Search Results (31,106)

Nearly all eukaryotic proteins are turned over by the ubiquitin (Ub)-26S proteasome system (UPS). Despite its broad cellular roles, only a handful of UPS members, particularly the Ub E3 ligases that specifically recognize a protein for ubiquitylation, have been characterized in plants to date. The challenge arises from the transient recognition and rapid degradation of ubiquitylation substrates by the UPS. To tackle this challenge, the emerging biotinylation-based proximity labeling (PL) offers an exciting tool for enriching transient interactors of Ub E3 ligases. In this study, we examined the efficacy of TurboID in identifying substrates of Arabidopsis Skp1-cullin1-F-box (SCF) ligases. We demonstrate that the Arabidopsis Skp1 Like (ASK)1-TurboID is not fully functioning in planta, which led us to discover a novel antagonism between biotinylation and ubiquitylation in regulating protein stability in vivo. This discovery lowers the effectiveness of PL in ubiquitylome studies. However, using one long-known SCF substrate, phytochrome A, we succeeded to apply its TurboID fusion for complementing the far-red-light response of the phyA-211 null mutant allele, suggesting an efficacy of PL in characterizing single ubiquitylation pathways. This study highlighted a limitation of PL in ubiquitylome studies, discovered a new antagonistic pathway of biotinylation, and developed a theoretical guidance for future PL-based characterization of ubiquitylation pathways. Full article

Nuclear factor erythroid 2-related factor 2 (NRF2) serves as a master transcriptional regulator of cellular antioxidant responses through orchestration of cytoprotective gene expression, establishing its significance as a therapeutic target in cerebral pathophysiology. Classical electrophilic NRF2 activators, despite potent activation potential, exhibit paradoxically reduced therapeutic efficacy relative to single antioxidants, attributable to concurrent oxidative stress generation, glutathione depletion, mitochondrial impairment, and systemic toxicity. Although emerging non-electrophilic pharmacological activators offer therapeutic potential, their utility remains limited by bioavailability and suboptimal potency, underscoring the imperative for innovative therapeutic strategies to harness this cytoprotective pathway. Non-pharmacological interventions, including neuromodulation, physical exercise, and lifestyle modifications, activate NRF2 through non-canonical, non-electrophilic pathways involving protein–protein interaction inhibition, KEAP1 degradation, post-translational and transcriptional modulation, and protein stabilization, though mechanistic characterization remains incomplete. Such interventions utilize multi-mechanistic approaches that synergistically integrate multiple non-electrophilic NRF2 pathways or judiciously combine electrophilic and non-electrophilic mechanisms while mitigating electrophile-induced toxicity. This strategy confers neuroprotective effects without the contraindications characteristic of classical electrophilic activators. This review comprehensively examines the mechanistic underpinnings of non-pharmacological NRF2 modulation, highlighting non-electrophilic activation pathways that bypass the limitations inherent to electrophilic activators. The evidence presented herein positions non-pharmacological interventions as viable therapeutic approaches for achieving non-electrophilic NRF2 activation in the treatment of cerebrovascular and neurodegenerative pathologies. Full article

