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Liver X receptors (LXRs), transcription factors belonging to the nuclear receptor superfamily, exist as two isoforms, LXRα (NR1H3) and LXRβ (NR1H2), that orchestrate cholesterol absorption, transport and excretion. Beyond their canonical roles in lipid homeostasis, LXRs modulate glucose metabolism, inflammatory responses and cellular proliferation. Emerging evidence implicates dysregulated LXRs activity in the pathogenesis of chronic liver diseases (CLDs), including viral hepatitis, metabolic dysfunction‑associated steatotic liver disease and hepatocellular carcinoma. However, the therapeutic potential of LXRs modulation remains paradoxical: While activation mitigates hepatic injury by maintaining cholesterol homeostasis and suppressing inflammation, concurrent upregulation of sterol regulatory element‑binding protein 1c exacerbates lipogenesis, potentially aggravating hepatosteatosis. The present review synthesized current insights into the dual regulatory mechanisms of LXRs in CLDs, critically evaluates their context‑dependent roles and highlights the imperative to balance therapeutic efficacy with metabolic side effects in future drug development. Show less

24 h behaviours (sleep, time awake in bed, moderate-to-vigorous physical activity [MVPA], light physical activity [LPA], and sedentary behaviour [SB]) may influence long-term mental health through their associations with affective experiences in everyday life. Here, we investigated the daily, prospective associations between 24 h behaviours and affect. Actigraphy-measured 24 h behaviours and self-reported affect data were collected across 7-15 consecutive days in healthy, community-dwelling adults (N = 354, M Associations between 24 h behaviours and next-day affect emerged at the within-person, not between-person level. Relative to the remaining behaviours, more LPA predicted 0.14 [95 % CI 0.03, 0.26] higher high arousal positive affect, whereas less SB predicted lower high and low arousal positive affect (-0.14 [-0.25, -0.02] and -0.12 [-0.24, -0.01], respectively) higher high arousal negative affect (0.13 [0.03, 0.23]). Further, within-person 30-min reallocation to LPA from SB, sleep, and time awake in bed also predicted ≥0.03 [0.00, 0.06] higher high arousal positive affect. 30-minute reallocation of time to LPA and MVPA from SB predicted 0.04 [0.01, 0.06] higher high arousal positive affect and -0.02 [-0.04, -0.00] lower low arousal negative affect. Findings provide stepping stone evidence for identifying optimal daily compositions of 24 h behaviours for affective enhancements in healthy individuals. Replacing time in SB with LPA and MVPA for improving affect should be experimentally tested in daily settings and clinical populations, to inform diagnostic and intervention strategies for better daily affect and mental health. Show less

This study was conducted to assess the clinical significance of programmed cell death-ligand 1 (PD-L1)-positive circulating tumor cells (CTCs) as predictive biomarkers for the efficacy of PD-(L)1 inhibitor-based treatment in advanced hepatocellular carcinoma (HCC). We enrolled 59 patients with unresectable HCC who received immunotherapy-based treatment and analyzed CTCs, PD-L1 CTCs were detected in 86.4% (51/59) of patients, with a PD-L1-positive rate of 83.7% (41/49). Compared with the "PD-L1 PD-L1 Show less

Aging, a complex biological process, is intrinsically linked to the pathogenesis of numerous age-related diseases. A key factor in the aging process is the accumulation of DNA damage and the subsequent activation or failure of the DNA damage response. To mitigate this damage, DNA repair mechanisms often involve the formation of DNA gaps. This study investigates the potential role of the Box A domain of High Mobility Group Box 1 (HMGB1) in modulating age-related changes. We utilized a label-free quantitative proteomic technique to analyze the plasma proteome of three female adult and eight female perimenopausal cynomolgus macaques (Macaca fascicularis), with the perimenopausal group receiving an intravenous administration of the Box A plasmid. Proteomic analysis revealed differential expressions in proteins primarily associated with stress response, immune regulation, lipid transport, and cellular homeostasis following Box A plasmid intervention. Notably, the expression levels of key proteins, such as apolipoprotein E (APOE) and sex hormone-binding globulin (SHBG), showed a reversal effect, restoring levels closer to those observed in the younger, adult monkeys. These findings highlight the potential of the Box A of HMGB1 plasmid as a therapeutic candidate to mitigate age-related proteomic alterations, offering a novel avenue for targeted interventions in aging and associated diseases. Show less

