Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are effective therapies for type 2 diabetes (T2D) and obesity, yet patient responses are variable, with GLP1R gene variation potentially linked to therapeutic outcomes. A GLP1R natural missense variant, A316T, protects against T2D and cardiovascular disease. Here, we generated and characterized a human GLP1R A316T mouse model. Human GLP1RA316T/A316T mice displayed lower fasting blood glucose versus wild-type littermates even under metabolic stress, as well as slower weight gain and alterations in islet cytoarchitecture, glucagon secretion, and liver metabolism under a high-fat, high-sucrose diet. This was however associated with blunted responses to pharmacological GLP-1RAs in vivo. Further investigations in β cell models demonstrated that human GLP1R A316T exhibits characteristics of constitutive activation but dampened GLP-1RA responses. Results are further supported by cryo-EM analyses and molecular dynamics simulations of GLP-1R A316T structure, collectively demonstrating that the A316T variant governs basal GLP-1R activity and pharmacological responses to GLP-1R-targeting therapies.

Accurate severity assessment is crucial in acute cholecystitis, yet commonly used inflammatory markers such as C-reactive protein, white blood cell count, and bilirubin have limited predictive accuracy. The triglyceride-glucose (TyG) index has emerged as a potential biomarker reflecting metabolic stress and inflammation. This retrospective observational study included 134 patients admitted with acute cholecystitis between 2020 and 2024. Disease severity was classified according to the Tokyo Guidelines 2018, and patients were grouped as non-severe (mild-moderate) or severe. Laboratory parameters obtained at admission were analyzed, and the TyG index was calculated as ln (fasting triglyceride × fasting glucose/2). Univariate and multivariable logistic regression analyses and receiver operating characteristic curve analysis were performed. Of the 134 patients, 26 (19.4%) had severe acute cholecystitis. Median fasting glucose (P = .031) and TyG index values (P = .029) were higher in the severe group, while triglycerides, C-reactive protein, white blood cell count, and bilirubin showed no significant differences. The TyG index was associated with severe disease in univariate analysis (odds ratio: 1.62; 95% confidence interval: 1.05-2.49; P = .028), but not after multivariable adjustment (P = .17). Receiver operating characteristic analysis demonstrated an area under the curve of 0.79 (95% confidence interval: 0.71-0.87; P < .001), with an optimal cutoff value of 8.8 (65% sensitivity, 80% specificity). The TyG index was higher in patients with severe acute cholecystitis and demonstrated moderate diagnostic performance. Although not independently associated with disease severity after adjustment, it may serve as an adjunctive marker for early risk stratification, warranting further prospective validation.

Toxic dinoflagellate blooms and microplastics are widespread coastal pollutants. In this study, the scallop, Argopecten irradians, was selected as an experimental organism to systematically investigate the single and combined toxic effects of polystyrene (PS) and the toxic dinoflagellate, Alexandrium pacificum. The results showed that both PS and algal cells could be ingested by A. irradians. The survival rate of A. irradians remained above 90% in both the single and combined treatment groups, indicating that 1 mg/L PS and 1500 cells/mL A. pacificum cells did not pose a serious threat to scallop survival in the short term. However, CAT, SOD, and GSH-ST activities, as well as MDA content, were all elevated in the combined treatment group. Transcriptomic analysis further revealed that A. pacificum primarily affected immune-related pathways, whereas PS might interfere with endocrine function through the release of additives. Combined exposure to PS and A. pacificum induced more complex synergistic effects, reflected in the metabolic stress of exogenous substances, and the disruption of developmental and homeostasis regulatory pathways. This study provides important theoretical support for assessing the threats posed by composite coastal pollution to aquaculture and marine ecological security.

