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An abnormal accumulation of immune cells and inflammation has been described in ascending aortic aneurysm, but the factor driving disease initiation remains elusive. Interestingly, ascending aortic dilatation often occurs alongside aortic regurgitation but rarely with aortic stenosis. We sought to investigate ascending aortic aneurysm initiation by assessing the relation between aortic regurgitation and vascular activation and inflammation. In this prospective cohort study, patients with tricuspid aortic valves undergoing elective open-heart surgery were included. Aortic specimens from organ donors were obtained through the University of Miami Tissue Bank. Spatial transcriptomics measured gene expression in nondilated aortic endothelium, intima, and subintima. Immunohistochemistry determined protein expression. Aortic dimensions were recorded preoperatively and 10 years after surgery using echocardiography. Aortic gene expression affected by physiological blood flow was previously measured in Wistar rats. We show a mesenchymal activation of endothelial cells, possibly mediated by bidirectional flow, in the nondilated ascending aorta of patients with aortic regurgitation, accompanied by intimal infiltration, retention, and oxidation of apoB-containing lipoproteins. We further observed intimal upregulation of genes coding for core proteins of lipoprotein-binding proteoglycans and the Our results highlight a distinct pathological role of aortic regurgitation in ascending aortic aneurysm formation by promoting mesenchymal activation of endothelial cells and lipoprotein-related immune cell infiltration and inflammation in patients with tricuspid aortic valves. We also provide novel insights into the long-term impact of surgical aortic valve replacement on ascending aortic growth and suggest a diagnostic or therapeutic target in oxidized low-density lipoprotein cholesterol. Show less

This study aimed to identify and characterize the sedentary behavior (SED) and breaks accumulation patterns of children and adolescents and investigate the associations of these derived patterns with adiposity indicators. A total of 348 children and 562 adolescents from China participated in this study. Accelerometers were used to measure the bouts of SED and breaks. Adiposity indicators included body mass index (BMI) z-score, fat mass percentage (FM%), and fat mass index (FMI). Latent profile analysis was used to identify the SED and breaks accumulation patterns on the basis of 11 compositions of SED bouts and breaks. Mixed-effects multivariable linear regression models were used to analyze the associations of accumulation patterns with adiposity indicators. Four accumulation patterns were identified in children: "prolonged sitters" (N = 77, 22.1%), "shortened sitters" (N = 90, 25.9%), "LPA breakers" (N = 69, 19.8%), and "MVPA breakers"(N = 112, 32.2%). "MVPA breakers" had significantly lower BMI z-score, FM%, and FMI than "prolonged sitters." No significant differences in adiposity indicators were observed among the other three patterns. In adolescents, "prolonged sitters" (N = 250, 44.5%), "moderate sitters" (N = 211, 37.5%), and "breakers" (N = 101, 18.0%) were identified. "Breakers" had the lowest BMI z-score, FM%, and FMI among the three groups, followed by "moderate sitters" and "prolonged sitters." Different accumulation patterns of SED and breaks were identified for children and adolescents in China. Among them, "MVPA breakers" and "Breakers" are most beneficial to maintain a normal weight status. Health promotion efforts could consider increasing MVPA and decreasing SED time for children and restricting SED to at least 30 min for adolescents to improve their adiposity indicators. Show less