Lipoprotein(a) [Lp(a)] is a primarily genetically determined, low-density lipoprotein-like particle that plays an important role in atherosclerotic cardiovascular disease (ASCVD) and calcific aortic valve disease (CAVD). Despite optimal control of traditional lipid levels, elevated lipoprotein(a) [Lp(a)] remains a significant contributor to residual cardiovascular risk, affecting up to 20% of the global population. We performed a literature search of PubMed/Medline and Google Scholar until July 2025 to provide a comprehensive overview of the genetics, structure, metabolism, and molecular mechanisms underlying Lp(a)'s pathogenicity. Structurally, Lp(a) consists of an LDL-like core covalently bound to apolipoprotein(a) [apo(a)], a polymorphic glycoprotein characterized by kringle IV type 2 (KIV-2) repeat variability. This copy number variation is the primary determinant of apo(a) isoform size and plasma Lp(a) levels. Small isoforms are produced more efficiently, resulting in higher concentrations. Lp(a) is synthesized in hepatocytes, and its plasma levels are predominantly governed by production rather than clearance. It carries a high burden of oxidized phospholipids (OxPLs), which confer pro-inflammatory and pro-atherogenic properties. Lp(a) promotes arterial inflammation, endothelial dysfunction, monocyte activation and impaired fibrinolysis via competition with plasminogen. It also plays a direct pathogenic role in valvular calcification by delivering OxPLs and autotaxin to valve interstitial cells, triggering osteogenic signaling cascades. While environmental factors such as inflammation and hormonal status can transiently modulate levels, genetic variation overwhelmingly dictates lifelong Lp(a) burden. As novel agents targeting Lp(a) enter late-stage clinical trials, mechanistic insights into Lp(a) biology will be essential to risk stratification and future clinical management. Show less

The triglyceride-glucose (TyG) index, an insulin resistance marker linked to the progression of metabolic dysfunction-associated steatotic liver disease (MASLD), underscores the redox imbalance-mediated crosstalk between MASLD and cardiovascular-liver-metabolic health (CLMH), although its causal mechanisms and molecular drivers remain unresolved. We employed a multi-omics framework to integrate Mendelian randomization (MR) and transcriptome-wide association studies (TWAS). MR leveraged 192 genome-wide significant single-nucleotide polymorphisms for TyG from the UK Biobank, employing inverse-variance weighted (IVW) and generalized summary-data MR (GSMR). Transcriptomic integration utilized four approaches: Multi-marker Analysis of GenoMic Annotation for gene-set enrichment; Joint-Tissue Imputation PrediXcan (JTI-PrediXcan) for tissue-specific expression; Sparse Multi-Tissue Imputation Xcan (SMulTiXcan) for cross-tissue meta-analysis; and Fine-mapping of Causal Gene Sets (FOCUS) for Bayesian fine-mapping. Comorbid genes were validated using Functional Summary-based Imputation (FUSION) and prioritized based on the Polygenic Priority Score (PoPS). Single-cell spatial transcriptomics (sc-ST) in embryonic mice (E16.5) mapped tissue-specific expression via genetically informed spatial mapping (gsMap). The MR analysis demonstrated a causal effect of TyG on MASLD risk [IVW: odds ratio (OR) = 1.58, 95% CI = 1.04-2.38, P = 0.030; GSMR: OR = 1.43, 95% CI = 1.27-1.61, P = 5.20 × 10 -9 ]. TWAS identified 12 comorbid genes (C2orf16/SPATA31H1, FNDC4, GCKR, GMIP, HAPLN4, LPAR2, MAU2, MEF2B, NDUFA13, NRBP1, TM6SF2, and ZNF513). Independent validation using the FUSION framework confirmed nine TyG-MASLD comorbid genes with genome-wide significant false discovery rate-adjusted associations. Notably, TM6SF2 (TyG-PoPS = 7.2491) and GCKR (TyG-PoPS = 6.7102) showed strong positive associations in TyG, whereas NDUFA13 exhibited negative scores in MASLD (PoPS = -0.5028). Spatial mapping revealed conserved enrichment of APOA1, APOB, and APOC4 (sc-ST, P < 0.001) in murine liver and vascular tissues. Organ-specific analysis showed significant MASLD signals including the liver (sc-ST, P = 6.43 × 10 -5 ), adrenal gland (Cauchy P = 0.0064), and connective tissue (sc-ST, P = 3.29 × 10 -5 ). This study establishes TyG as a causal MASLD driver mediated by redox-sensitive hubs and evolutionarily conserved apolipoproteins, linking hepatic lipid peroxidation to systemic metabolic dysregulation. Targeting these pathways may mitigate dual hepatic-cardiovascular risks, advancing precision therapies for CLMH. Show less