Background/Objective: Sacubitril/Valsartan are a combination drug approved for heart failure treatment, known to enhance natriuretic peptide activity and inhibit the renin–angiotensin–aldosterone system (RAAS). While its clinical efficacy is well-established, its broader impact on human metabolism remains insufficiently characterized. This study aimed to explore the time-resolved metabolic changes induced by Sacubitril/Valsartan in healthy individuals using an untargeted metabolomics approach. Methods: Fourteen healthy male volunteers received a single oral dose of Sacubitril/Valsartan (200 mg; 97.2 mg Sacubitril and 102.8 mg Valsartan) across two phases separated by a two-week washout period. Plasma samples were collected at eight individualized time points based on pharmacokinetic profiles. Metabolites were extracted and analyzed using high-resolution liquid chromatography–mass spectrometry (LC-QToF HRMS). Data processing included peak alignment, annotation via HMDB and METLIN, and statistical modeling through multivariate (PLS-DA, OPLS-DA) and univariate (ANOVA with FDR correction) analyses. Results: Out of 20,472 detected features, 13,840 were retained after quality filtering. A total of 315 metabolites were significantly dysregulated (FDR p < 0.05), of which 31 were confidently annotated as endogenous human metabolites. Among these, key changes were observed in the pyrimidine metabolism pathway, particularly elevated levels of uridine triphosphate (UTP) associated with cellular proliferation and metabolic remodeling. OPLS-DA models demonstrated clear separation between pre-dose and Cmax samples (R²Y = 0.993, Q² = 0.768), supporting the robustness of the time-dependent effects. Conclusions: This is the first study to characterize the dynamic metabolomic signature of Sacubitril/Valsartan in healthy humans. The findings reveal a distinctive perturbation in pyrimidine metabolism, suggesting possible links to drug mechanisms relevant to cardiac cell cycle regulation. These results underscore the utility of untargeted pharmacometabolomics in uncovering systemic drug effects and highlight potential biomarkers for monitoring therapeutic response or guiding precision treatment strategies in heart failure. Full article

Background: Breast cancer is the most common malignancy affecting women worldwide and continues to pose significant challenges despite progress in early detection and personalized therapies. While its pathogenesis has traditionally been associated with genetic, hormonal, and environmental factors, recent studies have highlighted the potential role of dysbiosis—an imbalance in gut and systemic microbiota—in breast cancer development and progression. This article aims to examine the mechanisms through which systemic dysbiosis may contribute to breast cancer risk and explore its therapeutic implications. Methods: This study seeks to analyze and compare the fecal microbiota profiles of breast cancer patients and healthy individuals from a single center in Craiova, Romania, in order to identify microbial signatures linked to breast cancer and BRCA mutation status. Special attention is given to the gut–liver axis and its influence on estrogen circulation, a key factor in hormone-sensitive breast cancers. Results: Evidence suggests that dysbiosis can influence breast cancer progression by promoting chronic inflammation, impairing immune regulation, and altering estrogen metabolism through the gut–liver axis. These effects may contribute to tumor development, immune evasion, and therapeutic resistance. Interventions aimed at restoring microbial balance show promise in preclinical studies for mitigating these effects. Conclusions: Systemic dysbiosis represents a potentially modifiable risk factor in breast cancer. Microbiota profiling may serve as a useful biomarker for risk stratification and therapeutic response. Future research into microbiome-based interventions could offer novel approaches for prevention and treatment in breast cancer care. Full article

Refugee mothers are at heightened risk of developing negative family dynamics due to traumatic experiences and unstable living conditions, often impacting their children in lasting ways. This partially mixed, explanatory mixed-methods pilot study examines the potential of Drama Therapy as a psychosocial intervention to reduce harmful parenting behaviors and strengthen parent–child relationships. The study engaged 20 refugee mothers who participated in a three-session intervention based on Emunah’s five-phase model. Data collection included pre-intervention demographic information, two standardized psychological scales—The Child–Parent Relationship Scale and the Parent Anger Scale—and post-intervention focus group discussions. The findings indicate that the Drama Therapy Intervention (DTI) helped reduce parental anger and improve emotional regulation, leading to more positive interactions with children and decreased conflict within the family. Focus group insights revealed that the mothers’ ongoing and past traumas significantly shaped their emotional responses and parenting styles. This pilot study highlights the importance of addressing maternal mental health in post-displacement contexts. Although one cannot draw causal inferences of efficacy in the absence of a control group, the findings provide preliminary evidence that Drama Therapy can be an effective tool for reducing parental maltreatment and improving family relationships among refugee populations. Full article