Patients suffering coronary artery disease (CAD) with calcific aortic valve disease (CAVD) are facing worse prognosis with more complex operation strategies. As the primary stage of CAVD, it is helpful to confirm the risk factors of aortic valve calcification (AVC) in advance for exploring the secondary prevention as well as early intervention strategies of CAVD for CAD patients. Lipoprotein(a) [Lp(a)] has been confirmed as the risk factor of both CAD and CAVD. But whether Lp(a) level still affects the occurrence and development of CAVD in CAD patients has not been demonstrated yet. We firstly investigate the predictive value of Lp(a) for new-onset AVC in patients with CAD. Patients who were admitted to the Department of Cardiology, Zhujiang Hospital, Southern Medical University from March 2021 to December 2022 and diagnosed with CAD by elective coronary angiography(CAG)were included when met the criteria. Baseline data were collected through the electronic medical record system. Patients were followed up to repeat echocardiography with an interval at least 6 months, which was up to September 2023. The primary endpoint was new-onset AVC, according to which patients were divided into new-onset AVC group (n = 43) and the opposite(n = 165). Analyses were conducted using SPSS 26.0 and GraphPad Prism 10.1.2. A total of 208 patients with CAD were included, with a median follow-up time of 16 (12, 20) months. Compared with AVC-free group, patients with new-onset AVC had higher body mass index (BMI) (p = 0.003), higher proportion of tree-vessel disease(p < 0.001), higher rates of diabetes (p = 0.001) and atrial fibrillation (p = 0.017), higher Lp(a) levels(p < 0.001), lower left ventricular systolic function (LVEF) (p < 0.001) and thicker left ventricular posterior wall (LVPW) (p < 0.001). Increased BMI, three-vessel disease, Lp(a) > 26.65 nmol/L, increased LVPW were found independent risk factors for new-onset AVC. Using a cutoff level of 26.65 nmol/L, Lp(a) predicted new-onset AVC with a sensitivity of 79.1% and a specificity of 59.4% (AUC: 0.740, 95% CI: 0.657-0.823, p < 0.001). When combined with BMI, there present a higher AUC value of 0.752(95%CI: 0.668-0.836, p < 0.001); however, the statistical significance remains limited (p = 0.732). High-level serum Lp(a) was independently associated with new-onset AVC in patients with CAD. Lp(a) demonstrates a significant predictive value for the onset of new AVC in CAD patients, with an established cut-off threshold of 26.65 nmol/L. Show less

Salmonella enterica serovar Typhimurium (S. Typhimurium) is a facultative intracellular bacterial pathogen that grows within a specialized membrane-bound compartment known as the Salmonella-containing vacuole (SCV). The molecular composition and regulatory mechanisms governing SCV dynamics remain incompletely understood. In this study, we employed proximity-dependent biotin identification (BioID) to analyze the SCV proteome during infection. For this, we targeted the UltraID biotin ligase to the SCV by fusing it to a type 3 secreted effector. We demonstrate that the bacteria express and translocate the effector-UltraID fusion protein directly into host cells for labeling of the cytosolic face of the SCV surface. Proteomic analysis of biotinylated proteins revealed previously undescribed proteins associated with the SCV, including regulators of vesicular trafficking, cellular metabolism and lipid transport. Among these, VPS13C, a lipid transporter and membrane contact site protein, was identified as a critical regulator of SCV morphology and fission. Functional studies revealed that VPS13C also promotes ER-SCV contact formation, controls SCV positioning in host cells, and facilitates cell-to-cell spread by the bacteria. Together, our findings highlight the utility of BioID as a tool to study host-pathogen interactions in the context of infection and characterize VPS13C as a novel modulator of the intracellular life cycle of S. Typhimurium. Show less

Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by a tendency to recur and a poor prognosis. Epithelial mesenchymal transition (EMT) and proliferation of nasal epithelial cells (NECs) play an important role in CRSwNP development. Secretogranin II (SCG2) is reported to be an EMT-related gene, but its role in CRSwNP has not been reported. In this study, human NECs were cultured in an air-liquid interface culture system and stimulated with IL-13 to maintain or promote the CRSwNP state. EMT-associated protein expression levels were examined by real-time quantitative PCR and Western blot. Dual luciferase, chromatin immunoprecipitation, and co-immunoprecipitation experiments were used to validate the regulatory relationship between SP1, SCG2, and ubiquitin-1 (UBQLN1). The nuclear translocation of Snail was examined by immunofluorescence assay. The results showed that the expression levels of SP1, SCG2, and UBQLN1 were all up-regulated in CRSwNP tissues. SCG2 knockdown inhibited EMT and proliferation of human NECs. Mechanistically, SP1 promoted the proliferation and EMT of human NECs by transcriptionally increasing SCG2 expression. SCG2 activated the AKT serine/threonine kinase (AKT)/glycogen synthase kinase-3 beta (GSK-3β)/Snail family transcriptional repressor 1 (Snail) pathway and promoted Snail nuclear translocation via UBQLN1. In short, SCG2, which is transcriptionally up-regulated by SP1, promotes the proliferation and EMT of human NECs by activating the AKT/GSK-3β/Snail pathway through binding to UBQLN1. Show less