Emotional and motivational aspects of teacher-student relationships are central to adolescents' psychological need satisfaction and academic development. However, few longitudinal studies examine how these relational experiences evolve during adolescence or co-occur with emotional-motivational functioning. Drawing on the Self-Determination Theory and recent models of emotion transmission in classrooms, this study aims to explore how students' emotional and motivational perceptions of teachers co-occur with psychological need satisfaction in distinct developmental profiles and to examine their transitions over time during adolescence. The sample consisted of 779 German secondary school students (57% female; aged 12-15) from high-track schools, surveyed in Grade 8 (T1) and Grade 9 (T2). Latent profile analyses (LPA) and latent transition analyses (LTA) were conducted using six indicators: socio-emotional teacher-student relationship, perceived teacher motivation (positive/negative), and satisfaction of autonomy, competence and relatedness needs. Gender and academic grades were included as covariates. Three distinct profiles emerged: (1) emotionally disconnected & controlled, (2) emotionally ambivalent & uncertainly self-determined and (3) emotionally safe & self-determined. While transitions towards the moderate profile were most common, extreme profiles remained relatively stable. Lower academic performance significantly predicted membership in less favourable profiles. Findings underscore the intertwined nature of emotional relationships and motivational experiences in adolescence. Socio-emotional teacher support emerged as a key differentiator between profiles. Interventions should target emotionally supportive climates to foster students' psychological need satisfaction and engagement. Show less

Myocardial infarction (MI) is the most severe clinical manifestation of coronary artery diseases (CVD) and serves as a critical driver of sudden cardiac death and heart failure (HF). Its pathophysiology begins with the abrupt cessation of coronary blood flow, leading to severe ischemia and subsequent cardiomyocyte necrosis. This study aimed to investigate the molecular mechanisms by which METTL14 regulates the progression of MI in mice via the OTUD1/DUSP6 signaling axis. An MI mouse model was established by ligating the left anterior descending (LAD) coronary artery. The progression of MI was evaluated through echocardiography, HE staining, Masson's trichrome staining, TUNEL assay, and assessment of inflammatory cytokines. Mechanistically, Me-RIP, PAR-CLIP Co-IP, and protein stability assays were performed to dissect the interactions within the METTL14/OTUD1/DUSP6 axis. Our results demonstrated that METTL14 was highly expressed in the MI mouse model. Silencing METTL14 significantly reduced the left Ventricular Internal Diameter at end-diastole (LVIDd) and left Ventricular Internal Diameter at end-systole (LVIDs), increased ejection fraction (EF) and fractional shortening (FS), and attenuated histopathological damage, apoptosis, and the levels of inflammatory cytokines (TNF-α and IL-β). Further analysis revealed that METTL14 promotes OTUD1 mRNA stability and expression by modulating its m Show less

Pharmacological preconditioning of mesenchymal stem cells (MSCs) is a promising strategy to enhance their therapeutic efficacy for end-stage liver disease; however, maximizing this benefit remains a major clinical challenge. Senkyunolide H (SNH), a small-molecule compound derived from Angelica sinensis, exhibits anti-inflammatory, antioxidant, and anti-apoptotic properties. Nevertheless, its capacity to optimize MSCs-based therapy for liver disease has not been fully elucidated. Here, we demonstrate that SNH preconditioning significantly enhances the therapeutic efficacy of bone marrow mesenchymal stem cells (BMSCs) in a murine model of liver cirrhosis. Specifically, SNH-pretreated BMSCs markedly alleviated hepatocellular injury, promoted hepatocyte proliferation, and attenuated collagen deposition. Mechanistically, SNH augments the therapeutic potency of BMSCs by partly binding to macrophage erythroblast attacher (MAEA), a subunit of the E3 ubiquitin ligase complex. This interaction stabilizes MAEA, which in turn facilitates the ubiquitination and proteasomal degradation of dual specificity phosphatase 6 (DUSP6), thereby activating ERK/STAT3 signaling and upregulating the secretion of hepatocyte growth factor (HGF). Collectively, our findings highlight SNH preconditioning as a robust approach to enhance the paracrine function and therapeutic potential of BMSCs, and identify MAEA as a novel therapeutic target for BMSCs-based interventions in liver cirrhosis. Show less

Dual-specificity phosphatase 6 (DUSP6) is a phosphatase specific for extracellular signal-regulated kinase (ERK). Dusp6-knockout mice are resistant to diet-induced hepatic steatosis, which appears to be linked to the downregulation of cytochrome P450 4 A (CYP4A); however, its mechanism remains unclear. This study aimed to elucidate how DUSP6 regulates CYP4A11 in human hepatocyte-lineage cells by focusing on forkhead box O1 (FOXO1). HepG2 and HuH-7 cells were challenged with palmitic acid and oleic acid to induce lipid accumulation while manipulating the expression of DUSP6, FOXO1, CYP4A11, ERK, and/or AKT. Lipid accumulation was reduced by DUSP6 knockdown, resulting in decreased CYP4A11 expression despite elevated phosphorylated ERK, AKT, and FOXO1. Inhibition of ERK increased lipid accumulation, while simultaneous inhibition of ERK and AKT decreased it. Knockdown of FOXO1 or induced expression of DUSP6 increased CYP4A11 expression and lipid accumulation, whereas induced expression of FOXO1 decreased them. Chromatin-immunoprecipitation showed that FOXO1 bound to CYP4A11 promoter. Immunoprecipitations revealed that DUSP6 bound to and anchored FOXO1 in the cytoplasm. These results indicate that DUSP6 interferes with FOXO1's repressive activity towards CYP4A11 by sequestering it in the cytoplasm and preventing its nuclear translocation, which ultimately unleashes CYP4A11 and promotes lipid accumulation. Show less

