Search Results (1,331)

Replication stress (RS) represents a major vulnerability of cancer cells treated with nucleoside analogs and related antimetabolites; however, tumors frequently acquire tolerance mechanisms that permit survival despite persistent DNA lesions. This review examines molecular determinants of RS tolerance, focusing on human T-cell leukemia virus type 1 (HTLV-1)-mediated adult T-cell leukemia/lymphoma (ATL) as a model of virus-mediated rewiring of DNA damage responses. Chain-terminating nucleoside analogs generate aberrant replication intermediates, including blocked 3’ DNA termini, mis-incorporated bases, and stalled replication forks. In ATL, viral oncoproteins suppress key components of replication stress response pathways, notably tyrosyl-DNA phosphodiesterase 1 (TDP1) and mismatch repair (MMR), thereby creating exploitable repair deficiencies. Consistent with this vulnerability, ATL cells exhibit marked sensitivity to replication stress–inducing agents such as irinotecan (CPT-11) and the chain-terminating nucleoside analog abacavir. Recent CRISPR-based functional genomics studies further identify Schlafen 11 (SLFN11) as an independent and dominant regulator of RS sensitivity. SLFN11 determines the fate of stressed replication forks independently of lesion processing, acting as an execution factor that converts otherwise tolerable RS into irreversible replication arrest. We conclude by discussing therapeutic strategies that exploit RS tolerance defects in ATL, including biomarker-guided nucleoside analog therapy, and rational combination approaches targeting compensatory RS pathways. Full article

The cold supply chain (CSC) reverse logistics segment remains underexplored in the risk assessment literature. Existing frameworks apply traditional failure mode and effects analysis (FMEA) with a three-criterion structure (severity, occurrence, detectability), which inadequately captures the time-sensitive and cost-intensive risk environment of CSC reverse logistics. This study proposes an integrated framework combining hazard analysis and critical control points (HACCP)-based node partitioning, an extended five-criterion FMEA incorporating timeliness and economic cost, triangular interval-valued fuzzy number (TIVFN) aggregation via the Aczél–Alsina operator, and cumulative prospect theory (CPT) to prioritize risk modes. Applied to a food-sector reverse CSC, 16 failure modes were identified across six HACCP-based process nodes. Severity and economic cost jointly account for 47.5% of total criterion weight. Monitoring and data management (node P6) consistently emerge as the dominant risk cluster, with data completeness (FM14), sensor accuracy (FM15), and early-warning functionality (FM16) occupying the top three positions across all weight scenarios. Relative to conventional models and the extended RPN, the TIVFN-CPT model assigns FM16 a substantially higher priority, demonstrating that CPT captures asymmetric, loss-averse risk perception that conventional methods fail to encode. Sensitivity analysis across five weight scenarios confirms the structural robustness of the rankings. By extending FMEA to a five-criterion behavioral framework and introducing TIVFNs as an uncertainty-preserving linguistic scale, this study indicates that information quality constitutes a risk factor of comparable priority to physical temperature maintenance, supporting a tiered resource allocation strategy that prioritizes investment at node P6 and targeted upgrades at nodes P1 and P4. Full article

