic status and ecological quality of the lagoon over the last decade, despite prior management interventions. The results from this research highlight the need to implement more effective conservation strategies, such as regulating nutrient inputs and increasing the water renewal time in the lagoon. Full article

Natural gas pipeline networks are subject to supply instability due to random fluctuations. Current forecasting methodologies often suffer from limited accuracy, inadequate uncertainty quantification, and poor integration with dynamic network evaluation mechanisms. To address these challenges, this study presents an integrated framework that bridges short-term demand forecasting with supply assurance assessment. A deep learning model that combines a graph convolutional network and a bidirectional long short-term memory network is developed to produce accurate 72 h demand forecasts. Forecasting uncertainty is quantified using the cumulative distribution function. Based on the probabilistic forecasts, a supply assurance evaluation model is constructed that accounts for the dynamic regulation capability of line pack. The comprehensive indicator system incorporates key metrics such as user satisfaction and the line pack demand−storage ratio. A case study was conducted with the proposed method based on a regional real-world pipeline network. The results demonstrate that the proposed model outperforms conventional baselines, achieving a mean absolute percentage error of less than 1%. The uncertainty quantification captures the risk probability associated with demand fluctuations. The proposed evaluation method identifies vulnerable sections and assesses supply margins under various scenarios, thus providing effective decision support for operational scheduling and supply assurance. Full article

DC–DC converters have become a key component in the structure of renewable energy systems, where an interface to increase and regulate the output voltage is required. This paper presents a modular non-isolated topology that achieves high voltage gain through interconnected switched-inductor cells. For the proposed converter, the design rules for sizing the energy storage elements for n number of cells are obtained, considering continuous, discontinuous, and boundary operation modes. Therefore, design equations are provided to support the precise selection of passive components according to voltage and power specifications. A nonlinear dynamic model is developed, and a model-based control scheme with inner current and outer voltage loops ensures robust regulation and fast transient response. Experimental validation on a 200 W prototype confirms theoretical predictions under steady-state and real-life dynamic conditions. Full article