Self-collection of biospecimens at-home, without specialized equipment or training, are increasingly being adopted in clinical practice due to convenience and patient preferences. However, sample instability during shipment means that remote access to common blood tests remains challenging. We hypothesized that the inaccuracy and imprecision in test results that develop because of sample instability could be modeled and controlled using knowledge of transit conditions captured by environmental sensors. We subjected 2685 blood samples from 65 participants to temperature cycles derived from real-world transit conditions. Training a model called Remote Control to predict change enabled accurate calibration of test results to approximate the time zero value at the point of collection, despite sample degradation. With calibration, unprocessed whole blood could be transported, for up to 9 days under ambient conditions and exposed to temperatures between 3.4 and 47.4 °C. Under these conditions, agreement with CLIA TEa ranged between 98.1 and 100%, with a |%bias| of 0.1-1.6%, a %CV of 2.2-4.9%, and a minimum sigma metric between 3 and 8.8σ for lipids (Cholesterol, HDL, LDL, Triglycerides, APO-A1, and APO-B). Performance was linear across measurement intervals (R Show less

Non-small cell lung cancer (NSCLC) is characterized by high morbidity and lethality, causing a great physical and psychological burden on patients. Therefore, effective treatment of NSCLC patients is very important. This study analyzes the impact of a nursing intervention of case management combined with cognitive-behavioral therapy on anxiety and depression and quality of life in postoperative NSCLC patients. A single-center, non-randomized controlled study in which 80 NSCLC patients from the Hospital were enrolled from May 2023 to January 2024, and were categorized into case management (CM) and cognitive-behavioral therapy (CBT) groups depending on treatment modalities, with case management care in both groups, and cognitive-behavioral therapy care added to the CM combined with CBT (CC) group. The Hamilton anxiety scale (HAMA), Hamilton depression scale (HAMD), self-perception burden scale (SPBS), life qualities (QLQ-C30), neurotransmitter levels, and clinical effectiveness were primarily assessed in both groups post-treatment. Secondary outcomes included pain level (VAS score), nursing satisfaction, adverse events, and complications. After treatment, the indicators of both groups were significantly different from those of the pre-treatment. Post-treatment, the CC group demonstrated significantly lower scores than the CM group in HAMA (10.18 ± 2.10 vs. 16.04 ± 3.89), HAMD (11.94 ± 2.91 vs. 16.81 ± 3.19), and SPBS (25.52 ± 3.17 vs. 33.50 ± 5.61) (all P < 0.05). Conversely, the CC group showed significantly higher QLQ-C30 scores and levels of 5-hydroxytryptamine (5-HT) and brain-derived neurotrophic factor (BDNF). The nursing intervention of case management combined with cognitive behavioral therapy has a good improvement effect on the anxiety and depression status of NSCLC patients. It can improve the quality of life, which is worth promoting and using in the clinic. Show less

Ultracentrifugation (UC) has long been considered the "gold standard" for extracellular vesicle (EV) isolation. However, due to its drawbacks such as high cost of an ultracentrifuge and rotors, time-consuming and labor-intensive protocol, low yield considering initial biofluid volume and low throughput, development of new EV isolation approaches is still ongoing. Here we compare three methods for isolating the most studied EV subtype, small extracellular vesicles (sEVs), from human plasma: ultracentrifugation (UC), express asymmetric depth filtration (ExADFi), and anti-CD9 immunoaffinity capture (AS-CD9) with focus on their Raman and proteomic profiles. For all three methods, purity and quality of the sEV isolation were assessed based on the level of contamination of the sEV fraction with major plasma proteins such as albumin and apolipoproteins (APOA1, APOH, APOA4, APOC2, APOC1, and APOC4). UC showed the highest ratio of protein to nanoparticle concentration. AS-CD9 and ExADFi provided comparable to UC purity and levels of non-vesicular contaminants with AS-CD9 requiring minimal time and labor. ExADFi showed characteristics including purity of the sEV samples, yield, and isolation time that is between the UC and AS-CD9 methods. Raman spectroscopy provided more details about characteristics of the isolated sEVs and confirmed differences observed in the proteomic profiles. The findings demonstrate that the AS-CD9 and ExADFi methods could be appropriate substitutes of the classical UC-based isolation method and be chosen depending on the final requirements and use of the purified sEVs such as further functional and biomarker studies. Show less

In the present study, a systematic revision in the Medline was conducted to determine the somatic mutation in gangliogliomas. A Medline search for relevant publications up to October 2024 using the key phrase "ganglioglioma mutation" led to the retrieval of 297 studies. This corpus provided the basis for the present review. The records without abstract or descriptions of somatic mutations were excluded. Only records in the English language were considered. A total of 43 papers were evaluated, reporting a total of 1360 cases of ganglioglioma. Among them, 528 cases presented mutations in 6 genes: BRAF BRAF Show less

