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N-Acetylcysteine (NAC), a thiol-containing antioxidant, has demonstrated neuroprotective potential in various neurological disorders. Recently, cold atmospheric plasma (CAP) technology has emerged as a promising approach for modifying the physicochemical properties of biomolecules. This study investigated the neuroprotective effects of plasma-activated N-acetylcysteine (PAN) in a rat model of intracerebroventricular streptozotocin (icv-STZ)-induced cognitive impairment, with particular emphasis on redox homeostasis and cholinergic function. The physicochemical properties of PAN were characterized using FTIR, LC-MS/MS, and DPPH assay. Male rats received a single icv-STZ injection (3 mg/kg) on day 0, followed by oral administration of NAC or PAN (50 mg/kg) every other day for three weeks. Cognitive performance and anxiety-like behaviors were assessed using the shuttle box, novel object recognition, and elevated plus maze tests. Subsequently, oxidative stress indices (TAC, GSH, SOD, CAT, MDA, NO), cholinergic markers (AChE activity, ACh levels), and the expression of AChE, α7 nAChR, Nrf2, Keap1 and BDNF genes were quantified in the hippocampus and cerebral cortex. FTIR and LC-MS/MS analyses revealed plasma-induced chemical modifications in NAC, resulting in the generation of novel compounds. The DPPH assay further demonstrated superior radical scavenging activity of PAN compared with NAC. Behaviorally, PAN administration significantly alleviated STZ-induced cognitive deficits and anxiety-like behaviors. Biochemically, PAN normalized TAC, GSH, MDA, NO, and ACh levels, increased CAT and SOD activities, and reduced AChE activity. At the transcriptional level, PAN upregulated α7 nAChR, Nrf2 and BDNF expression while downregulating AChE and Keap1. Collectively, these findings suggest that PAN mitigates behavioral impairments in the icv-STZ rat model of Alzheimer's disease, potentially through attenuation of oxidative stress and restoration of cholinergic neurotransmission. Show less

Gout is an acute inflammatory arthritis triggered by monosodium urate (MSU) crystal deposition and activation of innate immune responses. In addition to inflammasome signaling, emerging evidence suggests that metabolic reprogramming of arachidonic acid (AA) pathways amplifies inflammatory responses during gout flares. However, the contribution of upstream fatty acid desaturation processes that regulate endogenous AA availability remains poorly defined. 1,2,3,4,6-Penta-O-galloyl-β-D-glucose (PGG) is a naturally occurring polyphenol with reported anti-inflammatory activity, but its effects on MSU-induced fatty acid metabolism and gouty inflammation have not been well established. Publicly available bulk and single-cell transcriptomic datasets from human and mouse gout studies were analyzed to assess dysregulation of AA-associated pathways. MSU-induced inflammatory responses were examined in mouse bone marrow-derived macrophages and in a murine MSU-induced gout model. Macrophages were treated with PGG prior to MSU stimulation, and inflammatory cytokine production, phagocytosis, and expression of fatty acid desaturases were assessed. Lipidomic analysis of macrophages and plasma was performed using gas chromatography-mass spectrometry (GC-MS) to quantify arachidonic acid and related fatty acids. In vivo disease severity, cytokine expression, and anti-inflammatory markers were evaluated following PGG treatment. Analysis of public datasets revealed consistent dysregulation of arachidonic acid-associated inflammatory pathways during gout flares. In macrophages, MSU stimulation increased expression of fatty acid desaturases FADS1 and FADS2 and promoted accumulation of arachidonic acid, concomitant with robust production of pro-inflammatory cytokines. PGG treatment significantly suppressed MSU-induced FADS1, FADS2 and arachidonic acid levels, and attenuated pro-inflammatory cytokine production. PGG also markedly impaired macrophage phagocytosis of MSU crystals. In vivo, PGG treatment significantly reduced clinical disease severity in an MSU-induced gout model, suppressed fatty acid desaturation and arachidonic acid accumulation in plasma, decreased pro-inflammatory cytokine expression, and enhanced anti-inflammatory markers. These findings identify fatty acid desaturation as an important metabolic contributor to gouty inflammation and demonstrate that PGG suppresses MSU-induced inflammation by limiting endogenous arachidonic acid availability, reducing inflammatory amplification, and impairing MSU crystal phagocytosis. Targeting upstream fatty acid metabolism represents a potential therapeutic strategy for modulating acute gout flares beyond conventional anti-inflammatory approaches. Show less