Background: Obesity is a metabolic disorder characterized by excessive lipid accumulation, disrupted fatty acid homeostasis, and gut microbiota dysbiosis. Zanthoxylum bungeanum essential oil (ZBO) is a natural plant volatile oil with diverse bioactivities, but its anti-obesity effects and potential associations remain unclear. Methods: HFD-induced obese (DIO) mice were evaluated to determine the effects of ZBO. Physiological parameters, glucose tolerance, and serum biochemical markers were assessed. Potential correlates were explored using a multi-omics approach, including integrated serum untargeted metabolomics, 16S rRNA gene sequencing, and RT-qPCR analysis of key genes involved in lipid metabolism in the liver and white adipose tissue. Results: ZBO significantly mitigated HFD-induced body weight gain, visceral adiposity, hepatic steatosis, dyslipidemia, and glucose intolerance. Metabolomics indicated that ZBO administration was associated with alterations in the serum metabolic landscape, particularly in pathways related to fatty acid metabolism and AMPK/PPAR-α signaling. Consistently, ZBO treatment was associated with upregulated mRNA expression of lipid-oxidizing genes (AMPK, PPAR-α, CPT1) and downregulated lipogenic genes (SREBP-1c, ACC, FAS, SCD1, LPL). 16S rRNA sequencing suggested that ZBO was associated with increased gut microbial diversity, decreased the Firmicutes/Bacteroidota ratio, and enriched beneficial taxa (e.g., Ligilactobacillus, Alistipes) while suppressing pro-inflammatory genera. Correlation analysis established robust associations between ZBO-modulated microbes and key fatty acid metabolites, particularly acylcarnitines and AMPK/PPAR-α-related intermediates. Conclusions: Collectively, these multi-omics data suggest that ZBO administration is associated with remodeling of the gut microbiota and correlated changes in fatty acid metabolic pathways. These findings provide preliminary preclinical evidence supporting further investigation of ZBO in the context of dietary strategies for alleviating HFD-induced obesity. Full article

Obesity is a multifactorial metabolic disorder characterized by dysregulated energy homeostasis, impaired lipid metabolism, and altered hypothalamic appetite signaling. This study aimed to evaluate the anti-obesity effects and underlying mechanisms of a 95% ethanol extract of Artocarpus integer stem bark in a high-fat diet (HFD)-induced obese rat model. Obesity was induced in male Wistar rats using HFD feeding, followed by treatment with the extract (200–800 mg/kg/day, oral). Semaglutide and resveratrol were used as reference compounds. Body weight, food intake, adiposity, serum lipid profile, adipokines, histological changes, and gene expression related to lipid metabolism (Fas, Pparγ, Cpt-1, AdipoR1) and hypothalamic appetite regulation (Pomc, Mc4r, Npy) were evaluated. Phytochemical profiling was performed using LC–HRMS. The extract markedly reduced body weight gain, visceral adiposity, and food intake compared with the HFD control (p < 0.05), with the high-dose extract demonstrating a substantial weight-reducing effect that approached the magnitude of semaglutide. Treatment improved dyslipidemia by decreasing total cholesterol and triglycerides while increasing HDL levels. Adipokine imbalance was restored, as evidenced by reduced leptin and amylin and increased adiponectin levels. At the molecular level, the extract downregulated lipogenic genes (Fas, Pparγ), partially restored Cpt-1 expression, and normalized AdipoR1. In the hypothalamus, Pomc and Mc4r were upregulated, whereas Npy was suppressed. LC–HRMS analysis revealed the presence of stilbene, chalcone, and flavonoid derivatives. In conclusion, A. integer stem bark extract exerts anti-obesity effects through coordinated modulation of appetite signaling and lipid metabolism, supporting its potential as a multi-target phytotherapeutic agent for obesity management. Full article

Background: This narrative concept-generating review proposes a theoretical and heuristic framework for conceptualizing established and emerging interventions for posttraumatic stress disorder (PTSD) including three categories: top-down/conscious (e.g., cognitive processing therapy, CPT), bottom-up/non-conscious (e.g., pharmacotherapy) and hybrid/conscious and non-conscious integration (e.g., eye movement desensitization and reprocessing, EMDR). The categorization offers a preliminary novel classification of well established and emerging interventions, while highlighting gaps in current treatment approaches. Methods: Clinical guidelines and review articles from 2008 through 2026 were used to create the framework; PubMed and Google Scholar databases were searched for relevant meta-analyses, systematic reviews, narrative reviews, and randomized clinical trials. A total of 27 treatment modalities were included presenting effect size data from 43 published articles. Results: Treatments across categories present mixed results for efficacy. While guideline recommended treatments offer more robust evidence, many understudied emerging interventions exhibit preliminary efficacy. At the intersection of conscious and non-conscious approaches, hybrid modalities may present unique potential benefits. However, superiority determinations between modalities cannot be made and further empirical validation of categorization is needed. Conclusions: The proposed framework highlights the need for increased investigation of treatments that address PTSD as an interconnected whole-body disorder to potentially expand care options. Full article