Although increased maternal androgens, such as those in polycystic ovary syndrome (PCOS), are associated with a higher incidence of autism spectrum disorder (ASD) in offspring, a causal link has yet to be established. We assessed whether perinatal hyperandrogenization in a murine model recapitulates core ASD traits and compared this model to the maternal immune activation (MIA) model of ASD. Both models produced ASD-like phenotypes, yet they exhibited distinct behavioral subtypes and neurodevelopmental trajectories. Hyperandrogenized offspring showed greater reductions in social communication (neonatal USVs, d = 0.633-0.773; juvenile USVs, d = 1.103-1.216; social preference, d = 0.715), whereas only MIA offspring showed increased repetitive behaviors (d = 0.599). Ex vivo magnetic resonance imaging revealed volume increases in specific cortical regions in both models, with MIA additionally showing absolute cingulate cortex enlargement, and hyperandrogenized mice displaying focal increases in sexually dimorphic regions, despite a 36% reduction in overall brain volume (FDR 10%). Placentas from both groups showed reduced LIX (CXCL5), but distinct immune shifts also emerged: MIA placentas exhibited elevated IL-4 and IL-1β, whereas hyperandrogenized placentas showed increased TNFα. In neonatal brains, both conditions were associated with reduced IL-2, with MIA additionally decreasing IL-17A and IL-12p70, suggesting suppression of Th1/Th17-type cytokine signaling that normally supports proinflammatory and immune-neural interactions. DRD2 and BDNF protein were upregulated in hyperandrogenized fetal brains but downregulated with MIA. These results suggest that hyperandrogenization and MIA act through distinct mechanisms, producing subtle neurodevelopmental and behavioral differences consistent with human ASD subtypes. Show less

Lipoprotein(a) [Lp(a)] promotes atherosclerotic plaque vulnerability through pro-inflammatory and thrombogenic pathways, while the CatLet© angiographic score quantifies coronary lesion complexity. We hypothesized that their integration would improve prognostication in acute myocardial infarction (AMI) after emergency percutaneous coronary intervention (ePCI). In this retrospective cohort, 307 AMI patients undergoing successful ePCI (2020-2022) were stratified by 1-year major adverse cardiovascular/cerebrovascular events (MACCE). Serum Lp(a) and troponin I were measured post-admission. CatLet© and Gensini scores were assessed by blinded analysts. Multivariable logistic regression and ROC analyses evaluated predictive performance. MACCE patients (n = 78) exhibited higher Lp(a) (135.99 ± 33.07vs. 123.35 ± 42.70nmol/L, P = 0.0178) and CatLet© scores (33.58 ± 9.04vs. 30.80 ± 8.24, P = 0.0012) versus controls. Lp(a) (OR=2.339,95%CI:1.519-3.603, P <  0.001) and CatLet© score (OR=1.092, 95%CI:1.027-1.161, P = 0.005) independently predicted MACCE. The combined model Lp(a)≥70.70 nmol/L + CatLet© ≥ 18.6) significantly outperformed individual markers (AUC 0.862 [95%CI:0.83-0.96] vs. 0.780/0.833; DeLong's test confirmed the superiority of the combined model over individual predictors (P = 0.0089, Z = 2.64 vs. Lp(a); P = 0.034, Z = 2.12 vs. CatLet© score), with 88% sensitivity and 83% specificity. The Lp(a)-CatLet© synergy enhances MACCE risk stratification in ePCI-treated AMI, reflecting complementary pathobiological (Lp(a)-driven plaque vulnerability) and anatomical (CatLet©-quantified complexity) pathways. This dual-parameter approach could support post-PCI risk stratification and follow-up planning. Show less

Alzheimer's disease (AD) is a progressive disorder that affects the brain and leads to cognitive decline and memory loss, with postmenopausal women being unduly affected. Estrogen is believed to exert neuroprotective effects by influencing amyloid-beta accumulation, tau hyperphosphorylation, oxidative stress, synaptic function, neuroinflammation, and brain-derived neurotrophic factor (BDNF) signalling. This review examines the role of estrogen in AD pathogenesis among postmenopausal women. A systematic literature search was conducted using PubMed, Scopus, and Web of Science. Keywords included "estrogen", "Alzheimer's disease", "neuroprotection", "amyloid-beta," and "BDNF." Inclusion criteria were peer-reviewed studies from the past 10 years focusing on estrogen's effects on AD mechanisms, neurobiology, and therapeutic relevance. Articles were screened by title and abstract. Followed by a full-text review to ensure methodological rigour and relevance. Evidence indicates that estrogen reduces amyloid beta burden, inhibits tau phosphorylation, mitigates oxidative stress, preserves synaptic connectivity, and suppresses neuroinflammation. Estrogen also modulates ApoE-linked lipid metabolism and enhances BDNF signalling, supporting neuronal survival and cognitive resilience. Declining estrogen after menopause increases vulnerability to AD. Understanding estrogen's neuroprotective mechanisms may support targeted therapeutic strategies. Hormone replacement therapy (HRT) and selective estrogen receptor modulators (SERMs) show potential, but further research is needed to optimise timing, dosage, and patient selection in postmenopausal AD prevention and management. Show less