Viral and neurodegenerative proteases, such as the cysteine protease and aspartyl protease, offer strategic targets in a multitarget therapeutic approach for Alzheimer's disease, especially when viral infection may exacerbate neurological degeneration. To establish a multitarget therapeutic for treating Alzheimer's disease, we chose β-secretase (BACE-1), an aspartyl protease, and the SARS-CoV-2 main protease (Mpro), a cysteine protease, as dual targets. In search of BACE-1 and M Show less

Tumor-induced osteomalacia (TIO) is a rare disorder caused by a phosphaturic mesenchymal tumor (PMT) secreting fibroblast growth factor 23 (FGF23). The aim of this study was to analyze PMTs for their transcriptomic characteristics. We performed single-cell RNA (n = 3) alongside bulk RNA sequencing of PMTs (n = 5) and surrounding bone tissue (n = 4) obtained during tumor removal in 10 patients (age 44 (41;64), serum phosphate (Pi)- 0.54 (0.43; 0.59) mM/L, FGF23-113 (40; 205) pg/ml). We revealed a total of 22,449 cells divided into 13 different categories. We identified the heterogeneity of the PMT cell cluster and subsequently divided it into two tumor clusters 1 and 2 characterized by the deeper epithelial-mesenchymal phenotype transition, higher FGF23 expression as well as various SNP and CNV. We further identified tumor cell differentiation driving regulons ERG and EGR3, based on scoring by allele expression and velocity based pseudotime on a trajectory that may play a critical role in the tumorigenesis of PMTs. In both single-cell and bulk transcriptome analysis we found upregulation of vesicle-specific and exocytosis associated genes (SLC30A3, SYT1, STX1A and SNAP25) which most likely represent molecular mechanisms of active secretion in all PMT samples. We report transmembrane protein coding genes expressed in all PMTs specifically in tumor cell clusters (PHEX, ERBB4, PCDH7, LRRFIP2) which are suggested as potential diagnostic targets. We confirmed the presence of FN1-FGFR1 fusion genes and Klotho expression in most PMTs (6 out of 8). Conclusion: specific SNARE proteins gene upregulation along with transcriptional signatures of PMT offer new insights into its pathogenesis which may be further studied for diagnostic and therapeutic interventions. Show less

Metabolic diseases, like type 2 diabetes mellitus and obesity, show a growing public health concern in Sri Lanka. Genetic predisposition and diet contribute to metabolic disease risk, but there are limited investigations into the impact of gene-diet interactions on metabolic disease risk in the Sri Lankan population. In this study, we examined whether a metabolic genetic risk score (GRS), constructed from 10 single nucleotide polymorphisms (SNPs), interacts with dietary factors to influence metabolic health indicators in Sri Lankan adults. This cross-sectional study included 105 generally healthy adults aged 25-50 years from the GOOD (Genetics of Obesity and Diabetes) study. Anthropometric, biochemical, and dietary data using food frequency questionnaires were collected using validated methods. Genotyping was performed using the KASP A statistically significant interaction was identified between the 10-SNP metabolic GRS and polyunsaturated fatty acid (PUFA) intake on waist circumference (P This study provides novel insights to understand gene-diet interactions affecting metabolic traits in Sri Lankans. The findings suggest that higher PUFA intake may mitigate genetic susceptibility to central obesity, highlighting the importance of personalized dietary recommendations for metabolic disease prevention. Further studies in larger cohorts are warranted to confirm this finding. Show less

