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关键词： IRF7   Mice   OASL1   PRV   Type I IFNs  

摘要： Pseudorabies virus (PRV) infects various mammals and causes Aujeszky’s disease, posing a significant threat to the pig industry. The interaction between PRV and the host’s innate immune system, however, remains poorly understood. The interferon (IFN)-stimulated gene (ISG), 2’-5’ oligoadenylate synthetase-like 1 (OASL1), possesses antiviral properties and modulates type I IFN production by inhibiting the translation of IFN regulatory factor 7 (IRF7). This study explored the role of OASL1 in the host’s response to pseudorabies virus (PRV) infection using OASL1-deficient (Oasl1^−/−) mice. The results showed that PRV infection significantly increased OASL1 expression in bone marrow-derived dendritic cells, macrophages, and various organs, including the spleen, lung, and brain, of wild-type (WT) mice. In contrast, Oasl1^−/− mice showed significantly milder clinical symptoms and fewer histopathological lesions after PRV infection compared to WT mice, which suffered severe neurological symptoms and succumbed with 100% mortality. Additionally, Oasl1^−/− mice had substantially lower PRV viral loads in the spleen and reduced levels of pro-inflammatory cytokines in multiple organs. Notably, PRV-infected Oasl1^−/− mice demonstrated significantly higher levels of IRF7 protein in the spleen, lung, and brain, accompanied by increased secretion of type I IFNs. Mechanistically, IRF7 knockdown in Oasl1^−/− macrophages reversed the enhanced type I IFN response and restored viral replication, confirming that the antiviral phenotype conferred by OASL1 deficiency is functionally dependent on the IRF7 axis. These findings suggest that OASL1 negatively regulates antiviral immunity against PRV by suppressing IRF7-mediated type I IFN responses. Modulating OASL1 activity may thus represent a promising strategy to bolster host defense against PRV and related viral infections. © The Author(s) 2026.

关键词： Glp-1 receptor agonists   Glucagon-like peptide-1   Pediatric obesity  

摘要： Purpose of Review: The aim of this review is to provide a comprehensive summary of current clinical evidence on the relationship between GLP-1 receptor agonists and pediatric obesity, to evaluate these findings from metabolic and therapeutic perspectives, and to offer potential directions for future research in the field. Recent Findings: Obesity is a chronic disease that threatens health across all age groups, particularly children and adolescents. Lifestyle modification and nutrition-based approaches are regarded as the cornerstone strategies for treating pediatric obesity;however, they have important limitations in achieving sustainable long-term weight loss. This has increased interest in pharmacological treatment options. GLP-1 receptor agonists were originally developed for the treatment of type 2 diabetes mellitus, and they are now among the pharmacological agents with therapeutic indications not only in adults but also in pediatric and adolescent populations. As clinical evidence of their effects on body weight has accumulated, these agents have been incorporated into obesity treatment indications. In current clinical practice, the GLP-1 receptor agonists with approved indications for the treatment of pediatric obesity are liraglutide and semaglutide. Summary: Available evidence indicates that GLP-1 receptor agonists represent a promising pharmacotherapeutic option for the treatment of obesity in children and adolescents. Nevertheless, more comprehensive studies are needed regarding the long-term efficacy, safety profiles, and clinical positioning of these agents. Future research is expected to clarify the role of GLP-1 receptor agonists in the management of pediatric obesity. © The Author(s), under exclusive licence to Springer Nature Switzerland AG 2026.