Potato mop-top virus (PMTV) is a significant pathogen causing potato "spraing" disease worldwide. The PMTV 8K protein functions as a weak viral suppressor of RNA silencing (VSR), has viroporin activity and plays a role in pathogenicity by promoting viral long-distance movement and modulating host responses. Uniquely, PMTV can establish systemic infection in the absence of the 8K protein, though the infection is slightly delayed. To elucidate the molecular mechanisms underlying PMTV-host interactions, we conducted comprehensive RNA-seq analysis comparing wild-type PMTV with a mutant lacking the 8K gene (PMTV-Δ8K) in Nicotiana benthamiana. Our transcriptomic analysis shows that wild-type PMTV and PMTV-Δ8K elicit largely distinct transcriptional responses in the host, with more unique than shared differentially expressed genes. The analysis also revealed extensive reprogramming of metabolic pathways, stress responses, and defense mechanisms. Notably, wild-type PMTV induced more defense-related transcription factors, including 27 WRKY genes compared to 8 in PMTV-Δ8K infections. RNA silencing pathway genes displayed distinct expression patterns, with AGO2, RDR1, and AGO-MEL1 showing notably enhanced upregulation (up to 9.7-fold) in PMTV-Δ8K infections. Functional analysis identified chloroplast-associated genes GNS2, CHUP1, and KIN5l as host restriction factors. Virus-induced gene silencing experiments confirmed that GNS2 and CHUP1 restrict viral accumulation under both infection scenarios (wild-type PMTV and PMTV-Δ8K), while localization studies revealed that TGB2 protein and GNS2 co-localize at chloroplast structures. These findings provide insights into PMTV pathogenesis, suggest that 8K is a multifunctional protein operating through diverse mechanisms, and advance understanding of viral suppression strategies.

Continuous lactate monitoring is critical for early detection and management of sepsis, shock, and metabolic stress, yet current serum assays remain invasive, intermittent, and resource-intensive. We present a clinical evaluation of a minimally invasive microneedle-based electrochemical biosensor for real-time interstitial fluid (ISF) lactate monitoring. The microneedle biosensor features a platinum working electrode modified with a lactate oxidase reagent layer and a polyvinyl chloride anti-fouling membrane for H2O2-mediated amperometry, toward highly selective and stable ISF lactate detection. In a pilot study of twenty-one participants across an intensive care unit, emergency department, cardiopulmonary exercise testing, and controlled laboratory settings, two enzyme-based microneedle sensors placed on the forearm and thigh continuously tracked lactate for 4 h. Sensor performance demonstrated strong agreement with blood lactate assays (r = 0.94), high diagnostic accuracy for hyperlactatemia (>4 mmol/L; receiver operating characteristic analysis, area under the curve = 0.95), and minimal bias (-0.028 mmol/L) over a wide dynamic range (0.7-22.9 mmol/L) with high selectivity against interferents. No significant ISF-blood differences (p > 0.05) or adverse events were observed. These findings establish microneedle biosensors as a promising platform for precision medicine, with considerable potential to transform sepsis care, guide resuscitation, and improve assessment of exertional dyspnea.

Stress response of Carcinoscorpius rotundicauda eggs to Bacillus thuringiensis contamination in tropical coast of Peninsular Malaysia.

Frailty, a hallmark of systemic vulnerability in aging populations, is increasingly recognized in the clinical management of chronic respiratory diseases (CRDs). Molecular mechanism underpinning the relationships remain insufficiently elucidated. This study hence aimed to investigate whether proteomic biomarkers-circulating plasma proteins reflecting systemic inflammation, metabolism, and tissue remodeling-are associated with CRDs and may serve as potential mediators of the observed links. We analyzed data from a population-based cohort of 22,802 adults with proteomic measurements. Frailty was assessed by three phenotypes, including frailty index, physical frailty, and psychological frailty. Related-proteomic signatures were estimated by both linear and elastic regression models. Cox regression models were applied to explore the associations of frailty phenotypes and their proteomic signatures with incident CRDs, including asthma, chronic obstructive pulmonary disease (COPD), and idiopathic pulmonary fibrosis(IPF), as well as lung function outcomes, with full adjustments for potential confounders. Furthermore, mediation analyses were conducted to explore underlying mechanisms, complemented by pathway enrichment analyses to reveal relevant biological functions. Over a median follow-up of 13.2years, 617 participants developed asthma, 701 developed COPD, and 228 developed IPF. Higher frailty index was associated with elevated risks of asthma (HR 1.95, 95% CI 1.64 to 2.31) and COPD (2.02, 1.71 to 2.38). Corresponding proteomic signature also related to increased risks of asthma (HR 1.22, 1.11 to 1.34) and COPD (1.65, 1.53 to 1.78). Mediation analysis suggested that the frailty index partially mediated the association with COPD, accounting for 26.0% (95% CI: 18.7 to 37.5%) of the total effect, respectively, particularly for GDF15, WFDC2, and PLAUR. Pathway enrichment analysis showed that these mediating proteins were predominantly involved in immune activation, inflammatory signaling, and metabolic stress responses. Frailty phenotypes contribute to elevated CRDs risks, partly through proteomic dysregulation in inflammatory and metabolic pathways.