Metabolic (dysfunction)-associated steatotic liver disease (MASLD), the hepatic consequence of metabolic syndrome, affects 30% of the global population. Studies in animals and humans investigating the effect of fructose on MASLD present conflicting findings, while in vitro methods often fail to add meaningful evidence due to acute exposures (<72 h) and non-physiological concentrations. This study aimed to determine the effect of fructose on triglyceride (TG) accumulation in HepG2 cells following acute and chronic exposures and assess its effect on the expression of genes related to de novo lipogenesis (DNL). TG concentration was measured after 48 h in response to fructose (20 mM) or glucose (20 mM), with or without a fatty acid mixture (oleic acid/palmitic acid 110 µM/55 µM), in low (5.5 mM)- and high (25.5 mM)-glucose media. To model chronic exposure, cells were maintained in fructose, glucose, or fatty acids for 28 days and the TG concentration was determined every 7 days. The effect of fructose on DNL regulators ( Neither fructose nor glucose, with or without fatty acids, changed the TG levels in cells at 48 h and the media glucose concentration had no effect on this result. Similarly, fructose did not increase TG levels after 28 days. While fructose and glucose did not affect key DNL genes at 6 h, the fatty acid mixture reduced This study shows that fructose did not significantly impact TG synthesis or DNL gene expression in the HepG2 cell model. Future studies should consider using primary human hepatocytes or more complex in vitro models. Show less

Cardiovascular and metabolic disorders, particularly diabetes and obesity, are highly prevalent in the Middle East and North Africa (MENA) region, exhibiting some of the highest global incidence rates. These conditions significantly increase the severity of infectious diseases, notably COVID-19, leading to a rise in long-COVID cases among affected individuals. Furthermore, the MENA region's extreme temperatures exacerbate cardiovascular issues by elevating heart rates and blood pressure, increasing dehydration and blood viscosity. Extracorporeal therapies, such as apheresis, effectively reduces plasma lipids and inflammatory markers. Furthermore, apheresis has shown promise in reducing autoantibodies associated to long-COVID. Our previous research indicated that apheresis alleviates symptoms in patients with long-COVID and chronic fatigue syndrome. In this study, we treated 24 male patients from the MENA region suffering from chronic fatigue and/or different metabolic diseases such as diabetes, dyslipidemia, or obesity, using double filtration plasmapheresis. Comprehensive plasma analyses were performed before and after apheresis to assess lipid profiles, inflammatory markers, and autoantibodies, revealing significant changes following the procedure. Genetic analyses on a subgroup of the patients showed no mutations in the LDLR, APOB, APOE, PCSK9, LIPA, and LDLRAP1 genes known to be associated with predispositions to monogenic lipid disorders. However, all patients in this subgroup demonstrated an intermediate to high likelihood that their elevated lipid levels have a polygenic basis. These findings suggest that implementing apheresis in the MENA region could significantly improve health outcomes and life expectancy for affected individuals. Show less

The glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR) are important incretin receptors that are therapeutic targets for the treatment of type 2 diabetes and obesity. This study extensively characterised the metabolic phenotype of mice with global deletion of either the GLP-1R or GIPR side by side under identical conditions. Age-matched male wild-type (WT) C57Bl6NTac, GLP-1RKO or GIPRKO mice were placed on a high-fat or chow diet for 12 weeks, and a range of in vivo (weight gain, food intake, glucose tolerance, insulin tolerance, and whole-body energy metabolism) and ex vivo (white adipocyte lipolysis, brown adipose tissue and liver mitochondrial function, adipocyte and islet size, and hepatic steatosis) parameters were measured. While both WT and GLP-1RKO mice gained weight similarly on a HFD, obese high-fat-fed GLP-1RKO mice had altered glucose and insulin tolerance, and exhibited hepatic steatosis, highlighting the physiological importance of the GLP-1R in the regulation of blood glucose and lipid homoeostasis. In contrast, GIPRKO mice were partially resistant to diet-induced obesity compared to the WT mice, which was associated with a small reduction in food intake and intact epididymal and subcutaneous white adipocyte β-adrenoceptor-mediated lipolysis. Similarly, WT mice treated with a GIPR antagonist prevented weight gain due to a reduction in food intake on a HFD. These findings provide further support that the GLP-1R is important for normal glycaemic control, whereas the GIPR may play a role in the regulation of body weight. Show less

