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Imbalance in fatty acid (FA) metabolism is a critical factor in the development of type 2 diabetes (T2D). This study examined fatty acid composition and desaturase activities in the liver and spinal cord of male Zucker diabetic fatty (ZDF) rats, a genetic model of T2D. Heterozygous lean ZDF fa/+ animals served as controls, while homozygous obese ZDF fa/fa animals represented the diabetic group. FA profiles were determined by gas chromatography, and the activities of Δ5-desaturase (FADS1), Δ6-desaturase (FADS2), Δ9-desaturase (SCD1), and elongase of very long-chain fatty acids (ELOVL) were estimated. T2D rats displayed significantly elevated levels of monounsaturated fatty acids (MUFAs) and increased SCD1 activity in both the liver and spinal cord. In contrast, polyunsaturated fatty acids (PUFAs), particularly arachidonic acid (AA, C20:4 n-6), were reduced. Since AA plays a fundamental role in neuronal membrane structure and signaling pathways, these alterations have particular relevance to nervous system function. Tissue-specific alterations further suggested impaired FADS1 activity in the liver and reduced elongase/FADS2 activity in the spinal cord. These findings suggest that desaturase imbalance and FA remodeling in the spinal cord might represent characteristic features of T2D and that altered FA metabolism within the nervous system may potentially serve as an early indicator of neuropathy or a predictor of increased susceptibility to diabetes-related complications. Show less

Obesity is a complex metabolic disease associated with several health complications, including insulin resistance, hypertension, and type 2 diabetes mellitus. Growing evidence indicates that fatty acid profiles and the activity of desaturating enzymes-stearoyl-CoA desaturase-1 (SCD1), delta-5 desaturase (D5D), and delta-6 desaturase (D6D)-are important factors in the pathophysiology of obesity. This review aims to summarise the current understanding of the alterations in lipid metabolism and desaturase activity in obesity, its complications, and potential therapeutic interventions. A literature review was performed using the PubMed, Scopus, and Web of Science databases. Systematic reviews, meta-analyses, clinical studies, cross-sectional studies, and animal studies that assessed fatty acid profiles and desaturase activity in the context of obesity were included. Obesity is associated with significant changes in the profiles of saturated fatty acids (SFAs), monounsaturated fatty acids (MUFAs), and polyunsaturated fatty acids (PUFAs), as well as altered desaturase activity. Increased activity of SCD1 and D6D and decreased activity of D5D are observed even in childhood and correlate with metabolic risk markers. Genetic variation in genes encoding fatty acid desaturases, such as fatty acid desaturase 1 ( Fatty acid profile and desaturase activity are significantly altered in obesity and represent potential biomarkers and therapeutic targets for its treatment and the prevention of related complications. Their assessment may contribute to a more personalised approach to treating obesity and associated metabolic diseases. Show less

This study aimed to infer a causal gene network associated with bone metastasis in lung cancer and to validate its reliability through experimental gene expression analysis. Using DNA microarray data from the Gene Expression Omnibus, we analyzed samples from primary lung cancer and those with bone metastasis. Commonly expressed genes in both groups were identified, and a causal network was inferred using Bayesian network inference with Java Objects based on the Bayesian Dirichlet score. To evaluate the network, we predicted the expression changes of downstream genes following knockdown of a key upstream gene and compared these predictions with mRNA expression levels in fatty acid desaturase 1 (FADS1)-knockdown lung cancer cells. The genes FADS1, cardiotrophin-like cytokine factor 1 (CLCF1), chromosome 4 open reading frame 48, sushi, nidogen and EGF like domains 1, FK506-binding protein 15, and coenzyme Q10A (COQ10A) were identified as directly associated with lung cancer bone metastasis. Among them, FADS1 appeared to have a regulatory role, influencing downstream targets. Notably, CLCF1 and COQ10A showed significantly increased expression in FADS1-knockdown cells, consistent with the network's predictions. These findings suggest that Bayesian network analysis is a reliable machine learning approach for uncovering causal gene relationships in cancer metastasis. Furthermore, FADS1 may serve as a potential therapeutic target in lung cancer bone metastasis. The validity of this network was supported by in vitro experiments using a lung cancer cell line. Show less

Gallstone disease (GD) is a common gastrointestinal disorder with a significant genetic component. Despite known risk factors, the genetic basis of GD remains incompletely understood. We aimed to identify novel genetic loci associated with GD, explore their clinical implications and investigate their therapeutic potential. We conducted a genome-wide association study from the UK Biobank followed by a meta-analysis, integrating summary statistics from the FinnGen R11, with further replication from Biobank Japan. Using systematic bioinformatic approaches, we performed gene prioritisation, colocalisation analysis, transcriptome-wide association study, Mendelian randomisations, cross-trait genetic correlations, phenome-wide association study, clinical investigations and gene-environment interactions by leveraging data from the FinnGen, Genotype-Tissue Expression project and Liver Cell Atlas single-cell transcriptomics data set. Our study highlighted novel susceptibility loci near candidate genes (ie, This study provides new insights into the genetic basis of GD and highlights the role of hepatocytes in GD pathogenesis. These findings have implications for the personalised prevention strategies and new therapeutic interventions in individuals predisposed to GD. Show less