Hypertrophic scar (HS) represents a skin fibroproliferative disease characterized by a high incidence, frequent recurrence, and limited treatment options. Thus, identifying new targets to optimize the treatment of HS is of critical importance. Using summary statistics from the eQTLGen Consortium, Decode database, and FinnGen cohort, we conducted transcriptome-wide and proteome-wide Mendelian randomization (MR) to discover potential pharmacological targets against HS, with subsequent validation via RNA sequencing. Upstream regulators and downstream mechanisms were further investigated to better understand the roles of the pathogenic gene. Drug prediction, molecular docking, and molecular dynamics (MD) simulation were employed to estimate the value of potential drugs for HS. A high level of fibroblast growth factor receptor 1 (FGFR1) significantly increased the risk of HS according to transcriptome-wide (P = 0.011) and proteome-wide MR (P = 0.002) analyses. RNA-seq further validated the high expression of FGFR1 in HS. Gene-gene interaction network and enrichment analysis identified FGFR1 as the core gene driving the progression of HS, highlighting multiple biosynthetic processes. Pharmacological evaluation of candidate drugs predicted stable binding between Ro-4396686 and FGFR1. Our findings suggest that FGFR1 can serve as promising target for optimizing HS treatments, potentially reducing the costs of drug development. Show less

Previous studies have reported that genetic variants in the GCKR, FADS1, BCO1, and FGF21 genes are associated with lipid metabolism and may contribute to the development of dyslipidemia (DL). In this study, we aimed to explore the relationship between single-nucleotide variants (SNVs) rs780094/rs1260326-GCKR, rs174546-FADS1, rs6564851-BCO1, and rs838133-FGF21 and the lipid profile, as a cumulative effect, through a Genetic Risk Score (GRS) in the Mexican-Mestizo population. This study was conducted in a population of 1,925 Mexican adults from the Health Workers Cohort Study. Demographic and clinical data were obtained through a structured questionnaire and standardized procedures. Genotyping assays were performed with predesigned TaqMan probes, and association analyses with lipid profile were estimated using linear and logistic regression. Our findings confirm that GRS is a predictor of cardiometabolic risk. Our data can be used for developing dietary strategies to improve the health of the Mexican population. Show less

Invasive lobular carcinoma (ILC) comprises ∼10%-15% of breast cancers and is characterized by loss of the cell-adhesion molecule E-cadherin (encoded by CDH1), discohesive growth, predominant estrogen receptor (ER) positivity, low-to-intermediate proliferation, and atypical metastatic spread to bone and gastrointestinal/peritoneal sites. Diagnostic assessment is often challenging owing to diffuse infiltration, frequently yielding non-measurable disease per response evaluation criteria in solid tumors (RECIST). Molecularly, ILC is enriched for phosphoinositide 3-kinase (PI3K) activation and harbors emerging vulnerabilities-such as ROS1 synthetic lethality in CDH1-deficient tumors and fibroblast growth factor receptor 1 (FGFR1)/bromodomain and extra-terminal (BET) dependencies-now under study. Because metastatic ILC remains underrepresented in trials, systemic therapy often mirrors invasive ductal carcinoma (IDC). This short communication synthesizes current evidence to distinguish shared from plausibly lobular-specific signals; highlights near-term opportunities-including antibody-drug conjugates (ADCs), oral selective ER degraders (SERDs), and selective use of immunotherapy in an immune-enriched subset with higher tumor-infiltrating lymphocytes (TILs) and PD-L1; and outlines trial-design adaptations-such as incorporating 18F-fluoroestradiol PET (FES-PET)-to improve representation and interpretability in metastatic ILC research. Show less

Because the prognostic value of lipoprotein(a) [Lp(a)] levels in Japanese patients remains unclear, we assessed their distribution and association with long-term outcomes in ST-segment elevation myocardial infarction (STEMI). In our retrospective analysis of 868 consecutive patients with STEMI, the median serum Lp(a) level was 15.75 mg/dL at admission, and the median follow-up was 736.5 days. Using restricted cubic spline analysis, we stratified patients into high (≥47.26 mg/dL) and low (<47.26 mg/dL) Lp(a) groups. The high Lp(a) group had a higher proportion of older and female patients, with lower body weight, estimated glomerular filtration rate, and stent use, and higher dyslipidemia prevalence than those in the low Lp(a) group. The 5-year cumulative incidence of the composite primary endpoint (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or any revascularization) was significantly higher in the high Lp(a) group, primarily because of a high rate of any revascularization. Patients with elevated Lp(a) levels demonstrated higher rates of any revascularization for both de novo and restenotic lesions than those with lower levels. After adjusting for confounders, a high Lp(a) level was identified as an independent predictor of the primary endpoint (hazard ratio:1.932; 95% confidence interval:1.255-2.974). In Japanese patients with STEMI, elevated Lp(a) levels were independently associated with worse long-term outcomes. Show less