Sperm activation and movement are essential in freshwater fishes, where limited energy reserves and a short motility duration require rapid ATP-driven motility regulated by osmolality and ions. However, the physiological and molecular mechanisms underlying osmolality and ion regulation in mandarin fish (Siniperca chuatsi) remain unclear, and ions in aquaculture systems may exert additional effects. Here, we integrated physiology with transcriptomic and proteomic analyses to characterize the effects of osmolality and ions on sperm motility and identify key genes, proteins, and regulatory networks involved in sperm activation and movement. Low osmolality (<50 mOsm/kg) promoted sperm activation, with sperm motility progressively decreasing as osmolality increased. Although relatively high osmolality supported motility maintenance, the initial motility was comparatively low, indicating the limited energy reserves of freshwater fish spermatozoa. Na⁺ and K⁺ activation media enhanced motility, whereas Ca²⁺ supplementation suppressed activation. Ca²⁺ levels below a 1:500 molar ratio (<0.06 mM) did not significantly affect sperm motility, indicating the importance of limiting Ca²⁺ exposure during fertilization. Multi-omics analyses identified six differentially expressed genes, including grin3bb, cacna1c, and chrna7, and 35 differentially expressed proteins, including ATP1B, PRKCB, and CPT1A, as key molecules associated with Na⁺, K⁺, and Ca²⁺ signaling and energy metabolism. The calcium signaling pathway, cAMP signaling pathway, and oxidative phosphorylation were significantly enriched in KEGG enrichment analysis, while Gene Ontology (GO) enrichment analysis identified ion signaling and energy metabolism, including ion transport, the ATP metabolic process, and the glycolytic process. Our findings provide a putative regulatory network for sperm activation and movement in mandarin fish and a basis for optimizing artificial fertilization. Full article

Existing runway incursion risk approaches can estimate risk under specified conditions but have limited ability to represent how runway protection constraints weaken across operational stages. This study develops an integrated System-Theoretic Process Analysis (STPA)–Dynamic Bayesian Network (DBN) framework to examine how safety-constraint degradation propagates across predefined operational stages toward runway incursion risk. A Dynamic Causal Translation Logic (DCTL) provides principle-guided organization of STPA-derived artifacts into a traceable single-slice Bayesian Network (BN), which is subsequently extended across semantic stages through selected inter-slice transitions and sequential evidence updating. The model was parameterized using 66 manually coded runway incursion-related reports from the Aviation Safety Reporting System (ASRS). Intra-slice conditional probability tables (CPTs) were estimated and calibrated from these reports, while transition CPTs used expert-informed first-order Markov assumptions. The 2023 runway incursion event at John F. Kennedy International Airport (JFK) was used as a single case-informed demonstration of staged inference and does not constitute independent or cross-case validation. Posterior updating indicated weakened unobserved monitoring and verification constraints, higher unsafe control action likelihood, and sustained tendencies toward runway occupancy conflict and Category B severity. Scenario-based analysis showed that alternative safety-constraint states produced distinct local changes in downstream hazard and Category B posterior probabilities under their respective stage-specific conditioning settings. The framework supports tracing safety-constraint degradation and stage-specific runway safety management. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent liver disease associated with insulin resistance and hepatic lipid accumulation. Polyphenols have attracted considerable attention for their hepatoprotective and lipid-lowering activities. Our previous studies characterized a bound polyphenol extracted from the inner shell of foxtail millet (BPIS) and identified its major active components. In the present study, we investigated the molecular mechanisms underlying its biological activity using HepG2 cells and Caenorhabditis elegans. BPIS activated AMPK signaling, normalized intracellular glutathione (GSH) levels, and upregulated SLC7A11 and GPX4, suggesting modulation of ferroptosis-related pathways and improved cellular redox homeostasis. BPIS also alleviated endoplasmic reticulum stress by increasing GRP78 expression, inhibiting DRAK2, and regulating the ERK pathway, thereby improving the regulation of key lipid-metabolism-related signaling pathways, including SREBP1c, SCD1, CD36, FASN, and CPT1A. Consistent with these findings, BPIS reduced glucose- and free fatty acid-induced lipid accumulation and improved lipid-related phenotypes in C. elegans. Overall, BPIS attenuated hepatic steatosis through modulation of ferroptosis-related markers, endoplasmic reticulum stress, and lipid metabolism. These findings provide new mechanistic insights into the biological activities of BPIS and support its potential application as a nutraceutical ingredient for the prevention and management of MASLD. Full article