Unimolecular peptides targeting the receptors for glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and glucagon (GCG) have been shown to improve glycaemic management in both mice and humans. Yet the identity of the downstream signalling events mediated by these peptides remain to be elucidated. Here, we aimed to assess the mechanisms by which a validated peptide triagonist for GLP-1/GIP/GCG receptors (IUB447) stimulates insulin secretion in murine pancreatic islets. Islets were isolated from wild-type (WT), Gipr-knockout (Gipr The triagonist promoted glucose-stimulated insulin secretion (GSIS) to a greater degree than co-administration of conventional mono-agonists in WT mouse islets. The triagonist-induced increase in GSIS was unchanged in the absence of either Gipr or Gcgr. However, the triagonist failed to enhance insulin secretion in islets lacking both Glp-1r and Gipr and upon treatment with the GLP-1 receptor-specific antagonist exendin-3 (9-39). Similarly, the specific blocking of Gαq signalling with YM254890 or transient receptor potential melastatin 5 (TRPM5) with triphenylphosphine oxide (TPPO) suppressed the triagonist-induced enhancement of GSIS. In vivo assessment of high-fat-fed Trpm5 Triagonist-induced augmentation of GSIS is primarily mediated through its interaction with the GLP-1 receptor and subsequent activation of the Gαq-TRPM5 signalling pathway. Given that Gαq is a key player in the amplification of GSIS, particularly under diabetic conditions, these findings highlight a GLP-1 receptor-centric pharmacological profile that underlies the potent effects of this multi-receptor agonist. Show less

Ischemic stroke (IS) treatment remains a significant challenge. This study aimed to identify potential druggable genes for IS using a systematic druggable genome-wide Mendelian Randomization (MR) analysis. Two-sample MR analysis was conducted to identify the causal association between potential druggable genes and IS. This involved integrating data from the druggable genome, expression quantitative trait loci (eQTL), protein quantitative trait loci (pQTL), and genome-wide association study summary data of IS. Sensitivity and Bayesian colocalization analyses were used to validate the causal relationships. In addition, phenome-wide MR analysis was used to evaluate the side effects or other indications of the identified druggable genes, and their functions were explored using the Metascape database. Our MR analysis identified 16 potential druggable genes significantly associated with IS, three of which were significant in the two QTL datasets. Colocalization analysis revealed six druggable genes (two in the blood eQTL [CALCRL, KCNJ11], two in the brain eQTL [NEK3, THSD1], one in the blood pQTL [MMP12], and one in the brain pQTL [HSD17B12]) had a PP.H4 greater than 0.75. Phenome-wide MR analysis indicated that CALCRL is correlated with benign breast neoplasms, and HSD17B12 is associated with essential hypertension and hypertension. This study identified six potential druggable genes (CALCRL, KCNJ11, NEK3, THSD1, MMP12, and HSD17B12) associated with IS risk. Further research is required to explore the specific roles of these druggable genes in the onset and progression of IS. Show less

Given the heightened risk of complications during pregnancy in women of advanced maternal age (AMA), it is crucial to understand the metabolites in amniotic fluid and umbilical cord blood in this demographic.  METHODS: We analyzed the metabolites in amniotic fluid from 60 women, divided into two groups: the AMA group (aged 35 or above, n = 29), and the control group (aged below 35, n = 31). We then conducted a follow-up analysis on the metabolites of umbilical cord blood from a sample of 19 women (9 from the AMA group, and 10 from the control group). In total, we identified 96 differential metabolites in the amniotic fluid and 146 in the cord blood between the two groups. The significant changes in the metabolites of the amniotic fluid mainly involved sphingolipid metabolism, steroid hormone biosynthesis, and cholesterol metabolism. Conversely, the preliminary significant changes in cord blood metabolites were mainly linked to metabolism of arginine and proline, degradation of valine, leucine, and isoleucine, fatty acid metabolism, alanine, aspartate and glutamate metabolism, and the biosynthesis of unsaturated fatty acids. Further analysis revealed a significant upregulation of lysophosphatidylcholine (LPC), phosphatidylcholine (PC), and taurodeoxycholic acid in the amniotic fluid. In the cord blood, various forms of lysophosphatidic acid (LPA), sphingomyelin (SM), phosphatidylglycerol (PG), LPC, and PC were found preliminarily to be either upregulated or downregulated. Our results preliminarily showed that the metabolites of amniotic fluid and cord blood in AMA women differed significantly from the control group. These findings provide crucial insights for future research to explore the role of metabolomics in adverse pregnancy outcomes in AMA women. Show less