关键词： 1,2,4-Triazole   Cell migration   FAK inhibition   Indole   Pre-clinical Safety   Triple-negative breast cancer  

摘要： Focal adhesion kinase (FAK) is overexpressed and hyperactivated in triple-negative breast cancer, driving tumor aggressiveness and cancer stem cell–mediated therapy resistance. Therefore, targeting FAK signalling represents a promising therapeutic strategy. In this study, a series of indole and bis-indole-1,2,4-triazoles were synthesized and evaluated as anti-TNBC agents targeting FAK. Compounds 3c, 4c, and 5c displayed potent cytotoxicity (IC₅₀ = 41–77 µg/mL) with minimal toxicity to normal cells, outperforming precursor compound 2. Wound-healing assay revealed significant inhibition of cell migration, particularly by 4c. Cell cycle analysis revealed that 4c induced S-phase arrest in MCF-7 cells and G1-phase arrest in MDA-MB-231 cells, accompanied by significant apoptosis. In MDA-MB-231 cells, 4c triggered extensive total apoptosis (90.84%) with minimal necrosis. Gene expression studies demonstrated that 4c markedly downregulated PTK2 (FAK), CCL5, and BCL2, while upregulating CASP3, highlighting its dual role as FAK inhibitor and apoptosis inducer. Importantly, 4c efficiently suppressed FAK protein expression (61.3%) in TNBC, compared to the FAK inhibitor GSK-2256098 (70.7%). In vivo toxicity assessment confirmed good tolerability in mice without profound hepatic or renal impairments, while docking and ADMET analyses confirmed strong FAK binding affinity, and favourable pharmacokinetics of 4c. Collectively, 4c emerges as a promising FAK-targeted candidate for TNBC therapy. © The Author(s) 2026.

摘要： The last deglaciation provides an opportunity to assess the response of El Niño–Southern Oscillation to rapid warming and disruptions of the Atlantic Meridional Overturning Circulation, both projected in the near future. We present a reconstruction of deglacial El Niño–Southern Oscillation activity using finely laminated sediments from the El Niño–Southern Oscillation-sensitive Peruvian margin. An interannual record of titanium fluxes, a proxy for riverine discharge, shows that the frequency of extreme Eastern Pacific El Niño events and the amplitude of El Niño–Southern Oscillation variability were higher during the deglaciation and peaked during episodes of massive iceberg discharge into the North Atlantic. Maximum El Niño–Southern Oscillation variability occurred in the early phase of Heinrich event 1, at ~17.3–16.7 kyr BP, associated with at least five extreme floods per century in southern Peru. This proxy evidence linking El Niño–Southern Oscillation and the North Atlantic suggests a possible increase in El Niño-related extreme climatic events under future Atlantic Meridional Overturning Circulation weakening. © The Author(s) 2026.

摘要： Background: Malnutrition is a known cause of skin disorders, but the genetic mechanisms linking it to dermal dysfunctions, particularly skin elasticity, are not fully understood. This study aimed to investigate how protein malnutrition (PM) affects the structure of the skin by reducing elastic fiber components and to examine the underlying genetic mechanisms. Methods: We used a non-invasive skin pinch test to assess skin elasticity and conducted gene expression analysis. Mice were divided into a control group (20% casein diet) and a PM group (2% casein diet) and were fed for 28 days. Skin elasticity, histopathological changes, plasma biochemical parameters, and insoluble α-elastin levels were measured. Quantitative Polymerase Chain Reaction (qPCR) was used to analyze the expression of genes related to elastic fiber metabolism, including matrix metalloproteinases (MMPs), lysyl oxidase-like protein 1 (LOXL1), tropoelastin, and fibrillin-1. Results: Skin elasticity in the PM group was significantly impaired by day 7 and worsened until day 28. Histologically, PM induced epidermal thinning and dermal loosening by day 7, which persisted throughout the study. The elastic fibers content significantly decreased in the PM group by day 28. Gene expression analysis revealed that lysyl oxidase-like protein 1 (LOXL1), tropoelastin, and fibrillin-1 were significantly downregulated in the PM group. MMP expression showed minimal changes. Conclusions: These findings suggest that the observed skin structural defects and impaired skin elasticity under PM conditions are primarily caused by a substantial reduction in elastic fibers due to insufficient elastogenesis, rather than increased degradation. © The Author(s) 2025.