Background: Immunometabolic reprogramming is increasingly recognized as a fundamental driver of macrophage inflammatory activation. Although pomegranate polyphenols have been widely investigated for their anti-inflammatory activity, the underlying metabolic mechanisms remain poorly understood. Here, we investigated whether a pomegranate waste extract (PWE), obtained through a sustainable dimethyl carbonate (DMC)-based extraction process, modulates macrophage activation by targeting immunometabolic pathways. Methods: Human PBMC-derived macrophages stimulated with LPS and IFN-γ were treated with PWE. Inflammatory mediators, NF-κB transcription factor, histone H3 acetylation, and markers of inflammatory resolution were evaluated. Furthermore, the enzymatic activity of ATP citrate lyase (ACLY) and malic enzyme 1 (ME1) was determined. Rescue experiments with acetate, malate, and NADPH were performed to investigate the functional contribution of the ACLY–ME1 metabolic axis. Results: PWE significantly reduced NF-κB activation and the production of IL-1β, IL-6, TNF-α, ROS, NO•, and PGE₂ without affecting cell viability. Mechanistically, PWE functionally suppressed ACLY and ME1, two central enzymes linking citrate metabolism to cytosolic acetyl-CoA and NADPH generation. Indeed, acetate supplementation restored PGE₂ production and inflammatory cytokine secretion, whereas malate and NADPH rescued oxidative mediator production. PWE also lowered histone H3 acetylation, indicating that metabolic remodeling affected epigenetic regulation of inflammatory gene expression. Finally, PWE increased the expression of CPT1A, SLC25A20, Annexin A1, and FPR2, while enhancing IL-10 and 15-HETE secretion, consistent with activation of pro-resolving macrophage programs. Conclusions: These findings demonstrate that DMC-extracted PWE suppresses inflammatory macrophage activation primarily through immunometabolic modulation. By targeting the ACLY–ME1 metabolic axis, PWE limits acetyl-CoA- and NADPH-dependent inflammatory processes and fosters a shift toward a pro-resolving macrophage phenotype. Our work identifies this sustainable pomegranate waste extract as a promising modulator of macrophage immunometabolism. Full article

Astragalus membranaceus (AM) has been reported to support immune function, but its epigenetic mechanism on immune restoration of cyclophosphamide (CTX)-induced immunosuppression remains unclear. To evaluate the recovery of immune function, we assessed the injury of splenic pathology, cytokines levels in serum, proportional changes in CD4⁺ and CD8⁺ T cells, and the recall response of Hspx-specific T cell. In addition, to define the underlying epigenetic regulatory mechanism, we measured the expression levels of DNA methyltransferases (Dnmt1, Dnmt3a and Dnmt3b) and the methylation status of the Carnitine palmitoyltransferase 1A (Cpt1a) gene. The results showed that the crude extract of AM repaired the immunosuppression induced by CTX. This is reflected in the alleviation of splenic pathological injury, the elevated proportions of CD4⁺ and CD8⁺ T cells, and the increased levels of serum IL-2 and IFN-γ. The crude extract of AM also enhanced the recall response of Hspx-specific CD8⁺ T cells; that is, the frequencies of the resulting IL-2⁺ and IFN-γ⁺ cells were significantly higher than those in the CTX + Vaccine group. All these results indicate that the adaptive immune response induced by the crude extract of AM is significantly enhanced. On the other hand, AM crude extract reversed the CTX-induced downregulation of Dnmt3a mRNA and restored CpG methylation of Cpt1a gene to a level comparable to the vaccine group at molecular level. Consistent with the elevated CpG methylation, CTX-induced upregulation of Cpt1a mRNA was also reduced. These findings reveal that AM extract enhances the antigen-specific functional recall responses of CD8⁺ T cells in immunosuppressed mice were associated with Cpt1a gene methylation, thereby establishing a translational link between traditional herbal medicine and modern epigenetics. Full article