The number of people living with Alzheimer's disease (AD) is increasing worldwide as populations age. A hallmark of AD is the accumulation of amyloid-β (Aβ) in the brain, and pathways regulating amyloid-β precursor protein (AβPP) processing are of major interest for disease-modifying and preventive strategies such as exercise. Regular exercise is associated with a reduced risk of AD, potentially through limiting Aβ accumulation, yet the underlying cellular mechanisms remain unclear. Acute bouts of exercise induce the release of circulating signalling molecules that may influence AβPP metabolism. To investigate the effects of exercise on AβPP processing, human induced pluripotent stem cell (iPSC)-derived neurons and astrocytes were treated with serum collected before and immediately after high-intensity exercise. Both healthy control and familial AD (PSEN1 A246E) neurons and astrocytes were independently exposed to 10 % pre- or post-exercise serum for 30 min, after which markers of AβPP processing were quantified. Post-exercise serum contained increased amounts of Lacate, BDNF, IL-6, sAβPPα, and Aβ₁-₄₂, and reduced neprilysin activity (p < 0.05). Treatment with post-exercise serum acutely elevated ADAM10 activity in neurons, which was replicated by spiking lactate in pre-exercise serum. sAβPPα was also increased in PSEN1 neurons following post exercise serum treatment with increased Aβ₁-₄₂ secretion in both PSEN1 neurons and astrocytes (p < 0.05). These findings demonstrate that human post-exercise serum can modulate AβPP processing in iPSC-derived neural cells. This supports the concept that circulating exercise-induced factors can influence neuronal pathways relevant to AD pathology. Show less

Accurate and ongoing assessments of physical activity (PA) and sedentary time (SED) are needed to support public health surveillance, evaluate interventions, and advance the understanding of how movement behaviours relate to health. After six cycles of data collection (2007 to 2019) using the Actical (AC) accelerometer, the Canadian Health Measures Survey (CHMS) transitioned to the ActiGraph wGT3X-BT (AG). To understand how estimates from the AC accelerometer may compare with those from the AG in the context of the CHMS, this study compares AC and AG accelerometer estimates of PA, step counts, and SED using CHMS protocols. A convenience sample of 47 adults (aged 18 to 79 years) and 36 children and youth (aged 3 to 17 years) wore both AC and AG accelerometers on their waist for seven consecutive days. Estimates of PA and SED, step counts, and the percentage of those meeting PA recommendations were compared between the devices using descriptive, correlation, and agreement statistics. Agreement ranged from poor to excellent, with variability across PA intensities and age groups. Significant absolute differences in SED and light PA (LPA) were observed across all age groups, and in step counts among children and youth. Agreement was good to excellent across most age groups for moderate-to-vigorous PA (MVPA), and among adults for step counts. While the percentage of those meeting PA recommendations was higher with the AG, results were not statistically different. Similar comparisons could be made with the AG device when using the normal and low frequency extension filters. The results of the present study provide data users and researchers with an indication of the expected differences between the devices across various movement behaviour outcomes in the context of the CHMS. Results suggest that comparisons between cycles 1 to 6 and Cycle 7 onward of the CHMS for MVPA are acceptable, but they should be carried out with caution. Comparisons of SED, LPA, vigorous PA, and step counts are not recommended. Show less

The primary renal complication of diabetes mellitus is diabetic kidney disease (DKD). The precise pathogenic mechanisms of DKD remain poorly elucidated. The aim of this study was to identify potential energy metabolism-related genes associated with DKD. The GSE30529 and GSE30528 datasets were retrieved from the Gene Expression Omnibus, and energy metabolism-related genes were obtained from the GeneCards database. Differentially expressed genes (DEGs) between DKD and control groups were analyzed. The biological functions and signaling pathways of these DEGs were evaluated using Gene Ontology (GO), the Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set enrichment analysis (GSEA). The diagnostic performance of hub genes for DKD was assessed using receiver operating characteristic (ROC) curve analysis. Expression levels of five significant energy metabolism-related genes were validated through immunohistochemistry. The Nephroseq V5 tool was used to evaluate gene expression in DKD and to determine correlations between gene expression and renal function in patients with DKD. A total of 17 energy metabolism-related DEGs were identified. Five hub genes-ALB, IGF1, CD36, LPL, and UCP2-were identified. Among these, CD36 and LPL demonstrated relatively high diagnostic accuracy for DKD. The findings suggest that CD36, IGF1, LPL, and UCP2 may serve as potential biomarkers for DKD. The genes CD36, IGF1, LPL, and UCP2 represent potential energy metabolism-related biomarkers with possible applications in the diagnosis and treatment of DKD. Show less