This study aimed to investigate how nano curcumin (Nano-Cur) or nano-chromium chloride (Nano-CrCl) in comparison with metformin (Met), can reduce diabetic neuropathy caused by streptozotocin (STZ) in rats. Seventy Wistar albino male rats were randomly divided into seven groups (ten rats/group): control; STZ-induced diabetes; diabetic rats receiving daily oral doses of Nano-Cur, Cur, Nano-CrCl, CrCl, and Met. The present results show that all treated groups significantly alleviated diabetic neuropathy by restoring serum insulin and glucose levels, enhancing cerebral antioxidant activities and activating IR/PI3K/AKT, normalizing neurotransmitters, decreasing oxidative stress markers (MDA), and reducing inflammatory biomarkers and pyroptotic biomarkers. At the molecular level, the levels of GSK3B, JAK-2, STAT-3, AMPK, and BACE1 were significantly downregulated in all treated diabetic groups compared to the diabetic group, especially Nano-Cur and Met. However, Cur, Nano-CrCl, and CrCl did not cause any significant (p > 0.05) alteration in ACh levels compared to the diabetic group. Additionally, the Nano-Cur, Cur, and Met groups exhibited a marked increase in miRNA-223-3p and miRNA-124 levels, whereas Nano-CrCl and CrCl showed no significant changes in these miRNAs when compared to the diabetic group. Show less

Hepatocellular carcinoma (HCC) is a major malignancy with rising global incidence and mortality. Clinical treatment is limited by molecular heterogeneity and drug resistance. In recent years, endocrine-disrupting chemicals (EDCs) have attracted attention as emerging risk factors, but systematic pathogenic evidence for their roles in HCC initiation and progression remains insufficient. First, we predicted potential targets of EDCs using SwissTargetPrediction, STITCH, and ChEMBL, and intersected them with differentially expressed genes and key module genes from WGCNA in the GEO database to screen candidate key genes. Second, based on these candidates, we constructed diagnostic models using 14 machine-learning algorithms and evaluated feature importance via the SHAP framework to identify key biomarkers and their functional contributions. Molecular docking and molecular dynamics simulations were used to validate interaction mechanisms between EDCs and key target proteins. We then built a multivariable Cox proportional hazards model in the TCGA-LIHC cohort and performed stratified survival analysis, somatic mutation profiling, and immune evasion characterization. Subsequently, we evaluated the tumor immune microenvironment using CIBERSORT and ssGSEA, and integrated single-cell transcriptomic data to resolve cell-subtype heterogeneity, target expression distributions, and cell-cell communication. Meanwhile, we integrated the GDSC drug-sensitivity database to evaluate associations between risk scores and drug response, and conducted pan-cancer analyses to examine cross-cancer applicability. We identified 18 genes jointly associated with EDCs and HCC, significantly enriched in AMPK, p53, and FoxO signaling pathways and cell cycle-related pathways. Among models built with 14 machine-learning algorithms, CatBoost showed the best discriminative performance and identified CCNB2 and AKR1C3 as core driver genes. Docking and dynamics simulations indicated strong binding affinities and stable binding conformations between EDCs and target proteins including CCNB1 (-8.9 kcal/mol), AKR1C3 (-8.4 kcal/mol), and FADS1 (-8.5 kcal/mol). A multivariable Cox risk model based on nine key genes served as an independent prognostic predictor for HCC (HR = 1.746, 95% CI: 1.477-2.064, P < 0.001). The nomogram achieved AUCs of 0.836, 0.810, and 0.788 at 1, 3, and 5 years, respectively, indicating good predictive performance. The high-risk group was significantly associated with high tumor mutational burden (TMB), TP53 mutations, and low immune evasion scores. Regarding the tumor immune microenvironment, CIBERSORT and ssGSEA analyses showed marked enrichment of Tregs and M0 macrophages, while most effector immune cells and functions were suppressed. Single-cell transcriptomics further showed enrichment of endothelial cells, fibroblasts, hepatocytes, and macrophages in HCC tissues, with notable reductions in T cells, B cells, NK cells, and neutrophils, indicating an immunosuppressive microenvironment with stromal remodeling. Cell-cell communication analysis indicated that the MIF-CD74 receptor axis is central in immune-cell interactions. Drug-sensitivity analysis suggested that the high-risk group was more sensitive to GDC0810, BPD-00008900, and Fulvestrant, indicating potential beneficiary populations. Pan-cancer analysis showed that the risk model also had diagnostic and prognostic value in LUAD, KIRP, KIRC, and KICH, suggesting cross-cancer generalizability. This study systematically reveals that EDCs promote HCC initiation and progression by perturbing cell cycle, metabolic, and immune homeostasis through multi-target, multi-pathway mechanisms. The nine-gene risk model demonstrates superior performance in HCC diagnosis and prognosis and shows potential clinical translational value in drug-sensitivity prediction and pan-cancer analyses. This work provides a new perspective at the intersection of environmental toxicology and precision oncology and informs individualized therapeutic strategies. Show less

The fat mass and obesity-associated (FTO) gene, though widely studied in human obesity and livestock lipid accumulation, remains poorly understood in bovine adipogenesis. This study investigated its role in bovine adipocytes via overexpression, given its high expression in Guanling cattle adipose tissue. Results demonstrated that FTO significantly increased triglyceride content, adiponectin secretion, and lipid droplet accumulation (P < 0.01). It also upregulated key adipogenic markers (PPARγ, C/EBPβ, FABP4, LPL; P < 0.05). Transcriptomic analysis revealed that FTO promotes adipocyte differentiation and lipogenesis through regulating multiple lipid metabolic pathways. These findings reveal that FTO positively regulates bovine adipocyte differentiation by modulating lipid metabolic networks, thereby filling a critical gap in the understanding of FTO-mediated lipid metabolism in ruminants. Show less