Calcific aortic valve stenosis (CAVS) is the most prevalent valvular heart disease and a growing global health concern. Aortic sclerosis (ASc) and aortic stenosis (AS) represent a continuum of progressive disease characterized by leaflet thickening, inflammation, lipid deposition, and calcification. Lipoprotein(a) [Lp(a)], with its pro-atherogenic, pro-inflammatory, and pro-calcific properties, has emerged as a key contributor to this process. While its role in atherosclerotic cardiovascular disease is well established, the relationship between Lp(a) and CAVS has been demonstrated in several key studies; however, the available evidence remains limited in volume, and important gaps persist in understanding mechanisms, risk stratification, and therapeutic implications. A systematic literature search was conducted in PubMed, Cochrane Library, ScienceDirect, Medline, ResearchGate, Embase, and Google Scholar in accordance with PRISMA guidelines. Eligible studies included observational designs (cross-sectional, cohort, case-control) and randomized trials evaluating associations between Lp(a) levels, genetic variants, and CAVS. Study quality was assessed using the Newcastle-Ottawa Scale (NOS). Eighteen studies met the inclusion criteria, comprising six case-control, six cohort, and six cross-sectional studies with a total of 153,192 participants. No randomized controlled trials were identified. Elevated Lp(a) levels were consistently associated with an increased risk of AS and aortic valve calcification (AVC), with a dose-dependent effect. The risk was highest at levels ≥50 mg/dl, though some evidence supported risk at ≥30 mg/dl. Genetic analyses identified rs10455872 as a significant risk allele, while rs3798220 showed inconsistent associations. Multi-ethnic cohorts highlighted racial variability: Afro-Caribbean individuals had higher baseline Lp(a) levels but lower AVC prevalence than Caucasians. Lp(a) is an independent risk factor for CAVS, influenced by both concentration and genetic variation. Early screening and emerging Lp(a)-lowering therapies, including antisense oligonucleotides, small interfering RNA, and PCSK9 inhibitors, may help mitigate disease progression. Further randomized trials are needed to determine whether Lp(a) reduction translates into cardiovascular and valvular benefit. https://www.crd.york.ac.uk/PROSPERO/view/CRD42024533835, PROSPERO CRD42024533835. Show less

Gene-environment (GxE) interactions crucially contribute to complex phenotypes. The statistical power of a GxE interaction study is limited mainly due to weak GxE interaction effect sizes. Joint tests of the main genetic and GxE effects for a univariate phenotype were proposed to utilize the individually weak GxE effects to improve the discovery of associated genetic loci. We develop a testing procedure to evaluate combined genetic and GxE effects on multiple related phenotypes to enhance the power by merging pleiotropy in the main genetic and GxE effects. We base the approach on a general linear hypothesis testing framework for multivariate regression of continuous phenotypes. We implement the generalized estimating equations (GEE) technique under the seemingly unrelated regressions (SUR) setup for binary or mixed phenotypes. We use extensive simulations to show that the test for joint multi-phenotype genetic and GxE effects outperforms the univariate joint test of genetic and GxE effects and the test for multi-phenotype GxE effect concerning power when there is pleiotropy. The test produces a higher power than the test for the multi-phenotype marginal genetic effect for a weak genetic and substantial GxE effect. For more prominent genetic effects, the latter performs better with a limited increase in power. Overall, the multi-phenotype joint approach offers robust, high power across diverse simulation scenarios. We apply the methods to lipid phenotypes with sleep duration as an environmental factor in the UK Biobank. The proposed approach identified ten independent associated genetic loci missed by other competing methods. In a multi-phenotype analysis of apolipoproteins, ApoA1, and ApoB, our approach discovered two distinct loci considering sleep duration as the environmental factor. Show less