The core pathological basis of obesity and its associated metabolic diseases is excessive lipid deposition. Bioactive compounds from dietary resources, such as polyphenols and flavonoids, can significantly improve lipid homeostatic imbalance by activating autophagy pathways, especially lipophagy. This review gives a systematic analysis of the interaction mechanism between autophagy processes and lipid metabolism, focusing on the elucidation of Rab GTPase-mediated membrane transport, membrane proteins involved in lipid droplet recognition and encapsulation, as well as lipid metabolism enzymes facilitating autophagy-dependent lipid clearance. We further illustrate how dietary bioactive compounds modulate the autophagy network via multiple targets, such as the activation of AMPK or inhibition of mTOR to improve autophagy, the promotion of TFEB nuclear translocation to drive lysosomal production, and the enhancement of SIRT1 to coordinate metabolic stress response. Despite the encouraging lipid-lowering effects of these compounds, there are still challenges related to their pleiotropic targets, discrepancies between in vivo and ex vivo studies, limited bioavailability, and long-term safety. Multidisciplinary approaches should be incorporated into future research to facilitate clinical translation, structure-activity relationship analyses, and evaluations of synergistic effects. This review offers insights for developing autophagy-modulating natural dietary agents as interventions against obesity.

Mitochondria at the membrane provide a route to inflammatory cell death.

Introduction Neurological complications are increasingly recognized as a significant consequence of COVID-19; however, time-resolved, brain-specific characterization of transcriptional alterations underlying SARS-CoV-2–associated neuroinflammation and neuronal injury remain limited. We hypothesized that brain transcriptional responses evolve dynamically during acute SARS-CoV-2 infection, resulting in temporal transcriptional programs. Methods KRT18-hACE2 transgenic mice were intranasally inoculated with SARS-CoV-2. Brain was harvested at 4 and 6 days post-infection (dpi) for analyses. Results Immunohistochemical analyses confirmed a broad spectrum of viral neurotropism and gliotropism, accompanied by an increased apoptotic burden, particularly in cortical neurons (ClCas3/SATB2+). Robust activation of myeloid cells (Iba1+/CD68+) provided evidence of neuroinflammation. Cytokine/chemokine profiling demonstrated pronounced upregulation of inflammatory mediators (CXCL10, IL-12p40, CCL12), alongside reduced CX3CL1, suggesting impaired neuron–microglia communication. Whole-transcriptome and gene ontology analyses uncovered stage-dependent molecular programs, with early alterations at 4 dpi enriched in protein ubiquitination, vesicle trafficking, and synaptic processes, followed by intensified innate immune activation and engagement of chromosomal maintenance pathways at 6 dpi. In parallel, pronounced suppression of mitochondrial function at 6 dpi, pointing to energy exhaustion and transcriptional-translational discordance, as supported by digital PCR and a substantial reduction in COXIV protein levels. Discussion These findings provide a time-resolved molecular landscape of SARS-CoV-2–induced neuroinflammation and metabolic stress, highlighting CNS vulnerability during severe infection and suggesting pathways potentially relevant to COVID-19-associated sequelae.

Adaptive transcriptional strategies underpin host-specific virulence of the generalist oomycete Phytophthora capsici during early crown infection.