Metabolic side effects represent a major long-term concern in antipsychotic (AP)-treated early psychosis. We evaluated the weight gain and changes in related metabolic parameters in patients followed up for 12 months. We also explored DNA methylation of four genes associated with weight gain (ADRA2A, INSIG2, LEP, MC4R). We included patients aged 15-64 years followed in the Ribeirão Preto Early Intervention in Psychosis Program from two different cohorts (Clinical sample, n = 147; Epigenetic sample, n = 59). DNA methylation was analysed by pyrosequencing only at baseline, after several weeks of AP exposure. In both cohorts, 40% of patients initially received second-generation antipsychotics (SGAs), increasing to over 70% after one year. Clinical sample: At follow-up, patients exhibited significant increases in body mass index (p < 0.001), triglycerides (p < 0.001), HDL-c (p = 0.001) and LDL-c (p < 0.001). Patients predominantly on SGAs during the 12 months had almost three times higher chance of weight gain than those using haloperidol. Other factors associated with weight gain included non-white skin colour (OR = 2.6), fewer years of schooling (OR = 2.5) and a weight gain of at least 7% at three months (OR = 3.1). Epigenetic sample: Patients receiving SGA treatment (median = 23.4 weeks) at baseline showed hypermethylation within the MC4R promoter region in relation to patients using haloperidol (median = 18.6 weeks). No changes in the baseline methylation of other genes related to weight gain or AP drugs were observed longitudinally. MC4R promoter hypermethylation in SGA-treated patients suggests drug-induced metabolic alterations and a potential role of MC4R as a biomarker for predicting AP-related metabolic risk. Show less

Psychological well-being among university students is often examined using variable-centered approaches that assume population homogeneity. Using Ryff's eudaimonic model and a person-centered analytic framework, this study examined latent profiles of psychological well-being among Ghanaian undergraduates, offering insight into how the Western-derived model functions in a non-Western cultural context. A cross-sectional design was employed to sample 574 regular undergraduate students from a public university in Ghana. Students completed the 18-item Ryff's Psychological Well-Being Scale. Latent profile analysis (LPA) followed by Chi-square tests were performed using JAMOVI statistical software. Four distinct profiles emerged: fully flourishing students (38.7%), harmonious life seekers (45.1%), purposeful self-actualizers (7.5%), and aspiring actualizers (8.7%). The profiles differed primarily in levels of autonomy, personal growth, and environmental mastery. Well-being profile membership was not associated with gender but varied significantly by age, although the effect size was small. The study findings suggest meaningful heterogeneity in eudaimonic well-being among Ghanaian undergraduates and highlight the importance of culturally sensitive, profile-based mental health interventions beyond demographic assumptions. Show less

This research evaluated the efficacy of Withaferin A-conjugated mesoporous silica nanoparticles (WA-MSNs) in accelerating the restoration of neural tissue and improving the recovery of sensory and motor functions following a sciatic nerve injury (SNI) in male Wistar rats. WA-MSNs were evaluated for encapsulation efficiency, drug release, particle size, surface charge, and molecular interactions. A rat SNI model was created, and subjects were treated with WA-MSNs, free WA, unloaded MSNs, or received no treatment. The sham group was also included for comparison. Regeneration was measured through the sciatic functional index (SFI), Hargreaves test, and electrophysiology (CMAP and NCV). Complementary assessments included sciatic nerve histomorphometry, assessment of gastrocnemius muscle mass, and Enzyme-Linked Immunosorbent Assay (ELISA) for inflammatory cytokines and neurotrophic factors. WA-MSNs achieved a 74.6% encapsulation efficiency and provided sustained drug release over 72 h. DLS analysis showed a monodisperse colloidal system, with an average hydrodynamic diameter of approximately 198 nm and a zeta potential of -22.4 mV. WA-MSN-treated rats exhibited significantly faster motor and sensory recovery compared to controls (p < 0.001), with electrophysiological parameters approaching those of sham-treated rats. Histological analysis revealed improved axonal morphology, myelination, and recovery of gastrocnemius muscle mass. ELISA results showed modulation of cytokine profiles, characterized by a marked reduction in (IL-1β, IL-6, TNF-α), and substantial elevation in the levels of (IL-10, TGF-β), and elevated neurotrophic factors (NGF, BDNF, NT-3). WA-MSNs significantly promote functional and histological nerve regeneration after SNI by modulating inflammation and enhancing neurotrophic support. These findings support WA-MSNs as a promising therapeutic approach for clinical peripheral nerve repair. Show less