Background: Enhancing adipose tissue functionality is a promising cellular-level approach to combating obesity. White adipose tissue (WAT) can acquire beige or brown adipose tissue (BAT)-like properties, characterized by increased thermogenesis and energy dissipation. While the SIRT1-SRSF10–Lipin-1 axis has been identified in hepatocytes, where Lipin-1 regulates triglyceride metabolism, its role in adipocytes remains unclear. This study aimed to investigate the function of Lipin-1 in 3T3-L1 preadipocytes and its interaction with SIRT1, SRSF10, and PPARγ in promoting browning-like transcriptional responses. Methods: Mouse 3T3-L1 preadipocytes were treated during differentiation with either rosiglitazone (RGZ), the SIRT1 activator SRT1720, or the SIRT1 inhibitor EX527. Gene expression was assessed by real-time PCR, and protein levels were measured using the Simple Western blot system. Data were compared with untreated controls and analyzed using GraphPad Prism. Results: Lipin-1 expression was significantly upregulated by RGZ treatment, alongside increased transcription of Sirt1 and Srsf10, supporting the presence of this regulatory axis in adipocytes. Elevated Srsf10 favored the production of the Lipin-1b isoform, whereas SIRT1 inhibition reversed these effects, confirming its upstream role. Pathway activation further enhanced the expression of browning markers, including Ucp1, Pgc1a, PRDM16, and CIDEA. Conclusions: These findings demonstrate that Lipin-1 interacts with the SIRT1–PPARγ–SRSF10 axis in adipocytes and contributes to the acquisition of beige/brown-like characteristics in WAT. This regulatory pathway may represent a potential target for improving lipid metabolism and metabolic health. Full article

Skin wound healing and barrier restoration are complex, tightly regulated processes critical for maintaining skin integrity, particularly in aged or compromised skin. This study investigated the wound healing efficacy and epidermal barrier-restoring effects of ε-Viniferin, a bioactive resveratrol dimer, and Vino Chocolate™, a grape flower-derived extract from Vitis labruscana ‘Campbell Early’ cell cultures enriched with ε-Viniferin. An HPLC analysis confirmed a high concentration of ε-Viniferin (547.58 ppm) in the cell culture-derived extract. In vitro assays conducted on HaCaT keratinocytes and HDFn fibroblasts demonstrated that the treatment with ε-Viniferin and Vino Chocolate™ significantly enhanced fibroblast migration. ELISA analyses showed that both treatments induced a dose-dependent increase in pro-collagen type I (COL1A1), with ε-Viniferin at 1 ppm demonstrating superior efficacy compared to TGF-β1. Additionally, these compounds notably suppressed the expression of matrix metalloproteinases MMP-1 and MMP-3, displaying effects comparable to or greater than retinoic acid. The Western blot analysis further revealed an increased filaggrin expression in keratinocytes, suggesting an improved epidermal barrier function. Collectively, these results indicate that ε-Viniferin and Vino Chocolate™ effectively promote extracellular matrix remodeling, modulate inflammatory responses, and enhance epidermal barrier integrity. These findings highlight their potential as multifunctional bioactive agents for cosmeceutical applications and emphasize the advantages of plant cell culture technology as a sustainable, innovative platform for advanced skincare ingredient development. Full article