With the sharp increase in the incidence of papillary thyroid carcinoma (PTC), the disease-specific survival rate has not improved significantly. Cholesterol metabolism plays a crucial role in tumor proliferation, regulation of tumor immune escape, and tumor drug resistance. However, there are few studies on the role of cholesterol metabolism in the occurrence and development of thyroid cancer (THCA). This study aimed to investigate the predictive value of cholesterol metabolism-related genes (CMRGs) in THCA and the relationship between immune invasion and drug sensitivity. Cholesterol metabolism-related genes we identified from the molecular signatures database, and univariate Cox regression and least absolute shrinkage and selection operator(LASSO) were used to construct a predictive model of cholesterol metabolism-related genes based on the TCGA-THCA dataset. The TCGA dataset was randomly divided into a training group and a validation group to verify the model's predictive value and independent prognostic effect. We then constructed a nomogram and performed enrichment analysis, immune cell infiltration, and drug sensitivity analysis. Finally, TCGA-THCA and GSE33630 datasets were used to detect the expression of signature genes, which was further verified by the HPA database. Six CMRGs (FADS1, NPC2, HSD17B7, ACSL4, APOE, HMGCS2) we identified by univariate Cox and LASSO regression to construct a prognostic model for 155 genes related to cholesterol metabolism. Their prognostic value was confirmed in the validation set, and a highly accurate nomogram was constructed combined with clinical features. We found that the mortality rate of high-risk patients increased by 11.41 times, and the infiltration of immune cells in the high-risk group was significantly reduced. Moreover, through drug sensitivity analysis, we obtained sensitive drugs for different risk groups. The GSE33630 dataset verified the expression of six CMRGs, and the HPA database verified the protein expression of the NPC2 gene. Cholesterol metabolism-related features are a promising biomarker for predicting THCA prognosis and can potentially guide personalized immunization and targeted therapy. Show less

Identification of drug-repurposing targets with genetic and biological support is an economically and temporally efficient strategy for improving the treatment of diseases. We employed a cross-disciplinary approach to identify potential therapeutics for the prevention of metabolic-dysfunction-associated steatotic liver disease (MASLD) in at-risk individuals by using humans as a model organism. We identified 212 putative candidate genes associated with MASLD by using data from a large multi-ancestry genetic association study, of which 158 (74.5%) were previously unreported. From this set, we identified 57 genes that encode for druggable protein targets and for which the effects of increasing genetically predicted gene expression on MASLD risk align with the function of that drug on the protein target. We then used We then evaluated these potential targets for evidence of efficacy by using Mendelian randomization, pathway analysis, and protein structural modeling. Through these approaches, we present compelling evidence to suggest that the activation of FADS1 by icosapent ethyl, as well as S1PR2 by fingolimod, could be a promising therapeutic strategy for MASLD prevention. Show less

Osteoarthritis (OA) is a multifactorial disease influenced by both genetic and environmental factors. Recent studies suggest that genetic variants involved in nutrient metabolism may interact with dietary factors to modulate OA risk. Understanding these gene-nutrient interactions could inform personalized prevention strategies for OA. We conducted a cross-sectional study involving 500 participants to explore associations between specific genetic variants and OA susceptibility, considering dietary intake. Genotyping focused on polymorphisms in the FADS1 gene (rs174537) related to omega-3 fatty acid metabolism, the VDR gene (rs2228570) involved in vitamin D metabolism, and the IL-6 gene (rs1800795), a marker of inflammation. Dietary intake of omega-3 fatty acids, vitamin D, and antioxidants was assessed using validated food frequency questionnaires. Gene-nutrient interactions were evaluated using multivariable logistic regression models, adjusting for potential confounders. Individuals carrying the G allele of FADS1 who reported low omega-3 fatty acid intake exhibited a significantly increased risk of OA [Odds Ratio (OR) = 1.45; 95% Confidence Interval (CI): 1.10-1.90; Show less

Dietary guidelines recommend replacing saturated fatty acid with unsaturated fats, particularly polyunsaturated fatty acids. Cohort studies do not suggest a clear benefit of higher intake of polyunsaturated fatty acids but, in contrast, higher circulating linoleic acid (LA) levels-reflective of dietary LA intake, are associated with a reduced risk of type 2 diabetes. However, genetic variants in the fatty acid desaturase 1 gene (FADS1) may influence individual responses to plant-based fats. We explored whether FADS1 variants influence the relationships of LA and α-linolenic acid (ALA) intakes and nut consumption with plasma phospholipid fatty acid profiles and type 2 diabetes risk in a large-scale cohort study and a randomized controlled trial. In the EPIC-InterAct case-cohort (7,498 type 2 diabetes cases, 10,087 subcohort participants), we investigated interactions of dietary and plasma phospholipid fatty acids and nut consumption with FADS1 rs174547 in relation to incident type 2 diabetes using weighted Cox regression. In PREDIMED (492 participants in the Mediterranean Diet + Nuts intervention group, 436 participants in the control group), we compared changes in plasma phospholipid FAs from baseline to year 1. In EPIC-InterAct and PREDIMED, nut consumption was positively associated with LA plasma levels and inversely with arachidonic acid, the latter becoming stronger with increasing number of the minor rs174547 C allele (p interaction EPIC-InterAct: 0.030, PREDIMED: 0.003). Although the inverse association of nut consumption with diabetes seemed stronger in participants with rs174547 CC-genotype (HR: 0.73, 95% CI: 0.54-1.00) compared with CT (0.94, 0.81-1.10) or TT (0.90, 0.78-1.05) in EPIC-InterAct, this interaction was not statistically significant. FADS1 variation modified the effect of nut consumption on circulating FAs. We did not observe clear evidence that it modified the association between nut consumption and type 2 diabetes risk. Show less