Cholesteryl ester transfer protein (CETP) is a crucial therapeutic target for combating cardiovascular disease (CVD) due to its strong influence in modulating high-density lipoprotein (HDL) levels. CETP is responsible for the bidirectional transfer of cholesteryl esters (CEs) and triglycerides (TGs) between different lipoprotein fractions. Although CETP encounters both these neutral lipid substrates when it penetrates deep into lipoprotein cores and can acquire either lipid, prior studies have examined its conformational space only in the presence of CEs or TGs individually. Here, we investigate the uncharacterised dynamics of CETP in heterogeneous lipid environments (CE-TG and TG-CE) using molecular dynamics simulations. Compared to the stable, homogeneous CE-bound state, the introduction of TG, particularly in mixed CE/TG configurations, induces significant structural instability and protein expansion. Mixed-lipid occupancy leads to elevated flexibility in critical lipoprotein-binding loops and the distortion of vital secondary structural elements. Furthermore, large-scale collective motion analyses reveal that heterogeneous binding forces CETP into aberrant, asymmetric, and hyper-twisted conformations. This disrupts the symmetric bending-twisting balance essential for efficient lipid exchange. Free energy landscapes confirm that the TGs within the mixed-lipid systems exhibit varied conformational states and adopt orientations that deviate from their reported parallel N-N orientation for lipid transfer through CETP. These findings suggest that the simultaneous presence of CE and TG imposes considerable conformational strain, fundamentally impairing CETP's lipid transport mechanism and offering novel mechanistic insights for future CETP-targeted therapeutics. Show less

Remote ischemic preconditioning (RIpreC) is a strategy for remotely protecting target organs such as the brain by applying brief ischemia and reperfusion to the limb. However, the mechanisms underlying RIpreC-induced neuroprotection remain unclear. We aimed to investigate the neuroprotective effects of RIpreC on the peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α)/ fibronectin type III domain-containing protein 5 (FNDC5)/ brain-derived neurotrophic factor (BDNF) pathway in rat models of ischemic stroke. Rats were assigned to three groups: ischemia-reperfusion injury (IR, The online version contains supplementary material available at 10.1007/s12975-026-01422-z. Show less

Personality traits are associated with cognitive resilience to dementia-related neuropathology. This study examines whether personality traits are related to cognitive resilience to accelerated epigenetic aging. Participants were adults aged from 50 to 98 years (N = 2926, 58% female, Mean age = 68.72, SD = 9.57) from the Health and Retirement Study (HRS). Data on cognition and epigenetic aging measures (GrimAge and DunedinPoAM38) were obtained in 2016. Data on personality, demographic factors, and clinical, behavioral, and psychological covariates were obtained in 2014/2016. Cognitive resilience was defined as the residual from the regression of cognition on epigenetic aging measures. Controlling for demographic factors, linear regression analyses indicated that higher neuroticism was associated with worse-than-expected cognition relative to one's epigenetic aging for both GrimAge and DunedinPoAM38 epigenetic measures. Higher conscientiousness and openness were related to better-than-expected cognition relative to one's epigenetic aging across the two measures. Logistic regression further indicated that higher neuroticism was associated with a lower likelihood of cognitive resilience to accelerated epigenetic aging, whereas higher conscientiousness and openness were related to a higher likelihood of cognitive resilience. These associations were partially accounted for by disease burden, sleep quality, physical activity, smoking, depressive symptoms, childhood adversity, lifetime trauma, and APOE e4 status, and persisted when participants with cognitive impairment were excluded. There was little evidence that age or sex moderated the associations. The present study expands the literature on resilience from neuropathology to a broader systemic impact of aging to provide novel evidence that personality traits are associated with cognitive resilience to accelerated epigenetic aging. Show less

Atherosclerosis serves as the fundamental pathological process underlying numerous cardiovascular disorders, and the change of macrophage polarisation is the key to regulate the inflammatory response of AS. SIRT6 plays a protective effect in AS, but whether it regulates macrophage polarisation in AS remains uncertain. We aimed to characterise the mechanistic role of SIRT6 in atherosclerosis development mediated by macrophage polarisation. ApoE Show less

Acute lymphoblastic leukemia (ALL) is a genetically heterogeneous disease where current clinical practice guidelines remain focused on traditional cytogenetic markers. Despite recent advances demonstrating excellent diagnostic accuracy for gene expression signatures, a discontinuity exists between biomarker validation and clinical implementation. This study aimed to develop and validate a multiparametric gene expression signature using digital PCR (dPCR) to accurately diagnose pediatric ALL, with potential utility for monitoring measurable residual disease (MRD). We analyzed 130 bone marrow aspirates from pediatric patients from four clinical groups: non-leukemia, MRD-negative, MRD-positive and leukemia characterized by immunophenotype. Gene expression of an 8-gene panel ( Show less

Elevated lipoprotein(a) [Lp(a)] is an independent and causal risk factor for atherosclerotic cardiovascular disease. Increasingly, prevention societies recommend testing Lp(a) at least once for all adults. A quality improvement (QI) initiative aimed to increase the rates of Lp(a) ordering for patients was piloted in the general cardiology fellows' clinic at an urban academic medical center. QI project interventions focused on provider education and inclusion of electronic health record-based tools. Over a period of 10 months, the proportion of patients with an Lp(a) order increased from 10.1% to 20.9%, and the proportion of patients with an Lp(a) result increased from 7.0% to 11.2%. Ahead of results from ongoing clinical trials testing Lp(a)-targeted therapies, health systems can use QI methods to assess current Lp(a) ordering practices, identify patients who may benefit from future Lp(a)-targeted therapy, and plan for rapid expansion of Lp(a) testing. Show less