Patients with systemic lupus erythematosus (SLE) frequently experience poor sleep quality. This cross-sectional study aimed to identify distinct sleep disturbance profiles in SLE patients and examine their associations with demographic, disease-related, and psychosocial factors. A total of 331 patients with SLE were included. Latent profile analysis (LPA) was conducted using the tidyLPA package. Logistic regression models were constructed to assess associations between the identified sleep disturbance clusters and physical and psychological outcomes, based on factors significantly influencing the LPA results. The physical and psychological outcomes were estimated using the Hospital Anxiety and Depression Scale (HADS) and the Fatigue Severity Scale (FSS). Sleep clusters were analyzed through multivariate logistic regression. Three distinct sleep disturbance profiles were identified: Cluster 1 (severe sleep disturbance) (n = 42), Cluster 2 (moderate sleep disturbance) (n = 174), and Cluster 3 (mild sleep disturbance) (n = 115). LPA yielded an entropy value of 0.996 for the three-cluster model. The mean total Pittsburgh Sleep Quality Index (PSQI) score for the SLE samples was 7.59 ± 3.44. Among the various sleep quality domains, sleep latency and subjective sleep quality were the most significantly affected in SLE patients. The analysis revealed that disease duration, severity of fatigue, use of calcium supplements, impaired renal function, anxiety, and depression were all significant factors influencing cluster membership. This study identified three distinct patterns of sleep disturbance among SLE patients. Cluster 1 (severe sleep disturbance) was characterized by prolonged sleep latency despite high sleep efficiency and subjective sleep quality scores. Cluster 2 (moderate sleep disturbance) exhibited longer sleep duration than Cluster 1, while Cluster 3 (mild sleep disturbance) had the lowest scores across all sleep quality domains. These findings suggest that sleep disturbance profiling may facilitate personalized sleep management strategies for patients with SLE. Show less

As a vital component of the immune system, macrophages play a critical role in the progression of asthma. The two classic polarization states of macrophages, M1 and M2, exhibit distinct functions. M1-polarized macrophages eliminate pathogens through the secretion of pro-inflammatory cytokines, while M2-polarized macrophages secrete anti-inflammatory factors to facilitate tissue repair. However, in asthma, the activation of M1 macrophages is often associated with excessive inflammatory responses, whereas M2 macrophages contribute to airway remodeling and chronic inflammation. These processes collectively exacerbate airway inflammation and remodeling, thereby aggravating asthma symptoms. Reactive oxygen species (ROS), as crucial signaling molecules, have been shown to regulate macrophage polarization and promote both M1 and M2 polarization states. This review summarizes the primary endogenous and exogenous sources of ROS in asthma and elaborates on the mechanisms by which ROS influence M1/M2 polarization of macrophages. Endogenous ROS arise chiefly from NOX2, xanthine oxidase, peroxisomes and mitochondria, whereas ozone and fine particulate matter are major exogenous sources. ROS activate MAPK, NF-κB and NLRP3 cascades, boosting IL-1β, IL-6 and IL-27 release by M1 cells, while low NOX2 flux or mitochondrial H Show less

Symptoms of social anxiety and depression often co-occur, but many questions remain about symptom-level co-occurrence and the heterogeneity of symptom presentations across individuals, as well as their emotional functioning. This study aimed to investigate the co-occurrence of social anxiety and depressive symptoms in adults and variations in emotional functioning linking symptom heterogeneity. This study used a person-oriented approach, Latent Profile Analysis (LPA), to identify distinct profiles (i.e., subgroups) in a UK adult sample ( Four profiles were identified: Comorbid (12.61%), Dysphoric (10.36%), Socially Anxious (36.94%), and Low Distress (40.09%), replicating the four-profile solution revealed in prior research on adolescents. The Comorbid subgroup reported the most pronounced emotional dysfunction, with higher daily negative affect, lower positive affect, and greater emotion dysregulation than the other three subgroups. The Low Distress subgroup reported the best emotional functioning. The cross-sectional study design restricts our ability to evaluate the long-term stability of the identified profiles. Nevertheless, this study illuminates the diverse ways social anxiety and depression intertwine, underscoring the necessity of transdiagnostic interventions that cater to a wide range of symptom patterns and emotional functioning. Show less