Current evidence is unclear due to methodological limitations. We bridge critical knowledge gaps by quantifying the longitudinal changes in movement behaviours and their correlates from early childhood through adolescence. Longitudinal observational cohort study. General healthy child and adolescent sample in Singapore. Growing Up in Singapore Towards healthy Outcomes study participants. We used wrist-worn accelerometry and proxy-reported data to examine movement behaviours (sleep, inactivity, light physical activity (PA; LPA) and moderate-to-vigorous PA (MVPA) and screen-viewing) at ages 5.5, 8, 10 and 12 years and the sociodemographic and maternal lifestyle-related correlates using linear regression models with generalised estimating equations. Among 837 children, sleep, LPA and MVPA declined by 3% (from 9.1 to 8.8 hours/day), 24% (from 5.8 to 4.4 hours/day) and 44% (from 71.3 to 40.1 min/day), respectively, while inactivity and screen viewing increased by 26% (from 8.0 to 10.1 hours/day) and 155% (from 1.8 to 4.6 hours/day), respectively, from ages 5.5 to 12 years. The greatest annual increase in inactivity (0.6 hour/annum) and screen-viewing (0.8 hour/annum) and decrease in LPA (0.3 hour/annum) and MVPA (10.4 min/annum) occurred from ages 8 to 10 years. Girls of Malay ethnicity and lower socioeconomic status, and whose mothers had less favourable movement behaviours, had significantly less sleep, higher inactivity and screen-viewing and/or lower PA. Maternal PA levels and/or sitting time were associated with children's sleep, inactivity and MVPA up to age 8 years, while maternal sitting and screen-viewing behaviours were associated with children's screen-viewing at all ages. Using contemporaneous datasets relevant to the present day, we confirmed that children become less physically active and have longer screen-viewing as they transition into adolescence and highlighted characteristics to be prioritised in future interventions. Show less

Granulosa cell (GC) apoptosis is intrinsically linked to the ovarian dysfunction of polycystic ovary syndrome (PCOS). Although oxidative stress and apoptosis in GCs have been detected in PCOS patients, how reactive oxygen species (ROS) links to GC apoptosis in PCOS remains to be further elucidated. Here, by integrating public single-cell RNA-seq data with clinical GC sample validation, we found that the expression of the E3 ubiquitin ligase WWP2 was significantly reduced, whereas its role in PCOS has not been previously reported. Notably, we first demonstrated that WWP2 overexpression can effectively antagonize mitochondrial apoptosis and ROS in KGNs. Mechanistically, oxidative stress weakened the interaction between WWP2 and BAK and reduced WWP2 expression, thereby suppressing BAK ubiquitination at Lys113. This inhibition impaired proteasomal degradation and consequently increased BAK protein levels. Consistently, disrupting BAK ubiquitination (BAK-K113R mutant) or knocking down WWP2 facilitated KGN apoptosis, and genetic ablation of Wwp2 in PCOS mice further aggravated GC apoptosis and hormonal disturbances. This study elucidates the molecular mechanism by which oxidative stress modulates GC mitochondrial apoptosis through WWP2-mediated BAK ubiquitination, and establishes WWP2 as a potential therapeutic target for PCOS. Show less

The dental pulp is an immunologically active tissue that responds dynamically to cariogenic challenge. Peripheral pulp cells adjacent to dentine encounter bacterial stimuli earlier than cells located in the central pulp. To investigate signalling and immune interactions, this study profiled the transcriptomes of dentine-adherent cells (DACs) and central dental pulp cells (DPCs) cocultured with Streptococcus mutans. Primary cultures of both DACs and DPCs were obtained from healthy third molars of three female and three male donors aged 13-16. Cells were cocultured with viable S. mutans (2 × 10 RNA-Seq revealed a dynamic shift in the transcriptome of DACs and DPCs stimulated with S. mutans, while cells exposed to γ-inactivated or no bacteria did not. Although DACs and DPCs shared common DEGs (33 up, 8 down), several regulations were exclusive to DACs (22 up, 9 down) and DPCs (9 up, 25 down), highlighting a donor-independent functional specificity of the pulp subpopulations. Functional enrichment analysis revealed a strong and comparable activation of hypoxia-related pathways in both DPCs and DACs. However, DACs additionally showed enrichment in extracellular matrix organisation and cytokine signalling, while DPCs were characterised by intracellular stress responses and protein folding pathways. Additionally, protein-protein interaction analysis identified IL-6 as a key hub in DACs, while ANGPTL4 was central in DPCs. Following exposure to S. mutans, mechanically isolated DACs and DPCs displayed distinct transcriptomic profiles, indicating functional heterogeneity in the pulpal immune response. DACs engaged immunomodulatory pathways, while DPCs were marked by cellular stress responses, suggesting divergent contributions to tissue defence and homeostasis. Show less