The existence of a definite direct causal relationship between vitiligo and diverse autoimmune disorders remains unknown due to the influence of confounding factors and potential reverse causality. Mendelian randomization (MR) is a technique employed to explore causal connections between two phenotypes. In our research, bidirectional two-sample MR analyses were utilized to evaluate the causal connections between vitiligo and multiple autoimmune diseases (systemic lupus erythematosus, Graves' disease, inflammatory bowel disease, alopecia areata [AA], type 1 diabetes mellitus [T1MD], and rheumatoid arthritis [RA]). Furthermore, we utilized summary-based Mendelian randomization (SMR) analysis to search for common susceptibility loci between two diseases that reciprocally elevate each other's risk. Finally, colocalization analyses were used to validate the robustness of the selected genes. There was an indication of potential causation between RA and vitiligo (IVW OR = 1.19; 95% CI = 1.05-1.13; p = 0.008). Furthermore, evident causal connections exist between vitiligo and AA (IVW OR = 1.14; 95% CI = 1.04-1.26; p = 0.008), T1MD (IVW OR = 1.14; 95% CI = 1.06-1.23; p < 0.001), and RA (IVW OR = 1.08; 95% CI = 1.03-1.13; p < 0.001). In SMR analyses and colocalization analyses, we identified three shared genes associated with both vitiligo and RA, including: FCRL3, FADS1, and FADS2. Our findings demonstrated that vitiligo and RA mutually act as risk factors for each other. Additionally, vitiligo had significant causal relationships with AA and type 1 diabetes. Show less

Cholesteryl ester transfer protein (CETP) gene polymorphisms influence CETP expression and high-density lipoprotein cholesterol (HDL-c) levels, yet their genetic impact remains unexplored in the Bangladeshi population, where low HDL-c is prevalent. This study examined the association of CETP -629C/A and 277C/T polymorphisms with circulating HDL-c levels in 402 individuals (217 males, 185 females). Serum lipid profiles were measured using an automated analyzer, and CETP polymorphisms were genotyped using PCR-RFLP. The -629C/A and 277C/T polymorphisms were in Hardy-Weinberg equilibrium, with heterozygous genotypes being the most frequent. While -629C/A genotypes showed no significant difference between the high and low HDL-c groups, individuals carrying the -629AA and CA + AA genotypes had significantly higher HDL-c levels compared to CC carriers (p = 0.023, p = 0.043). For the 277C/T, TT genotype differed significantly between the high and low HDL-c groups (p = 0.011, OR = 0.37) and, individuals carrying the 277 TT and CT + TT genotypes had significantly higher HDL-c compared to the CC genotype (p = 0.002, p = 0.019). Additionally, allelic analysis suggested a marginal association between the 277T allele and increased HDL-c levels (p = 0.051, OR = 0.59). Multiple regression analysis confirmed an inverse association between -629CC (β = -1.106, p = 0.038) and 277CC + CT (β = -0.963, p = 0.016) with HDL-c levels. However, no significant differences were observed in total cholesterol, triglycerides, LDL-c, or apolipoprotein levels across genotypes. These findings suggest that CETP -629CC, 277CC, and CT genotypes contribute to low HDL-c levels in the Bangladeshi population, highlighting the potential role of CETP genetic screening as a biomarker for identifying individuals at risk of HDL-c deficiency and associated cardiovascular complications. Show less

The Parent-Child Relationship plays a crucial role in the development of adolescents' psychological behaviors. Previous studies have confirmed its association with adolescents' cognitive development, academic performance, and emotional regulation, and have identified gender differences in this association. However, current research lacks a systematic integrated analysis of multi-dimensional variables such as physical-psychological-social adaptation. It also fails to identify the heterogeneity of the Parent-Child Relationship from a gender perspective and has not conducted in-depth and systematic discussions on the differential impacts on adolescents of different genders. This study aims to systematically explore the types of Parent-Child Relationship among adolescents of different genders using Latent Profile Analysis (LPA) and regression mixture models, and to conduct an in-depth analysis of the psychological and behavioral characteristics of adolescents corresponding to various types of Parent-Child Relationship. A multi-stage stratified cluster sampling method was adopted. In May 2023, a questionnaire survey was conducted among 3,922 students from 10 middle schools in 5 regions of Xinjiang. The measurement tools used included the Parent-Child Relationship Intimacy Scale, the Depression-Anxiety-Stress Scale, the Psychological Resilience Scale, and the School Adjustment Scale. The average age of the study subjects was 16.06 ± 0.98 years, including 1,884 males (48%) and 2,038 females (52%). Two types of Parent-Child Relationship were identified among adolescents in Xinjiang: the poor group and the good group. Among females, the "poor group" accounted for 38.86% (n = 792), and the "good group" accounted for 61.14% (n = 1,246). Among males, the "poor group" accounted for 43.68% (n = 823), and the "good group" accounted for 56.32% (n = 1,061). There were gender differences in the behavioral and psychological characteristics of adolescents under different Parent-Child Relationship patterns.In the female group, Anxiety, Depression, and Stress of all severity levels were predictive factors for the poor Parent-Child Relationship group (all OR > 1, P < 0.05). In the male group, only moderate Anxiety (OR = 0.463, 95% CI [0.296, 0.724]) and moderate Depression (OR = 0.436, 95% CI [0.292, 0.652]) reached a significant level.In terms of Psychological Resilience, females with poor Psychological Resilience had an approximately 5.87-fold higher probability of being classified into the "poor group" (OR = 6.874, 95% CI [4.500, 10.501]). In contrast, males with poor Psychological Resilience were more likely to be classified into the "good group" (OR = 0.116, 95% CI [0.069, 0.194]).In terms of School Adjustment, females in the "good group" scored higher than those in the "poor group" in School Attitudes and Emotions, Routine Adaptation, Academic Adjustment, Peer Relationship, and Teacher-Student Relationship (all P < 0.001), with chi-square test values ranging from 116.613 to 208.797. In the male group, although the "poor group" also scored significantly lower than the "good group" in the five dimensions (all P < 0.001), with chi-square values ranging from 20.632 to 102.774, the difference between the groups was smaller than that in females. There is heterogeneity in the Parent-Child Relationship patterns of adolescents. Under different Parent-Child Relationship patterns, there are gender differences in the behavioral and psychological characteristics of adolescents, which are specifically reflected in Anxiety, Depression, Stress, Psychological Resilience, and School Adjustment. However, these characteristics are not related to physical indicators (Sleeping Hours, Myopia) or demographic characteristics (age, Father's Education Level, Mother's Education Level, etc.). This study provides empirical evidence from Xinjiang, China, for the differentiated intervention of adolescents' health status. Show less