This study aimed to assess the anti-inflammatory properties of mare milk by analyzing immune markers in mice following gavage of mare milk. Metagenomic sequencing was employed to examine variations in the composition and functional profiles of the intestinal microbiota across different experimental groups. Bacterial diversity, abundance, and functional annotations of gut microbiota were evaluated for each group. The results show that, compared to the control group, the mare milk group exhibited a significant decrease in the pro-inflammatory cytokine IL-6 levels and a significant increase in secretory immunoglobulin A (SIgA) levels (p < 0.05). The fermented mare milk group and the pasteurized fermented mare milk group demonstrated a significant downregulation of the pro-inflammatory cytokines TNF-α and IL-1β, along with a significant increase in the anti-inflammatory cytokine IL-10 levels (p < 0.05). Additionally, metagenomic analysis revealed that both the mare milk and fermented mare milk groups were able to regulate the imbalance of the intestinal microenvironment by improving the diversity of the gut microbiota and reshaping its structure. Specifically, the mare milk group enhanced gut barrier function by increasing the abundance of Bacteroides acidifaciens, while the fermented mare milk group increased the proportion of Bacillota and the relative abundance of beneficial bacterial genera such as Faecalibaculum and Bifidobacterium. KEGG pathway annotation highlighted prominent functions related to carbohydrate and amino acid metabolism, followed by coenzyme and vitamin metabolism activities. In conclusion, mare milk and its fermented products demonstrate anti-inflammatory effects, particularly in modulating immune responses and inhibiting inflammatory cascades. Additionally, the administration of mare milk enhances the composition and metabolic activity of intestinal microbiota in mice, supporting intestinal microecological balance and overall gut health, and offering valuable insights for the development of mare milk-based functional foods. Full article

Background: Undergraduate nursing students (UNSs) often enter clinical training just as they are still mastering the emotional labor of the profession. In Nepal, where teaching hierarchies discourage upward dialogue and hospitals routinely struggle with overcrowding, supply shortages, and outward nurse migration, these learners confront a distinct, under-documented burden of psychological distress. Objective: This study examines how UNSs interpret, negotiate, and cope with the mental health challenges that arise at the intersection of cultural deference, resource scarcity, and migration-fueled uncertainty. Methods: A qualitative design employing reflexive thematic analysis (RTA), guided by the Reflexive Thematic Analysis Reporting Guidelines (RTARG), was used. Fifteen second-, third-, and fourth-year Bachelor of Science in Nursing students at a major urban tertiary institution in Nepal were purposively recruited via on-campus digital flyers and brief in-class announcements that directed students (by QR code) to a secure sign-up form. Participants then completed semi-structured interviews; audio files were transcribed verbatim and iteratively analyzed through an inductive, reflexive coding process to ensure methodological rigor. Results: Four themes portray a continuum from silenced struggle to systemic constraint. First, Shrouded Voices, Quiet Connections captures how students confide only in trusted peers, fearing that formal disclosure could be perceived as weakness or incompetence. Second, Performing Resilience: Masking Authentic Struggles describes the institutional narratives of “strong nurses” that drive students to suppress anxiety, adopting scripted positivity to satisfy assessment expectations. Third, Power, Hierarchy, and the Weight of Tradition reveals that strict authority gradients inhibit questions in classrooms and clinical placements, leaving stress unvoiced and unaddressed. Finally, Overshadowed by Systemic Realities shows how chronic understaffing, equipment shortages, and patient poverty compel students to prioritize patients’ hardships, normalizing self-neglect. Conclusions: Psychological distress among Nepalese UNSs is not an individual failing but a product of structural silence and resource poverty. Educators and policymakers must move beyond resilience-only rhetoric toward concrete reforms that dismantle punitive hierarchies, create confidential support avenues, and embed collaborative pedagogy. Institutional accountability—through regulated workloads, faculty-endorsed wellbeing forums, and systematic mentoring—can shift mental health care from a private struggle to a shared professional responsibility. Multi-site studies across low- and middle-income countries are now essential for testing such system-level interventions and building a globally resilient, compassionate nursing workforce. Full article