Aging is associated with increased susceptibility to metabolic stress and chronic liver disease, yet the interactions between age and metabolic stressors and the potential for ameliorating interventions remain incompletely understood. Here, we examined the hepatic response of young (7-month-old) and old (25-month-old) C57BL/6 male mice to a 9-week high-fat diet (HFD) and assessed whether rapamycin, a well-established pro-longevity intervention, could mitigate age-exacerbated effects. While both age groups developed metabolic-associated steatohepatitis (MASH), older mice displayed more severe hepatic steatosis, inflammation, and transcriptional dysregulation. Transcriptomic profiling of whole livers and purified hepatocytes revealed that aging amplifies HFD-induced inflammatory and metabolic gene expression changes, including activation of immune pathways and suppression of metabolic pathways. Notably, treatment of aging mice with rapamycin reversed the majority of HFD-driven transcriptional alterations, including upregulation of pro-inflammatory regulators such as Stat1, and dysregulation of metabolic gene networks. Rapamycin also reduced hepatosteatosis, total body weight, and a tumorigenic transcriptomic signature associated with hepatocellular carcinoma risk. These findings demonstrate that aging intensifies hepatic sensitivity to dietary metabolic stress and identify rapamycin as a promising therapeutic to counteract age-related liver dysfunction and metabolic dysfunction-associated steatotic liver disease (MASLD) progression.

SIRT1-PINK1-Parkin axis orchestrated mitophagy and renal repair by dapagliflozin in diabetic nephropathy.

Introduction: Blood Flow Restriction (BFR) training has proved to be a viable option to cause muscular adaptations under low loads, thus ideal for persons who cannot tolerate highresistance training. By creating external pressure that limits venous return with continued arterial inflow, BFR causes local hypoxia, metabolic stress, and enhanced recruitment of muscle fibres. These physiological processes create adaptations equivalent to high-intensity training, which has endeared BFR as a valuable option for athletes and fitness enthusiasts seeking to enhance performance with less mechanical tension on joints and tissues. Aim: To examine the effect of BFR on muscular strength, hypertrophy, endurance, and aerobic capacity in healthy, active subjects. Materials and Methods: A scoping review was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses – Scoping Review Extension (PRISMA-ScR ) guidelines, for a period of six months i.e., from February 2025 to July 2025. Electronic databases such as PubMed, Scopus, Web of Science, and Sports Documentation and Information Service were searched for peer-reviewed English-language articles from inception until 2025. Eligible studies were experimental and observational designs that studied BFR in recreationally active healthy adults. A total of 25 Randomised Controlled Trials (RCTs) were included after screening. Results: BFR training improved muscle strength and hypertrophy in all age groups and training backgrounds with consistency. Such improvements were present even at low intensities {(20- 30%, one Reptition Maximum (1RM)}, where the results were often as good as high-load training. A number of studies also showed that muscular endurance and systemic adaptations, including cross-education effects, were improved. Aerobic capacity and vascular function outcomes were inconsistent with probable protocol differences. BFR exercise was safe and tolerated well, with minor and transient side-effects. Personalised occlusion pressures and training loads optimised safety and efficacy. Conclusion: BFR is a potent, low-load training modality that increases strength, hypertrophy, and muscular endurance in healthy individuals. It provides a joint-sparing intervention for those with load constraints and has future potential in sport and rehabilitation. Standardisation of training parameters and additional research on long-term adaptations, gender differences, and ideal pressure values are required to further develop its clinical and sporting application.

2-Deoxy-D-glucose attenuates lipopolysaccharide-induced inflammation and restricts Zika, Chikungunya, and Mayaro virus replication in monocyte-derived macrophages.

A spirocyclization-based two-color fluorescent probe for monitoring mitochondria-lipid droplets interactions under metabolic stress

Beyond the cold: New insights for neuroprotection and neurorecovery from functional genomics.

Protein CoAlation is regulated by and integrated with growth factor signalling and the cellular antioxidant response.

Periostin: A candidate mediator of muscle-tendon ECM remodeling in obesity.

Tirzepatide reverses hypothalamic inflammation, cellular stress, and neuropeptide imbalance in metabolic-menopausal dysfunction.