Polyunsaturated fatty acids (PUFAs) including omega-3 and omega-6 are obtained from diet and can be measured objectively in plasma or red blood cells (RBCs) membrane biomarkers, representing different dietary exposure windows. In vivo conversion of omega-3 and omega-6 PUFAs from short- to long-chain counterparts occurs via a shared metabolic pathway involving fatty acid desaturases and elongase. This analysis leveraged genome-wide association study (GWAS) summary statistics for RBC and plasma PUFAs, along with expression quantitative trait loci (eQTL) to estimate tissue-specific genetically predicted gene expression effects for delta-5 desaturase (FADS1), delta-6 desaturase (FADS2), and elongase (ELOVL2) on changes in RBC and plasma biomarkers. Using colocalization, we identified shared variants associated with both increased gene expression and changes in RBC PUFA levels in relevant PUFA metabolism tissues (i.e., adipose, liver, muscle, and whole blood). We observed differences in RBC versus plasma PUFA levels for genetically predicted increase in FADS1 and FADS2 gene expression, primarily for omega-6 PUFAs linoleic acid (LA) and arachidonic acid (AA). The colocalization analysis identified rs102275 to be significantly associated with a 0.69% increase in total RBC membrane-bound LA levels (p = 5.4 × 10 Show less

Adolescence is a developmental period characterized by heightened plasticity. Yet, how ongoing development affects sensory processing and cognitive function is unclear. We investigated how adolescent (postnatal day 20-42) and adult (postnatal day 60-82) mice differ in performance on a pure tone Go/No-Go auditory discrimination task of varying difficulty. Using dense electrophysiological recordings, we measured spiking activity at single neuron resolution in the auditory cortex while mice were engaged in the task. As compared to adults, adolescent mice showed lower auditory discrimination performance in a difficult task. This difference in performance was due to higher response variability and weaker cognitive control expressed as higher lick bias. Adolescent and adult neuronal responses differed only slightly in representations of pure tones when measured outside the context of learning and the task. However, cortical representations after learning within the context of the task were markedly different. We found differences in stimulus- and choice-related activity at the single neuron level representations, as well as lower population-level decoding of the difficult task in adolescents. Overall, cortical decoding in adolescents was lower and slower, especially for difficult sound discrimination, reflecting immature cortical representations of sounds and choices. Notably, we found age-related differences, which were more pronounced after learning, reflecting the combined impact of age and learning. Our findings highlight distinct neurophysiological and behavioral profiles in adolescence, underscoring the ongoing development of cognitive control mechanisms and cortical plasticity during this sensitive developmental period. Show less

Intensive aquaculture frequently utilizes high-fat diets (HF) as a cost-effective strategy, yet this practice often induces hepatic steatosis, oxidative stress, and chronic inflammation in carnivorous fish. Betaine, a natural methyl donor, has shown potential as a functional feed additive, but its comprehensive protective mechanisms under HF stress remain to be fully elucidated. Juvenile largemouth bass (Micropterus salmoides) were fed one of four isonitrogenous diets for 8 weeks: a normal-fat control (Control), a high-fat diet (HF), and two high-fat diets supplemented with 0.5% (HFB0.5) or 1.0% (HFB1) betaine. Growth performance, digestive enzyme activities, serum biochemical parameters, hepatic antioxidant capacity, and the expression of genes related to antioxidant defense, lipid metabolism, and inflammation were analyzed. The HF group exhibited significantly impaired growth, digestive function, and antioxidant capacity, along with elevated lipid peroxidation, dyslipidemia, and pro-inflammatory cytokine expression. Betaine supplementation restored growth performance and feed efficiency to control levels, ameliorated digestive enzyme activities (particularly enhancing lipase), and activated the hepatic Nrf2-Keap1 pathway, upregulating antioxidant genes (nrf2, sod1, cat, gpx, ho-1, gr) and enhancing enzyme activities. Betaine also improved serum lipid profiles, upregulated genes related to fatty acid oxidation (pparα, cpt-1) and lipolysis (lpl, hsl), suppressed lipogenic genes (srebp-1, fas), and rebalanced inflammatory cytokines by reducing tnf-α and il-1β while increasing tgf-β1 and il-10. Dietary betaine effectively counteracts HF-induced metabolic stress in M. salmoides through coordinated multi-pathway regulation. It enhances antioxidant defense, reprograms hepatic lipid metabolism toward catabolism, and restores inflammatory homeostasis. These findings underscore betaine's role as a multi-functional feed additive capable of mitigating HF-related metabolic disorders and promoting overall health in carnivorous fish aquaculture. Show less