This study evaluates operational optical to near-infrared (NIR) band (400–1050 nm) atmospheric transmittance simulation at the Ali-CPT site (5250 m above sea level). Monthly mean profiles from a 20-year Modern-Era Retrospective Analysis for Research and Applications, Version 2 (MERRA-2) reanalysis were combined with precipitable water vapor (PWV) constraints from the POM-02 sun photometer and validated against DTF-8 sun photometer measurements under fixed aerosol parameters (visibility of 75 km, Clean Continental mode). Mode 1 used real-time lidar extinction profiles; Mode 2 used built-in aerosol modes scaled by aerosol optical depth (AOD). Both modes achieved correlation coefficients greater than 0.93. Mode 1 showed root mean square errors (RMSEs) of 0.034–0.040 in the 400–870 nm range, while Mode 2 exhibited a systematic negative bias (RMSE 0.040–0.052) due to the mismatch between the fixed visibility assumption and the much cleaner winter conditions. The errors in the 940 nm water vapor absorption band were dominated by the vertical structural deviation of the MERRA-2 water vapor profile during high-PWV summer conditions. The results confirm the feasibility of reanalysis-based operational transmittance simulation at data-sparse high-altitude sites. Full article

Objectives: This study focuses on exploring the mechanism by which Schisandrin B (Sch B) regulates metabolic dysfunction-associated steatotic liver disease (MASLD) mice induced by a high-fat methionine–choline-deficient (MCD) diet through the activation of peroxisome proliferator-activated receptor γ (PPARγ). Methods: Male C57BL/6 mice were fed a high-fat MCD diet for 8 weeks to establish a mouse MASLD model, and the effects of Sch B on MASLD and the mechanisms were investigated. PPARγ overexpression (OE) was induced by adeno-associated virus (AAV) administration via intrahepatic portal vein injection in mice, and a negative control (NC-OE) was also established. Body weight; wet liver weight; hepatic index; serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β); and hepatic triglyceride (TG) levels were measured in the mice. The histopathology and lipid deposition were observed by hematoxylin and eosin (H&E) staining and Oil Red O staining, while the fibrosis was assessed using Masson staining. Western blot was employed to detect the expression levels of PPARγ, sterol regulatory element-binding protein 1c (SREBP-1c), carnitine palmitoyltransferase 1A (CPT1A), transforming growth factor β1 (TGF-β1), α-smooth muscle actin (α-SMA), collagen type I (collagen I), Smad family members 2/3 (Smad2/3), c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (p38), and extracellular signal-regulated kinase 1/2 (ERK1/2), along with the phosphorylation activation status of these kinases. Results: It was confirmed that Sch B caused effects similar to those induced by PPARγ overexpression, reducing the hepatic index, AST, and ALT levels while alleviating lipid accumulation and fibrosis; and upregulating PPARγ and CPT1A while inhibiting SREBP-1c; and the phosphorylation of the TGF-β/Smad and MAPK pathways were involved in the mechanisms. Conclusions: Sch B can alleviate high-fat MCD-induced MASLD by activating PPARγ in mice. Full article