This study aims to examine the health characteristics of female sex workers (FSWs) in entertainment venues and to investigate the relationship between these characteristics and sleep quality. This study employed a cross-sectional design and was conducted from January to April 2024 in Wuhan, China. Participants were FSWs recruited through snowball sampling from entertainment venues, including hotels, restaurants, nightclubs, karaoke bars and dance halls. Data were collected via structured questionnaires covering sociodemographic information, work experience, psychological stress, health status, sleep quality and circadian rhythms. Latent profile analysis (LPA) was employed to identify health characteristic profiles among FSWs, and multivariate logistic regression was used to examine the associations between these profiles and sleep quality. Among the 1,036 FSWs surveyed, 45.1% had poor sleep quality. LPA classified FSWs’ health characteristics into three profiles: the high overall functioning group, the lower physical–emotional functioning group and the lower psychosocial functioning group. Multivariate logistic regression analysis showed that FSWs in the lower physical–emotional functioning group had higher odds of poor sleep quality (OR = 2.184) compared with those in the high overall functioning group. FSWs in the lower psychosocial functioning group had substantially higher odds of poor sleep quality (OR = 7.755) than that in the high overall functioning group. FSWs demonstrate substantial heterogeneity in health characteristics and exhibit lower overall sleep quality compared with the general population. Psychological and physiological factors are major influencing factors for their sleep quality, suggesting the importance of prioritising mental and physical health in this population. Show less

Intracerebral hemorrhage (ICH) is a destructive cerebrovascular disease, whose secondary injury can trigger severe neuroinflammatory responses. Resolvin D1 (RvD1), as an endogenous specific pro-resolving mediator, has been demonstrated to possess significant anti-inflammatory effects. However, how brain networks relate to RvD1 biosynthesis and the therapeutic potential of RvD1 in post-hemorrhagic repair processes within the brain remain unclear. Serum RvD1 levels were measured at admission and discharge in 40 ICH patients, and their correlation with neurological functional outcomes was analyzed. Combining neuroimaging and Mendelian randomization, we investigated the association between brain network integrity and genetically predicted plasma RvD1 levels. Network pharmacology identified key targets, and an oxyhemoglobin-induced BV2 microglial model validated RvD1's BDNF-dependent anti-inflammatory and anti-apoptotic effects. Serum RvD1 levels decreased from admission to discharge during recovery, with significant correlation between its changes and neurological improvement. Neuroimaging and MR analysis revealed that brain network integrity is significantly associated with genetically predicted plasma RvD1 levels, partially explaining interindividual prognostic variation. Mechanistically, RvD1 modulates microglial metabolism, alleviates oxidative stress, and promotes anti-inflammatory polarization involving the BDNF/AKT signaling network. Genetically predicted plasma RvD1 levels correlate with macro-level brain network integrity while simultaneously promoting micro-level neural repair. This approach overcomes limitations of previous single-pathway or static indicator studies, offering novel biomarkers and intervention strategies with predictive and therapeutic potential for ICH. Show less

Hypercholesterolemia is a major risk factor for cardiovascular disease, necessitating the development of effective and safe lipid-lowering interventions. This study evaluated the antihypercholesterolemic effects of KGC11 Show less

Alzheimer's disease (AD), the leading cause of dementia, is characterized by synapse damage and loss, correlating strongly with cognitive decline. APOE4, the strongest genetic risk factor for AD, impairs synapses with the mechanisms remaining unclear. APOE, the central nervous system's primary lipid and cholesterol carrier, is critical for axonal growth, synapse formation, and spine remodeling. To investigate how APOE4 affects cholesterol and synaptic dysfunction, we studied male and female human APOE3 and APOE4 knock-in mice. Cholesterol levels were measured in brain homogenates, synaptosomes, and mitochondria using bioluminescent assays, and APOE protein expression was analyzed via immunoblotting. Proteomics of synaptosomes and mitochondrial respiratory function assessments were performed using mass spectrometry and the Seahorse XF Analyzer, respectively. We found that cholesterol levels did not differ between APOE3 and APOE4 mice in brain homogenates or synaptosomes. However, male APOE4 mice exhibited lower cholesterol levels in synaptic mitochondria than APOE3 mice, with no changes in non-synaptic mitochondria or female mice. APOE protein was present in synaptosomes and mitochondrial fractions without changes due to APOE4 expression. Synaptosomal proteomics uncovered synaptic mitochondrial membrane proteins were differentially expressed in APOE4 versus APOE3 mice. Proteomic analysis also revealed altered neurotransmitter signaling and metabolic pathways in the APOE4 mice, predominantly in males. Notably, proteins involved in synaptic vesicle endocytosis and aerobic respiration were differentially expressed. Mitochondrial respiratory function was disrupted in female APOE4 mice, which displayed increased maximal respiration and spare respiratory capacity at the synapse. These findings identify a role for APOE in regulating synaptic mitochondrial cholesterol, protein expression, and respiratory function in a sex-dependent manner, contributing to synaptic dysfunction in AD. Show less