Agrin, encoded by AGRN , plays a vital role in the acetylcholine receptor clustering pathway, and any defects in this pathway are known to cause congenital myasthenic syndrome (CMS) 8 in early childhood with variable fatigable muscle weakness. The most severe or lethal form of CMS manifests as a fetal akinesia deformation sequence (FADS). To date, only one family has been reported with an association of null variants in AGRN and a lethal FADS. We identified a nonconsanguineous couple with recurrent pregnancy loss. Detailed phenotyping of fetuses was performed via perinatal autopsy. Genetic evaluation was performed along with split-read analysis to identify variants. Perinatal phenotyping revealed FADS in the family, and genomic testing identified novel null variants in AGRN . First, whole-exome sequencing revealed the maternally inherited heterozygous variant c.952+1₉₅₂₊₃del in AGRN in fetuses. Split-read analysis of the exome led to the identification of the paternally inherited second variant, a heterozygous deletion of 41.33 kb, encompassing exons 1 and 2 of AGRN. This study highlights the importance of incorporating split-read analysis in clinical practice and emphasizes the association of null variants in AGRN with the FADS. To the best of our knowledge, this is the second report explaining FADS and null variants in AGRN . Show less

Diabetic nephropathy (DN) is the most intractable complication of diabetes. Despite decades of research, accurate diagnostic markers and effective therapeutic drugs are still elusive. Abnormal copper metabolism is also implicated in diabetes and its complications. This study aims to identify copper metabolism-related biomarkers and potential drugs for DN. DN datasets and copper metabolism-related genes (CMGs) were obtained from Gene Expression Omnibus (GEO) and GeneCards. Differentially expressed CMGs (DE-CMGs) were identified using the limma package and the Venn algorithm. Functional enrichment analysis and protein-protein interaction (PPI) network were performed to identify candidate hub genes. The single gene with an area under the receiver operating characteristic (ROC) curve > 0.7 was identified as a potential diagnostic biomarker of DN. Finally, these biomarkers were validated by quantitative real-time polymerase chain reaction (qRT-PCR) in high-glucose-treated human proximal tubular (HK-2) cells. These validated hub genes were used to construct a combined prediction model, confirmed by additional GSE30528 and GSE30529 datasets. The correlation analysis between the expression level of the hub genes and the estimated glomerular filtration rate (eGFR) was carried out. Additionally, immune cell infiltration and potential target drugs were investigated for these biomarkers. Five hub genes associated with copper metabolism, namely CD36, CCL2, CASP3, LPL, and APOC3, were identified as biomarkers for the early diagnosis of DN. Utilizing multiple biomarkers enhanced diagnostic accuracy and specificity. CD36, CCL2, and CASP3 correlated negatively with eGFR levels, while LPL and APOC3 correlated positively. Additionally, these hub genes were significantly linked to various immune cell types, including macrophages M1 and M2, T cells, gamma delta resting dendritic cells, neutrophils, and NK cells. Furthermore, 15 agents targeting these biomarkers were retrieved from the DrugBank database. Our study identified key genes possibly related to copper metabolism in the pathological mechanism of DN that could serve as novel targets for the diagnosis and therapy of DN. Show less

Mental health among college students represents a significant and growing public health concern. Negative bias in prospection is closely related to depression and anxiety. Prospection bias (PB) encompasses increased negativity, reduced positivity and overgeneralization, which exhibit intricate co-occurrence patterns and exert a complex influence on mental health. However, the presence of distinct patterns of PB and their impact on mental health remain unknown. We recruited 1,030 Chinese college students to complete assessments of PB, depression, anxiety, stress and resilience. Latent profile analysis (LPA) was used to identify distinct PB profiles. Linear regression was then applied to examine their effects on mental health outcomes. The results suggested six profiles: (1) high levels of increased negativity and overgeneralization but a low level of reduced positivity (contradictory overgeneralizers), (2) low PB, (3) moderate low PB, (4) a high level of increased negativity but low levels of reduced positivity and overgeneralization (simple contradictory), (5) high PB, and (6) moderate high PB. Regression analyses demonstrated that high prospection bias predicted more severe stress, depressive and anxious symptoms, as well as lower resilience. Additionally, the results implied that handling increased negativity and reduced positivity of prospection might be potential ways to improve mental health. These findings may facilitate the early detection of mental health issues among college students and contribute to the refinement of future interventions. The online version contains supplementary material available at 10.1186/s12888-025-07732-0. Show less

Adolescent psychological wellbeing is a critical determinant of lifelong health. Global data suggest a concerning decline in adolescent wellbeing. While the 24-hour movement behaviours, moderate to vigorous physical activity (MVPA), light physical activity (LPA), sedentary time, and sleep, have been linked to mental health outcomes; their associations with specific domains of adolescent psychological wellbeing remain underexplored. This study used compositional data analysis (CoDA) to examine how time-use relate to domain-specific wellbeing in Australian secondary school adolescents. Data were drawn from 124 adolescents (aged 13–17 years) participating in the TransformUs Secondary effectiveness trial. Wrist worn Actigraph GT9X accelerometer captured 24-hour movement behaviour over at least three valid days (≥ 16 h/day). Wellbeing was assessed using the EPOCH Measure of Adolescent Wellbeing, which includes five domains: engagement, perseverance, optimism, connectedness, and happiness. CoDA was used to examine associations between the composition of daily movement behaviours and EPOCH domains using isometric log-ratio (ILR) transformations. A compositional time reallocation analysis (30-minutes) was also performed to explore hypothetical associations with wellbeing outcomes. The average daily time-use composition was 680.9 min (47.3%) sedentary time, 473.0 min (32.8%) sleep, 250.7 min (17.4%) LPA, and 35.3 min (2.5%) MVPA. Greater time spent in LPA relative to other behaviours was significantly associated with higher happiness scores ( Adolescent daily movement behaviour composition was associated with domain-specific psychological wellbeing, particularly happiness. LPA was a potential contributor to positive psychological wellbeing. These findings suggest that even modest changes in daily routines, such as replacing sedentary time and LPA, may support adolescent flourishing. Future research should confirm these findings longitudinally and employ in intervention studies. The online version contains supplementary material available at 10.1186/s44167-025-00094-8. Show less