Background: Freeze tolerance is an uncommon but highly effective strategy that allows certain vertebrates to survive prolonged exposure to subzero temperatures in a frozen, ischemic state. While past studies have characterized the metabolic and biochemical adaptations involved, including cryoprotectant accumulation and metabolic rate suppression, the contribution of post-transcriptional gene regulation by microRNAs (miRNAs) remains largely unexplored. This study investigated freeze-responsive miRNAs in cardiac tissue of the gray tree frog, Dryophytes versicolor, to better understand the molecular mechanisms that support ischemic survival and tissue preservation. Methods: Adult frogs were subjected to controlled freezing at −2.5 °C, and cardiac tissue was collected from frozen and control animals. Total RNA was extracted and analyzed via small RNA sequencing to identify differentially expressed miRNAs, followed by target gene prediction and KEGG pathway enrichment analysis. Results: A total of 3 miRNAs were differentially expressed during freezing, with significant upregulation of miR-93-5p and let-7b-5p and downregulation of miR-4485-3p. Predicted targets of upregulated miRNAs included genes involved in immune signaling pathways (e.g., cytokine–cytokine receptor interaction), steroid hormone biosynthesis, and neuroactive ligand–receptor interaction, suggesting suppression of energetically costly signaling processes. Downregulation of miRNAs targeting cell cycle, insulin signaling, and WNT pathways indicates possible selective preservation of cytoprotective and repair functions. Conclusion: Overall, these results suggest that D. versicolor employs miRNA-mediated regulatory networks to support metabolic suppression, maintain essential signaling, and prevent damage during prolonged cardiac arrest. This work expands our understanding of freeze tolerance at the molecular level and may offer insights into biomedical strategies for cryopreservation and ischemia–reperfusion injury. Full article

Sustainable financial inclusion is an essential factor for economic development, social justice, and environmental sustainability. The primary objective of this bibliometric analysis is to investigate trends in sustainable financial inclusion publications using 1467 Scopus and WoS-indexed documents published between 2007 and 2025. The review visualized major trends, intellectual structures, and thematic clusters using VOSviewer and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) protocol. This analysis identified eight thematic clusters, including digital finance, Environmental, Social, and Governance (ESG) integration, green finance, and financial literacy, which demonstrate the multidimensional nature of the field. Since 2017, research on sustainable financial inclusion has grown, led by China, India, and the USA, revealing geographic imbalances and underrepresentation of the Sub-Saharan Africa and Central Asia regions. Major barriers identified were financial illiteracy and uncoordinated regulations among institutions. This review suggests critical insights for scholars, policymakers, and practitioners should align inclusive finance with the Sustainable Development Goals (SDGs) and advocate for a shift from mere financial access to systemic, sustainability-driven models. It calls for collaboration between decision-makers and financial institutions to foster inclusive, fair, sustainable, and environmentally responsible financial ecosystems. Full article

Hypovirus infection is known to reduce the pathogenicity of Cryphonectria parasitica, the causative agent of chestnut blight. Isoforms derived from a viral protein p48 have been discovered in host mitochondria and vesicles, which may contribute to virulence attenuation, as reported in earlier work using two-dimensional electrophoresis (2-DE). In this study, a total of 1739 fungal proteins were identified in fungal vesicles through Tandem Mass Tag (TMT)-based quantitative proteomics. The infection of CHV1-EP713 was associated with 75 up-regulated and 201 down-regulated proteins, predominantly involved in vesicular transport process and related cellular functions, including protein folding, membrane fusion, retrograde transport, autophagy, and ER stress responses. The down-regulation of calnexin, COPI, ArfGAP, importin-β, and Atg8 is consistent with impairments in protein folding, retrograde transport, and autophagy. Meanwhile, the up-regulation of clathrin, dynamin, Vps10p, HSP70, and t-SNAREs indicated enhanced trafficking to vacuoles and increased stress response activity. Overall, our findings indicate that hypoviral infection is associated with extensive alterations in the vesicular transport system of C. parasitica, likely mediated through changes in the abundance of multiple key protein regulators. These alterations may underlie attenuation of virulence by impacting crucial cellular processes. Full article