关键词： Metabolism prediction   Sites of metabolism   Xenobiotic metabolism  

摘要： Predicting likely sites of metabolism (SOMs), i.e., the atoms in a molecule where metabolic reactions are initiated, is an important component of the computational development pipeline for pharmaceuticals, agrochemicals, and cosmetics. Among SOM prediction tools, FAME3, introduced in 2019, is one of only a few non-commercial models capable of predicting both Phase 1 and Phase 2 SOMs for a wide range of xenobiotics. However, its original implementation posed challenges in maintainability, scalability, and interoperability, which hindered broader adoption. To overcome these limitations, we developed FAME3R, an enhanced version of FAME3 designed to improve computational efficiency and facilitate integration with contemporary cheminformatics workflows. FAME3R introduces several new features, including a novel reliability assessment method based on Shannon entropy and the option to select among various featurization strategies. The tool is available as an open-source Python package, offering both a Python API and a CLI for flexible usage. Additionally, trained FAME3R models can be accessed via a GUI and a REST API hosted on the NERDD web platform. © The Author(s) 2026.

关键词： 1,3-propanediol   Glucose   Glycerol   Klebsiella pneumoniae  

摘要： Background: 1,3-Propanediol (1,3-PDO) is a bulk chemical that can be produced by Klebsiella pneumoniae using glycerol as a substrate. In the 1,3-PDO synthesis pathway, part of the glycerol is oxidised to maintain intracellular NADH balance. Consequently, the theoretical maximum yield of 1,3-PDO from glycerol was lower than 1 mol/mol. Results: In this study, engineered K. pneumoniae strains were constructed to direct all glycerol toward 1,3-PDO synthesis, with NADH being supplied through the catabolism of glucose. However, glycerol utilisation was inhibited in the presence of glucose. To alleviate this carbon catabolite repression (CCR), ptsG and crr were individually knocked out. The dha pathway is responsible for 1,3-PDO synthesis. Key genes in the oxidation branch of this pathway, including dhaK, dhaL, dhaD, and gldA, were knocked out to block this pathway. However, the expression of the dha operon was impaired in these strains, resulting in low 1,3-PDO production. In contrast, knocking out dhaM, which encodes a subunit of dihydroxyacetone kinase II, effectively blocked the glycerol oxidation pathway while maintaining the activity of the dha operon. Additionally, glpK was knocked out to block the sn-glycerol-3-phosphate formation from glycerol. Glucose to glycerol with the ratio of 0.5:1 mol/mol was the optimal value for 1,3-PDO production by K. pneumoniae ∆dhaM∆ptsG∆glpK, leading to a balance of NADH generation and consumption. Microaerobic conditions were favourable for 1,3-PDO production than anaerobic or aerobic conditions. In fed-batch fermentations, this strain produced 58.6 g/L of 1,3-PDO after 70 h, achieving a yield of 0.93 mol/mol glycerol, 2 mol/mol glucose, 0.63 mol/mol substrate. Conclusions: A highly efficient 1,3-PDO production technology that using glycerol and glucose as co-substrates was established. © The Author(s) 2025.

关键词： CO2 methanation   La modification   Low temperature   Ni-based catalyst   TUD-1  

摘要： CO₂ methanation is an important and effective approach to realize carbon resource recycling and mitigate the greenhouse effect. However, designing low-cost, highly active catalysts for low-temperature CO₂ activation remains a major challenge. Herein, we prepared a La-modified Ni/TUD-1 catalyst for CO₂ hydrogenation to methane. The 5% La-Ni/TUD-1 catalyst exhibited a CO₂ conversion of 64% and CH₄ selectivity of 99% at 225 °C, 2.0 MPa, and GHSV of 3600 mL·g_cat⁻¹·h⁻¹, which is far superior to traditional Ni-based catalysts. Structural characterizations confirm that TUD-1 increases the specific surface area of the catalyst while maintaining a moderately strong interaction between Ni and the support, thus promoting the dispersion of active metallic Ni species. More importantly, the incorporation of La not only enhances H₂ dissociation and CO₂ adsorption capacities, but also improves the electron transfer efficiency at the La-Ni/TUD-1 interface. In-situ DRIFTS results showed that CO₂ methanation follows the HCOO* and CO₃* pathways. This study demonstrates that controlling the morphology and structure of the support, as well as rationally selecting modifiers, can improve catalytic performance by optimizing the dispersion of active components and regulating electronic interactions. It provides a key reference for the design and synthesis of highly active Ni-based CO₂ methanation catalysts.