Endothelial dysfunction is a key pathological mechanism in atherosclerotic cardiovascular disease, and methylglyoxal (MGO) has been identified as a major contributor to endothelial cell damage through its overabundance. In this study, the effects of MGO on atherosclerotic human endothelial cells were investigated. Human Umbilical Vein Endothelial cells (HUVECs) were first pre-treated with 1 mM palmitic acid (PA) for 24 h to induce lipotoxic conditions and then treated with 60 and 400 µM MGO for an additional 24 h. A total of six experimental groups were included: Control, 60 µM MGO, 400 µM MGO, PA, PA + 60 µM MGO, and PA + 400 µM MGO. Intracellular lipid accumulation was investigated using Oil-Red O staining. Apoptotic changes were assessed by flow cytometry, while nitric oxide (NO) levels were measured using the Griess assay. Gene expression patterns associated with angiogenesis, inflammation, lipoprotein, and cholesterol metabolism were investigated by real-time PCR. Based on findings, the distribution of lipid droplets was detected exclusively in the PA-treated group, while no such accumulation was observed in the MGO (60 and 400 µM)-treated groups. Furthermore, co-treatment with PA-MGO (60 and 400 µM) significantly reduced apoptosis, while PA with 60 µM MGO elevated NO levels (p < 0.05). HUVECs' exposure to MGO remarkably upregulated levels of LPL, LPA, IL-8, and IFN-γ (p < 0.05), whereas IL-6 levels were elevated only in the PA-MGO group (p < 0.05). The PA-MGO combination significantly altered the expression of angiogenesis-related genes (p < 0.05). MGO dose-dependently exacerbated the harmful effects of PA on HUVECs through increased inflammatory responses, impaired angiogenesis, and induction of nitrosative stress. Additionally, high concentrations of MGO altered the expression of genes related to lipid metabolism, including LPL and LP(a). Overall, the results indicate that MGO and PA may play a synergistic role in the occurrence of inflammation, lipid and angiogenesis disorders, and endothelial damage associated with CVDs. Show less

Cyclophosphamide (CTX), a cornerstone in breast cancer combination chemotherapy, frequently induces adverse effects including myelosuppression, gastrointestinal disturbances, hepatic impairment, and alopecia. Chemotherapy-induced alopecia severely impacts patients' quality of life and psychological well-being. Modified Huanjingjian (MHJJ), a traditional Chinese herbal formula, demonstrates clinical efficacy in alleviating chemotherapy-related side effects, yet its mechanisms against CTX-induced alopecia remain uncharacterized. And our main aim was to explore the efficacy and the mechanism of MHJJ in mice. UPLC-QE-Orbitrap-MS characterized MHJJ's chemical composition. A CTX-induced alopecia murine model was established. Systemic toxicity was evaluated through body weight monitoring, automated biochemical analysis (ALT/AST levels), and hematological profiling (WBC/PLT counts). Hair follicle histopathology was assessed via H&E staining. IHC and IF staining quantified proliferation markers and hair follicle stem cell (HFSC) biomarkers. Reduced representation bisulfite sequencing (RRBS) was used to map DNA methylation patterns. Wnt pathway dynamics were analyzed through qRT-PCR and IF staining. We identified 110 bioactive compounds in MHJJ. MHJJ intervention attenuated alopecia severity, restored follicular architecture, and increased follicular density compared to CTX monotherapy (p<0.05). HFSC proliferation markers (Ki67/CD34) showed significant upregulation, while apoptosis markers (Caspase-3) were suppressed. RRBS revealed MHJJ-mediated hypomethylation in differentially methylated regions, with gene body methylation constituting 60% of total methylation changes. Methylation-modulated genes predominantly localized to Wnt signaling pathways: MHJJ enhanced Wnt3/Wnt10a expression while suppressing Cer1/Axin1. Corresponding methylation reductions at promoter and gene body regions were confirmed at mRNA and protein levels. MHJJ mitigates CTX-induced alopecia through epigenetic regulation of HFSCs, specifically via DNA hypomethylation-mediated activation of Wnt3/Wnt10a and suppression of Cer1/Axin1. This mechanism promotes follicular regeneration by restoring Wnt signaling homeostasis, positioning MHJJ as a promising adjuvant for chemotherapy-induced alopecia management. Show less

The scaffold protein IQGAP3 is highly upregulated in most epithelial cancers. While recent studies have highlighted its pivotal roles in cancer cell proliferation and metastasis, a deeper mechanistic understanding of IQGAP3 is currently lacking. We have here used TurboID to map IQGAP3 proximity partners and identified the Wnt signaling members Axin1 and CK1α as IQGAP3-interacting proteins. Our functional studies demonstrated that overexpression of IQGAP3 increases β-catenin levels, while IQGAP3 depletion reduces β-catenin levels in gastric cancer cells. Mechanistically, IQGAP3 disrupts Axin1-CK1α interaction, thereby inhibiting β-catenin phosphorylation and ultimately leading to its accumulation. Importantly, we discovered that IQGAP3 itself is regulated by Wnt signaling, suggesting its involvement in a positive feedback loop in Wnt/β-catenin signaling through interactions with Axin1 and CK1α. These findings identify IQGAP3 as a novel mediator of β-catenin stabilization and underscore its potential as a target for cancer therapy. Show less