In response to the challenges of reduced efficiency and compromised seeding accuracy in conventional soybean planters operating at high speeds, this research introduces a novel precision seeding system powered by an electric drive, aiming to enhance both operational reliability and sowing precision. The entire system is powered by the tractor’s 12 V battery and incorporates an OGWO-Fuzzy PID control strategy to regulate the seeding motor speed. To achieve faster and more accurate regulation of the seeding motor speed, this study employs a ternary phase-diagram-based strategy to optimize the weight allocation among the α, β, and δ wolves within the Grey Wolf Optimization (GWO) algorithm. Based on engineering requirements, the optimal weight ratio was determined to be 16:2:1. Simulation results indicate that the optimized OGWO-Fuzzy PID control strategy achieves a settling time of only 0.17 s with no overshoot. In bench tests, the OGWO-Fuzzy PID control strategy significantly outperformed both GWO-Fuzzy PID and Fuzzy PID in terms of seed-metering speed regulation time and accuracy. The average qualified seeding index reached 95.68%, demonstrating excellent seeding performance at medium-to-high operating speeds. This study provides a practical and technically robust approach to ensure seeding quality during medium–high-speed soybean planting Full article

The global population surge and continuously rising energy demand have led to the rapid depletion of fossil fuel reserves. Over-exploitation of non-renewable fuels is responsible for the emission of greenhouse gases, air pollution, and global warming, which causes serious health issues and ecological imbalance. The present study focuses on the potential of algae-based biofuel as an alternative energy source for fossil fuels. Algal biofuels are more environmentally friendly and economically reasonable to produce on a pilot scale compared to lignocellulosic-derived biofuels. Algae can be cultivated in closed, open, and hybrid photobioreactors. Notably, high-rate raceway ponds with the ability to recycle nutrients can reduce freshwater consumption by 60% compared to closed systems. The algal strain along with various factors such as light, temperature, nutrients, carbon dioxide, and pH is responsible for the growth of biomass and biofuel production. Algal biomass conversion through hydrothermal liquefaction (HTL) can achieve higher energy return on investments (EROI) than conventional techniques, making it a promising Technology Readiness Level (TRL) 5–6 pathway toward circular biorefineries. Therefore, algal-based biofuel production offers numerous benefits in terms of socio-economic growth. This review highlights the basic cultivation, dewatering, and processing of algae to produce biofuels using various methods. A simplified multicriteria evaluation strategy was used to compare various catalytic processes based on multiple performance indicators. We also conferred various advantages of an integrated biorefinery system and current technological advancements for algal biofuel production. In addition to this, policies and market regulations are discussed briefly. At the end, critical challenges and future perspectives of algal biorefineries are reviewed. Algal biofuels are environmentally friendly as well as economically sustainable and usually offer more benefits compared to fossil fuels. Full article

Background: Assistance dogs can support children with autism by improving emotional regulation and social functioning, but access is limited. The Family Dog Service was developed to help families of autistic children gain similar benefits through companion dogs. It offers tailored support for selecting, training, and integrating a dog into the home. This study explored parent perspectives on the service and perceived impacts of companion dogs. Methods: A cross-sectional online survey was conducted among UK residents who attended Family Dog Service workshops. The survey included demographic data, mental health and wellbeing measures, and questions about human–animal interactions. Quantitative data were analysed descriptively; qualitative responses underwent thematic analysis. Results: Of 118 participants, 101 (85.6%) owned a dog, while 17 (14.4%) were considering acquisition. Most owners reported improvements in their child’s mood (75.2%; n = 76) and reduced anxiety-related behaviours (70.3%, n = 71) following dog acquisition. Nearly half (49.5%, n = 50) rated the child–dog relationship as ‘very’ or ‘extremely’ positive within the first month, increasing to 86.1% (n = 87) by the time of data collection. Families also reported enhanced dynamics and reduced caregiver stress. Despite some challenges, the service was valued for its autism-specific guidance and ongoing support. Conclusions: The Family Dog Service may offer a practical, accessible alternative to assistance dogs, supporting autistic children’s wellbeing and strengthening family relationships through positive interactions between children and their dogs. Full article