Findings of previous studies on associations between dairy consumption and metabolic health status were inconsistent. This study aimed to assess the link between consumption of dairy foods and metabolic health status, brain-derived neurotrophic factor (BDNF) and adropin levels in adults. Cross-sectional. An observational study in Isfahan, Iran. Adults (n=527) selected by multistage cluster random sampling. Dietary intakes were assessed via a validated 168-item food frequency questionnaire. Anthropometric indices, blood pressure and biochemical parameters were assessed. The criteria proposed by Wildman Participants had a mean age of 42.66 years (45.7% women). Moderate consumption of total dairy was, respectively, linked to 58% lower odds of MU (OR Moderate consumption of total and low-fat dairy was associated with lower odds of being metabolically unhealthy in Iranian adults, but high-fat dairy intake was not. Hypertension was less common among individuals with higher dairy intake. No association was found between dairy intake and serum levels of BDNF or adropin. Show less

Papillary thyroid carcinoma (PTC) is the most common form of thyroid cancer, with the majority of cases driven by genetic alterations that activate the MAPK signaling pathway. The BRAF V600E mutation is the most frequent alteration, while BRAF fusions are relatively rare but increasingly recognized as oncogenic drivers. These fusions typically involve the loss of BRAF's autoinhibitory N-terminal domain, leading to constitutive MAPK pathway activation. Here, we report a novel SORBS2::BRAF fusion in a case of PTC, further expanding the spectrum of BRAF alterations in thyroid cancer. A 32-year-old male was incidentally found to have a left thyroid nodule during a routine physical examination. Follow-up examinations revealed changes in the nodule's characteristics, prompting fine-needle aspiration biopsy, which identified atypical follicular epithelial cells suggestive of papillary thyroid carcinoma. Histopathological examination confirmed the diagnosis, and next-generation sequencing (NGS) revealed a novel in-frame fusion between SORBS2 exon 18 and BRAF exon 9. The resulting fusion protein retains the BRAF kinase domain while replacing its autoinhibitory domains with those of SORBS2. RT-PCR and Sanger sequencing confirmed the presence of the SORBS2::BRAF fusion. Quantitative PCR profiling of MAPK transcriptional output genes (DUSP6, CCND1, ETV4, c-Myc, and c-FOS) revealed marked upregulation in the tumor versus adjacent normal tissue, providing functional evidence for pathway activation. The SORBS2::BRAF fusion has not been previously reported in PTC or any other tumor type. Given the deletion of BRAF's inhibitory domain, this fusion likely acts as a tumor driver through constitutive activation of the MAPK pathway. This case underscores the importance of molecular diagnostics in identifying rare genetic alterations and highlights the need for further research into targeted therapies for BRAF fusion-driven cancers. The discovery of this novel fusion expands our understanding of the molecular landscape of PTC and provides a foundation for future therapeutic development. 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

The molecular features determining the risk of metachronous metastases in clear cell renal cell carcinoma (ccRCC) are poorly defined. This study aimed to identify molecular factors associated with the risk of metachronous metastasis. Using a systematic tumor transcriptome deconvolution approach, we investigated the genomic and transcriptomic profiles of 192 ccRCC primary tumors with extended clinical follow-up to identify cancer- and stromal cell-specific molecular features associated with metastatic risk. Based on these features, we applied multivariate Cox regression to develop a compact 5-gene predictive model for metachronous metastasis. At the genomic level, we identify a significantly higher frequency of copy number loss at 1p31-36 in primary tumors that later progress with metastases. Tumor transcriptome deconvolution identifies significant down-regulation of epithelial cell polarity, including PATJ (1p31), and fatty acid metabolism, including CYP4A11 (1p33), in cancer cells of tumors that develop metastatic progression. We develop and benchmark a compact 5-gene predictive model (5G) that demonstrates improved accuracy over existing ccRCC gene signatures in the prediction of metachronous metastasis risk. Overall, our study highlights convergent genomic and transcriptomic alterations in chromosome 1p, driving dysregulation of epithelial cell polarity and fatty acid metabolism, as putative risk factors of metachronous metastasis in ccRCC. Show less