Retirement is a major life transition that can alter patterns of movement behaviors (physical activity, sedentary behavior and sleep). While some studies indicate an increase in physical activity post-retirement, others report a rise in sedentary behavior. However, evidence is lacking on how individuals re-allocate time among movement behaviors, particularly using analytical approaches that account for the co-dependence of 24-hour time-use data. Furthermore, little is known about how pre-retirement occupational physical activity (OPA) levels influence physical activity after retirement. This study examined changes in the relative time spent in sleep, sedentary behavior (SB), light physical activity (LPA), and moderate-vigorous physical activity (MVPA) over retirement, and how these changes vary by pre-retirement OPA levels. Data were drawn from the Swedish Retirement Study, which followed 112 participants (47 men, 65 women; age: 60–72) at three timepoints during the retirement transition. Movement behavior and sleep data were collected over a week-long period using thigh-worn accelerometers and wrist-worn actigraphs. Compositional data analysis (CoDA) was employed to account for the co-dependent nature of 24-hour time-use data. Multivariable linear mixed models, adjusted for sociodemographic and health covariates, were used to evaluate the associations between retirement, OPA tertiles, and movement behaviors. In the overall sample, changes in movement behaviors mainly involved sleep. However, substantial variation was observed across OPA tertile groups. The sleep-to-wake time ratio increased in the high OPA group and, to a lesser extent, in the medium OPA group. Regarding physically active and sedentary time, a convergence between the high and low OPA groups was observed, as pre-retirement differences diminished. Specifically, the ratio of physically active time to SB decreased in the high OPA group and increased in the low OPA group. The findings indicate that pre-retirement OPA is a significant factor in understanding changes in movement behaviors during the retirement transition. The reduction in post-retirement physical activity among high-OPA workers may represent a healthier rebalancing rather than a decline, which aligns with the “physical activity paradox” and the “Sweet-Spot Hypothesis”. This evidence highlights the need for tailored interventions for retirees, particularly those from physically demanding occupations. The online version contains supplementary material available at 10.1186/s11556-025-00395-6. Show less

Previous studies suggest that total screen time does not comprehensively predict health behavior. The effects on health behaviors vary by app type. This study examines the association of different app categories (social, entertainment, game, education) related to physical activity (PA) and sedentary behavior (SB) patterns among university students. This study followed 345 university students aged 18–22 for 7 days. Physical activity (PA), and sedentary behavior (SB) were objectively measured using the ActiGraph GT3X-BT accelerometer. Smartphone app usage was tracked via objective daily survey logs. After the 7-day tracking period, semi-structured interviews were conducted to gather detailed information on app usage and physical activity. Data analysis was performed using SPSS 26.0 and R software. In 248 participants (139 males, 109 females), Males had higher daily energy expenditure and more sedentary time (ST) compared to females, who spent more time in light-intensity physical activity (LPA) but less in vigorous-intensity physical activity (VPA). Males showed a positive correlation between entertainment app usage and ST ( Different smartphone app categories show distinct associations with physical activity and sedentary behavior, with social apps linked to more light activity and entertainment/gaming apps to more sedentary patterns, especially in males. Show less

Schiff bases derived from 3-acetyl-4-hydroxycoumarin represent a promising yet underexplored scaffold in medicinal chemistry. Here, we report the efficient synthesis of a series of bisimine derivatives (3a-j) through condensation with structurally diverse amines, achieving yields of 68-95%. Spectroscopic characterization (NMR, IR, MS) confirmed their unique architectures, with 3j emerging as a standout candidate exhibiting anticancer activity comparable to doxorubicin but with superior selectivity against MCF-7 and A549 cell lines. Among the tested derivatives, compound 3a exhibited the most potent antibacterial activity, with the lowest MIC values observed against Gram-positive strains. Notably, 3f (a thiourea analog) demonstrated broad-spectrum antifungal efficacy (MICs: 1.95-31.25 µg/mL), while 3c surpassed ascorbic acid in radical scavenging (96.7% DPPH inhibition). Molecular docking revealed robust interactions between lead compounds (3b, 3c, 3j) and key therapeutic targets (FGFR1, cIAP1-BIR3), suggesting a dual inhibitory mechanism. These findings underscore the potential of coumarin bisimines as versatile platforms for addressing antibiotic resistance and oxidative stress-related pathologies. Show less

Mutations in LRRK2, a leading genetic cause of Parkinson's disease (PD), are linked to immune dysregulation, but the immune profiles in the periphery and central nervous system (CNS) remain incompletely defined. This study utilized a large cohort of serum samples (n = 651) and matched CSF samples (n = 129) from LRRK2 mutation carriers and non-carriers, with and without PD, to assess immune regulators using Luminex immunoassay. After correction for multiple comparisons, LRRK2 mutations were associated with significantly elevated serum levels of SDF-1 alpha and TNF-RII, while CSF markers such as BAFF, CD40L, and IL-27 were nominally reduced. Regardless of LRRK2 status, PD was associated with nominally lower levels of inflammatory analytes in CSF, with minimal changes observed in serum. Correlation analyses revealed distinct immune profiles between serum and CSF, suggesting compartmentalized immune responses. These findings highlight immune alterations in LRRK2 mutation carriers and PD, providing potential serum markers for monitoring immune responses and avenues for mechanistic studies. Show less