The rice field eel (Monopterus albus) is an economically important aquaculture species widely distributed in Southeast Asia. However, the lack of nationally approved varieties and the increasing demand for high-quality eel products have highlighted the necessity of developing improved germplasm resources for aquaculture production. In this study, morphometric morphology and muscle texture traits were evaluated in 367 wild eel individuals, and a genome-wide association study (GWAS) based on whole-genome resequencing was conducted to identify genetic variants and candidate genes associated with economically important traits, including body length (BL), tail length (TL), tail height (TH), head length (HL), head width (HW), head height (HH), hardness, chewiness, springiness, and resilience. The GWAS identified three significant and seventeen suggestive SNPs associated with body shape traits, with most loci located on chromosome 4. Candidate gene analysis of the associated genomic regions revealed several candidate genes potentially associated with growth regulation, nutrient metabolism, and skeletal development, including b4galnt4a, tmem86a, cpt1b, mrpl23, lama1, gcm2, wnt3a, thrab, and bmpr1a. Additionally, four suggestive SNPs associated with muscle texture traits were detected, and candidate genes related to muscle development and extracellular matrix regulation, including fstl1b, col5a3a, and pnn, were identified. These findings provide new insights into the genetic basis underlying morphometric variation and muscle texture diversity in M. albus. The identified SNP markers and candidate genes provide potential molecular resources for understanding the genetic basis of body morphology and muscle texture variation in rice field eel. Full article

This paper presents a numerical analysis of liquefaction-induced lateral spreading at Brest Pokupski in Croatia, observed during the 2020 M_w6.4 Petrinja earthquake. The site is composed of Holocene alluvial deposits consisting of loose to medium-dense sands, silty sands, and sandy silts with high groundwater levels, locally confined by low-permeability cohesive layers, which together created favourable conditions for excess pore pressure generation, liquefaction and lateral spreading. During the 2020 Petrinja earthquake, the area experienced large-scale ground failures, including widespread soil deformations, sand ejecta, ground cracking and settlement, making it one of the most prominent manifestations of earthquake-induced liquefaction in the affected region. The study applies dynamic analyses using the advanced constitutive models and soil parameters derived from laboratory tests and CPT investigations. The model simulates excess pore water pressure development and resulting ground deformations, with displacements evaluated at advanced stages of dissipation. During the dissipation phases, the model exhibits a high sensitivity to hydraulic conductivity, which may be attributed to slight residual numerical imbalances at the end of shaking. Consequently, scaling factors of 100 and 1000 result in horizontal displacements of approximately 20–30 cm and 60–70 cm, respectively, within the liquefiable layer. Trends of ground displacement with distance along the profile, however, remain consistent regardless of the applied scaling factors, and can therefore be used in conjunction with displacement measurements to assess the response. Numerical results are used in conjunction with InSAR observations from the European Ground Motion Service (EGMS) and geodetic benchmark measurements to assess the displacement field changes along the profile. The comparison from two points showed a shift in the displacement direction towards the river by about 14^∘. Full article

Newborn screening (NBS) for inborn errors of metabolism is challenged by high false-positive rates, which may lead to parental anxiety and increased healthcare costs associated with diagnostic follow-up. False-positive results often arise from changes in metabolite concentrations that mimic metabolic disorders as a consequence of differences in perinatal factors or nutritional status. To address this, Collaborative Laboratory Integrative Reports (CLIR) and the associated post-analytical tools (PATs) using multivariate interpretation and covariate-adjusted reference intervals may be used to improve specificity of NBS algorithms. In the current study, we examined whether CLIR can be applied to optimize the Dutch NBS program by reducing the false-positive rates. We developed and validated a CLIR-based PAT for CPT1 deficiency, GA-I, IVA and MSUD within the Dutch NBS program. Single-condition tools (SCTs) and multivariate approaches, including marker ratios and covariate adjustments, were evaluated for their ability to discriminate true- and false-positive referrals. For CPT1 deficiency, age-adjusted SCT combined with birthweight, location correction, and the C18:1/methionine ratio substantially reduced false positives. For GA-I, C3DC-based ratios improved specificity while preserving true-positive detection, potentially reflecting postnatal renal immaturity in some cases. For IVA, the dual scatter plot fully separated true- and false-positive referrals, highlighting the limitations of single-marker screening. For MSUD, differences between false-positive and true-positive cases were more pronounced, yet a similar number of false positives were still referred; valine-related markers contributed to false positives, while leucine and the Xle/Phe ratio better identified true positives. CLIR-based post-analytical tools enhanced NBS specificity through covariate-aware, multivariate interpretation. This provides important input for decision makers in both the Dutch NBS, as well as the NBS community worldwide. Full article