Neuroplasticity, the brain's capacity to adapt and reorganize in response to experiences and environmental changes, is fundamental to cognitive aging. As individuals age, cognitive functions such as memory, processing speed, and executive function commonly decline, driven largely by changes in neuroplasticity mechanisms like synaptic plasticity, neurogenesis, and functional reorganization. Synaptic plasticity is a well-established mechanism supporting learning and memory across the lifespan, whereas adult neurogenesis, robustly demonstrated in rodents, remains highly limited and controversial in the adult and aged human brain, with evidence largely restricted to rare post-mortem observations and injury-associated conditions. Functional reorganization allows the brain to adapt to structural changes, helping to preserve cognitive function despite age-related decline. Several factors, including oxidative stress, neuroinflammation, and hormonal shifts, exacerbate the decline in neuroplasticity, accelerating cognitive deterioration. Various interventions, including cognitive training, physical exercise, and pharmacological approaches, have demonstrated the potential to promote neuroplasticity and support cognitive health in aging populations. However, one of the major challenges is tailoring these interventions to the unique needs of individuals, as well as identifying novel therapeutic targets for intervention. To effectively address the cognitive decline associated with aging, future research should focus on developing personalized strategies and innovative techniques to enhance or modulate specific neuroplasticity-related processes under defined conditions in the aging brain. These advancements may provide better tools for delaying, mitigating, or even reversing age-related cognitive decline, improving quality of life for older individuals. Show less

Osteoporosis frequently affects older women and is strongly linked to their daily routines, which include both sedentary behavior (SEB) and physical activities (PA) of different intensities. This study investigates the dose-response relationship of different SEB and PA patterns among community-dwelling older women and assesses the potential impact of time reallocation on osteoporosis risk through an isotemporal substitution analysis. In this study, 1,106 older women aged between 60 and 70 years in Tianjin participated. Their moderate to vigorous physical activity (MVPA), light physical activity (LPA), and SEB were objectively assessed using an accelerometer. The connection between MVPA, LPA, SEB, and osteoporosis was assessed using binary logistic regression models and isotemporal substitution models. The osteoporosis group and non-osteoporosis group comprised 461 and 645 subjects respectively, accounting for 41.68 and 58.32% of the total cohort. The osteoporosis group had significantly higher daily SEB compared to the non-osteoporosis group ( PA and SEB in older women exhibit a significant dose-response relationship with osteoporosis. Avoiding prolonged sitting and increasing PA duration both offer protective effects against osteoporosis in older women, with achieving a certain level of MVPA being the most effective protective measure. Show less

Post-stroke seizures are a common and debilitating complication with limited therapeutic options, underscoring the need to identify novel molecular targets. Disruption of chloride homeostasis via impaired potassium chloride cotransporter 2 (KCC2) activity is a key driver of neuronal hyperexcitability. While microglia are a predominant source of brain-derived neurotrophic factor (BDNF) in the acute phase after brain injury, the role of microglial BDNF and its signaling in KCC2 dysregulation and early post-stroke seizure susceptibility remain poorly defined. Using a middle cerebral artery occlusion-reperfusion (MCAO-R) mouse model and oxygen-glucose deprivation/reoxygenation (OGD/R) in hippocampal neurons, we assessed KCC2 function, neuronal excitability, and seizure susceptibility. Pharmacological tools, including the microglial inhibitor minocycline, the TrkB antagonist K252a, the loop diuretic furosemide (FUR), repurposed here as a KCC2-stabilizing agent, and the KCC2 activator CLP290, were employed. Techniques included immunofluorescence, Western blotting, patch-clamp electrophysiology, electroencephalography (EEG), and behavioral seizure assessment. MCAO-R and OGD/R significantly reduced membrane KCC2 expression, leading to a depolarizing shift in the GABA equilibrium potentials (E Our findings identify microglia-derived BDNF/TrkB signaling as a critical upstream pathway mediating KCC2 dysfunction in early post-stroke seizure. Targeting this axis by inhibiting microglial activation, blocking TrkB, or directly enhancing KCC2 function with activators like CLP290 represents a promising therapeutic strategy for stroke-related epilepsy. Show less

Neurodegenerative diseases such as Alzheimer’s and Parkinson’s are associated with genetic and environmental factors, including exposure to mercury, a heavy metal with neurotoxic effects. To identify and analyze alleles and genes linked to neurodegenerative diseases in relation to mercury exposure in Colombia. Scientific literature and population genotype data from public databases were reviewed, covering 94 Colombian adults genotyped under the CLM (Colombians from Medellín) reference. Data traceability was ensured through ID registration in the 1000 Genomes project database, guaranteeing informed consent and bioethical approval. Eleven genes (GSTP1, ATP7B, BDNF, GCLC, GCLM, MT1A, MT4, ABCC2, ABCB1, GPX1 y GPX4) with 18 polymorphisms distributed across ten chromosomes were analyzed using the SNPstatsTM program. The c² test was applied to evaluate the Hardy-Weinberg equilibrium, considering deviations with p < 0.05 as significant. The results showed a high probability of an association between neurodegenerative diseases such as Alzheimer’s and Parkinson’s and mercury exposure in individuals with genetic variants related to glutathione metabolism and mercury transport and excretion pathways. Genetic alterations or their expression involving mercury bioaccumulation, its crossing of the blood-brain barrier, central nervous system inflammation, and oxidative stress from reactive oxygen and nitrogen species increase the risk of developing Alzheimer’s and Parkinson’s disease. Show less