Surufatinib is a novel, China-developed small-molecule tyrosine kinase inhibitor that demonstrates high selectivity for VEGFR, FGFR1, and CSF1R. Surufatinib has been approved for the treatment of neuroendcrine tumors, including pancreatic neuroendocrine tumors (PNEN) and non-pancreatic neuroendocrine tumors (N-pNEN). The purpose of this retrospective study is to assess Surufatinib's safety and effectiveness in patients with various advanced solid malignancies. The general clinical statistics and follow-up data of patients treated with Surufatinib for advanced solid tumors at Zhejiang Provincial People's Hospital between January 2021 and April 2024 were gathered. Enhanced CT was used to assess the effectiveness during that time, and cases side effects were gathered. Survival rates of different diseases were analyzed using the Kaplan-Meier method. A total of 28 eligible patients were enrolled in this study. At the end of follow-up, treatment with Surufatinib resulted in the following outcomes: Complete response (CR) in 0 cases (0.0%), Partial response (PR) in 5 cases (17.9%), Stable disease (SD) in 7 cases (25.0%), and Progressive disease (PD) in 16 cases (57.1%). Objective response rate (ORR) and Disease control rate (DCR) were 17.9% and 42.9%, respectively. In the PNEN group, ORR was 33.3%, DCR was 66.7%, median progression-free survival (mPFS) was 11 months, while median overall survival (mOS) was 17 months. In the N-pNEN group, ORR was 14.3%, DCR was 42.3%, mPFS was 6 months and mOS was 7 months. ORR was 8.3%, DCR was 25%, mPFS was 2 months, and mOS was 2 months. The most common adverse reactions included hypoproteinemia, proteinuria, bone marrow suppression and gastrointestinal toxicity, and which of them were grade 1 to grade 2. In advanced solid tumors beyond PNEN, Surufatinib demonstrates clinically meaningful survival benefits for patients refractory to standard therapies, with a generally manageable safety profile. Show less

Senescence of mesenchymal stem cells in bone tissue (BMSCs), the primary progenitors of osteoblasts, is a key contributor to age-related osteopenia and osteoporosis. Aged cells exhibit elevated cellular stress and abnormal accumulation of stress granules (SGs), which contain G-quadruplex (G4) structured nucleic acids and G4-binding proteins. Dhx36, a helicase that unwinds G4 structure, may play a protective role in this context. In this study, we investigated the function of Dhx36 in BMSCs and bone homeostasis by silencing Dhx36 expression in vitro and in vivo. Dhx36 deficiency increased SG formation and impaired their resolution in BMSCs. This was accompanied by reduced expression of G4-containing autophagyrelated genes and diminished autophagic activity. Loss of Dhx36 also enhanced senescence features and impaired BMSC osteogenic differentiation. Dhx36 expression was significantly lower in bone tissue and BMSCs from aged mice, compared to young mice. Moreover, 8-week-old mice with BMSC-specific Dhx36 knockout exhibited reduced bone volume and trabecular number, indicating premature bone loss. Analysis of public singlecell RNA sequencing data further showed that stress induced by 5-fluorouracil in mice suppressed Dhx36 expression in BMSCs, and downregulated genes related to ossification and osteoblast differentiation. Collectively, our findings identify Dhx36 as a regulator of BMSC aging, linking SG dynamics and autophagy to bone homeostasis, and suggest Dhx36 as a potential therapeutic target to prevent age-related bone loss. [BMB Reports 2025; 58(12): 501-510]. Show less

Glioblastoma is the most aggressive form of primary brain tumor, characterized with poor prognosis and resistance to conventional therapies. Increasing evidence points to oxidative stress and redox dysregulation as important contributors to glioblastoma progression. Previously, chloride intracellular channel protein 4 (CLIC4), a redox-sensitive protein, has been implicated in cancer biology. However, its roles in glioblastoma remain poorly understood. Here, we found that CLIC4 expression is upregulated in glioblastoma tissues and cell lines, and is positively correlated with tumor malignancy and poor survival outcomes in patients with glioblastoma. Gene silencing of CLIC4 significantly reduces glioblastoma cell viability, migration, and proliferation in vitro and suppress tumor growth in vivo. Mechanistically, CLIC4 appears to maintain redox homeostasis by regulating mitochondrial functions, including membrane potential, mass, ROS production, and the activity of complexes III and IV. Moreover, a G-quadruplex (G4) structure located in CLIC4 promoter region is related to CLIC4 upregulation by oxidative stress in glioblastoma. This G4 structure can be readily oxidized to a parallel conformation, thereby enhancing its binding with DHX36 protein to promote gene transcription. Collectively, these findings position CLIC4 as a pivotal modulator of oxidative stress in glioblastoma and a potential target for developing therapeutic approaches for the treatment of glioblastoma. Show less

R-loop is a common chromatin feature consisting of a displaced single-stranded DNA and an RNA-DNA hybrid, and dysregulation of R-loop surveillance results in genomic and transcriptomic instability. Although the RNA moiety of most R-loops originates from linear transcripts, circular RNAs (circRNAs), outputs from back-splicing, can also hybridize with the complementary strand of a DNA duplex. However, how circRNA-associated R-loops (ciR-loops) are monitored remains elusive. Here, we identify the DEAD-box RNA helicase Brr2 as an evolutionarily-conserved ciR-loop repressor with dual roles in inhibiting circRNA generation and resolving harmful ciR-loops. Accumulation of ciR-loops caused by loss-of-function of this dual-action factor induces antisense transcription and premature transcription termination for many genes and generates significant DNA damage, which further leads to a series of defects in DNA replication, cell division and cell proliferation. We propose that functional integration of multilayered regulation by a single protein can be an efficient double protection against genome instability. Show less