关键词： Obstructive sleep apnea   Chronic kidney disease   Kidney injury molecule-1   Glomerular filtration rate   Albumin   creatinine ratio  

摘要： Purpose Obstructive sleep apnea (OSA) increases the risk of chronic kidney disease (CKD) through exposure to nocturnal hypoxemia. Elevated urine Kidney Injury Molecule-1 (KIM-1) can reflect kidney injury before conventional measures of CKD [estimated glomerular filtration rate (eGFR) and urine albumin: creatinine ratio (ACR)] become abnormal. We investigated if urine KIM-1 is elevated in patients with OSA and if this is associated with an increased estimated risk of CKD progression. Methods Adults (n = 1271) completed diagnostic OSA testing and quantification of eGFR, ACR and KIM-1. OSA severity and nocturnal hypoxemia were quantified using the oxygen desaturation index (ODI, 4%), mean oxygen saturation (SpO(2)), and the duration of SpO(2) < 90% (T90). Mean KIM-1 concentrations were compared between patients with no/mild (ODI < 15), moderate (15 <= ODI <= 30) and severe OSA (ODI > 30) and the associations between urine KIM-1 and nocturnal hypoxemia with the estimated risk of CKD progression were assessed. Results In the entire cohort, participants with severe OSA (n = 411) had higher KIM-1 than the no/mild (n = 545) and moderate OSA (n = 315) groups (all comparisons, p <= 0.047). KIM-1 was positively associated (standardized beta;95% CI) with ODI (0.11;0.05-0.17) and T90 (0.12;0.06-0.18) and negatively associated with mean SpO(2) (-0.14;-0.21--0.08). Similar relationships were found in a sub-group of participants (n = 976) with normal eGFR and ACR. Higher KIM-1 was also associated with an increased estimated risk of CKD progression. Conclusion OSA-related hypoxemia is associated with increased urine KIM-1, reflecting kidney injury, both after and, more importantly, before eGFR and ACR become abnormal. Furthermore, elevated KIM-1 is associated with an increased estimated risk of CKD progression.

摘要： Cardiac ischemia‒reperfusion (I/R) injury is a leading cause of disability and mortality worldwide, but the underlying mechanism remains largely unknown. Despite the emerging recognition of circular RNAs (circRNAs) as pivotal regulators of cardiac development and disease, their roles in cardiac I/R injury have yet to be thoroughly investigated. In this study, we identified a circRNA named circArhgap26, which is regulated by m6A modification. The expression of circArhgap26 was significantly decreased in the I/R myocardium. Cardiac-specific overexpression of circArhgap26 ameliorated cardiac dysfunction and reduced the infarct area and cardiomyocyte apoptosis in I/R model mice. Mechanistically, circArhgap26 directly bound to PKP1, thereby inhibiting the interaction between PKP1 and the palmitoyltransferase ZDHHC1. The subsequent palmitoylation of PKP1 and its protein stability are subsequently diminished, leading to a reduction in APAF1 protein synthesis and the inhibition of the Caspase-9/Caspase-3 signaling pathway, thereby mitigating cardiomyocyte apoptosis. Most importantly, the expression of circArhgap26 in the plasma of patients undergoing percutaneous coronary intervention (PCI) was decreased. This study not only elucidates the dual regulatory mechanisms of circArhgap26, m6A modification and posttranslational modification (palmitoylation), in combating I/R injury but also provides a theoretical foundation for circRNA-based therapies. Its dual value as a prognostic biomarker and therapeutic target holds promise for advancing precision cardiovascular medicine and improving outcomes in globally prevalent I/R-related diseases. © The Author(s) 2026.