Frailty is associated with increased risks of falls, disability, hospitalization, and mortality. The 24-h movement behaviors (24HMB) framework conceptualizes sleep, sedentary behavior (SB), light-intensity physical activity (LPA), and moderate-to-vigorous physical activity (MVPA) as mutually constrained components of daily time use and may inform frailty prevention and management. This scoping review maps evidence on associations between 24HMB and frailty and identifies methodological gaps to inform future research and nursing practice. This review adheres to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) and follows Joanna Briggs Institute (JBI) guidance. We searched PubMed, Embase, CINAHL, and Web of Science. We included observational studies of adults aged ≥18 years. Exposures were objectively measured or validated self-reported sleep, SB, LPA, and MVPA, including step counts, breaks in SB, isotemporal substitution models (ISM), and compositional data analysis (CoDA). Outcomes were frailty or prefrailty assessed using validated instruments. Quality was appraised with JBI tools. Thirty-three studies showed good methodological quality. Longer SB, particularly prolonged, uninterrupted bouts, was associated with higher frailty. Greater MVPA was consistently associated with lower frailty. Light-intensity physical activity was generally beneficial but often attenuated when MVPA or total activity volume was modeled. Sleep fragmentation and poor sleep quality were associated with frailty. Isotemporal substitution models and compositional data analysis indicated that reallocating sedentary time to MVPA would yield the largest theoretical benefit, followed by reallocating to LPA. Higher daily step counts and more frequent or higher-intensity breaks in SB were associated with lower frailty. Evidence supports a 24-h integrated movement-behavior approach centered on MVPA, combined with reducing prolonged SB and improving sleep quality, for the prevention and nursing management of frailty. The study design and analytical protocol were prospectively registered on the Open Science Framework (OSF). The unique identifier is S39Y4, and the publicly accessible URL is https://doi.org/10.17605/OSF.IO/S39Y4. Show less

BackgroundAlthough the molecular basis of Alzheimer's disease (AD) is often studied in Caucasians, its genetic basis in Bangladesh remains elusive.ObjectiveWe explored the association between single-nucleotide variants (SNVs) of Apolipoprotein E ( Show less

Arterial thrombectomy (AT) is a cornerstone in the treatment of acute ischemic stroke (AIS) due to large vessel occlusion. However, the optimal therapeutic time window and the best management strategy for patients presenting beyond the conventional 4.5-hour timeframe remain areas of active investigation and debate. This retrospective cohort study aimed to analyze the effect of timing of AT on recovery in AIS. We retrospectively analyzed 117 AIS patients admitted between January 2021 and January 2023. Participants were categorized into 3 groups: early AT (onset-to-AT < 4.5 hours), late AT (onset-to-AT ≥ 4.5 hours), and late AT + intravenous thrombolysis (IT). Outcomes compared included clinical efficacy, National Institutes of Health Stroke Scale (NIHSS) scores, serum levels of neurotrophic factors, brain-derived neurotrophic factor, vascular endothelial growth factor, residual stenosis, vessel reocclusion, 3-month mortality, and 1-month complications. The total effective rate was higher in the early AT and late AT + IT groups than in the late AT group. Pretreatment NIHSS scores and serum neurological marker levels were comparable across all groups. After treatment, the early AT and late AT + IT groups showed significantly lower NIHSS scores, higher serum levels of neurological markers, and improved treatment efficiency compared to the late AT group. Prognosis-related markers also indicated better outcomes in these 2 groups. Additionally, complications such as mucocutaneous ecchymosis, gastrointestinal bleeding, and intracranial bleeding were significantly reduced in the early AT and late AT + IT groups. AT within 4.5 hours of stroke onset improves efficacy, reduces neurological injury, and decreases complications. For patients presenting beyond 4.5 hours, combining AT with IT achieves comparable therapeutic benefits. Show less

This study aimed to identify blood pressure-associated metabolites and explore their underlying pathways using multiomics data from 1188 Chinese participants. Serum metabolite levels were profiled using untargeted and widely targeted metabolomic technologies. The associations of metabolites as well as ratios with blood pressure were assessed using generalized linear models (GLM). Targeted metabolomics was used to replicate a subset of metabolites. Genome-wide association studies (GWAS) were performed on all metabolites identified. Potential causality was examined using two-sample Mendelian randomization (MR) analyses, with partial validation against GWAS results from an independent cohort. This study identified 10 blood pressure-associated metabolites supported by GLM and MR analyses. Cortisol demonstrated the strongest association with blood pressure, with l-glutamic acid and its ratios identified as key drivers. Multiomics integration revealed that a genetic variant near the omega-3 metabolism genes ( Show less