A few species have evolved multiple sex chromosome systems with more than two Xs or Ys due to sex chromosome-autosome translocations. Among vertebrates, frogs (Anura) have the highest known number of such neo-sex chromosome systems, making them interesting for studying how such systems evolve. In this work, we investigated two Leptodactylus species, L. pentadactylus (LPE) and L. paraensis (LPA), with large ring multivalents in male meiosis, using genomic and cytogenetic investigation of repetitive DNA sequences, including satellite DNAs (satDNAs), and transposable elements (TEs). SatDNA mapping identify individual chromosomes in the LPE ring, and morphologies suggest that all chromosomes are shared with the LPA ring although a common ring origin is not firmly supported. In situ mapping suggests recent satDNA accumulation in subtelomeric regions since the split from the outgroups, likely unrelated to the translocations that created sex-linkage, which probably involved breaks in the pericentromeric regions. Show less

The transition from elementary to junior high school presents developmental challenges, particularly for students with neurodevelopmental traits. This study examined how autism, attention-deficit/hyperactivity disorder (ADHD) traits and effortful control (EC) were related to changes in mental health during this transition in a large Japanese community sample (N = 2,564). This longitudinal study used data from a community-based cohort of Japanese students and their parents/guardians (N = 2,692). Autism traits were measured using the Autism Spectrum Screening Questionnaire (ASSQ). ADHD traits were assessed with the Attention Deficit/Hyperactivity Disorder Rating Scale (ADHD-RS). Effortful control (EC) was evaluated using the "Effortful Control" subscale of the Early Adolescent Temperament Questionnaire-Revised (EATQ-R). Mental health problems were assessed using the Strengths and Difficulties Questionnaire (SDQ) before and after the transition. Generalized estimating equations (GEE) and latent profile analysis (LPA) were conducted to examine associations among autism and ADHD traits, EC, and mental health across the transition. GEE revealed that higher autism and ADHD traits and lower EC predicted more severe mental health problems. The LPA identified three distinct subgroups characterized by high, moderate, and low SDQ scores across the transition. The high-SDQ group showed elevated autism and ADHD traits and low EC, whereas the low-SDQ group showed low auism and ADHD traits and high EC. The moderate group exhibited intermediate levels for all measures. These findings suggest that pre-existing mental health problems tend to persist during the transition period. Importantly, students with higher autism and ADHD traits and lower EC exhibited diverse adaptation patterns-some improved while others worsened-highlighting that high autism traits are not necessarily associated with post-transition mental health deterioration. This underscores the need for support tailored to neurodevelopmental and self-regulatory profiles. Show less

Cardiovascular disease remains a major global health challenge, with dyslipidaemia being a key modifiable risk factor. While low density lipoprotein cholesterol (LDL-C) is the primary target for lipid-lowering therapies, recent evidence highlights the importance of triglycerides, apolipoprotein B (apoB), and lipoprotein(a) [Lp(a)] for residual cardiovascular risk. Current lipid-lowering therapies target key enzymes and proteins involved in cholesterol and lipid metabolism. Statins inhibit HMG-CoA reductase, reducing cholesterol biosynthesis and increasing LDL receptor (LDLR) expression in the liver. Bempedoic acid inhibits ATP citrate lyase, the enzyme upstream of HMG-CoA reductase in the mevalonate pathway, offering an alternative to statins by selectively acting in the liver, minimizing muscle-related side effects. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors [evolocumab, alirocumab, inclisiran, lerodalcibep, and enlicitide decanoate (MK0616)] prevent LDLR degradation, while ezetimibe limits intestinal cholesterol absorption. Emerging lipid-lowering targets include angiopoietin-like 3 protein (ANGPTL3) and apolipoprotein C-III (apoC-III). Inhibiting ANGPTL3 reduces both triglycerides and LDL-C independently of LDL receptor. Inhibition of apoC-III unleashes lipoprotein lipase (LPL) activity, promoting triglyceride-rich particle catabolism, even in complete LPL deficiency. Cholesteryl ester transfer protein (CETP) inhibition also increases the catabolism of apoB-containing lipoproteins. Ongoing research into strategies to reduce Lp(a), primarily but not exclusively through antisense therapies, aims to demonstrate the cardiovascular benefits of targeting this lipoprotein. In summary, the field of targets for lipid and lipoprotein lowering is constantly evolving and offers new strategies for patients resistant to current therapies or with specific lipid profile abnormalities. Show less

Glucose-dependent insulinotropic peptide receptor (GIPR) stimulates insulin release and regulates metabolic homeostasis. GIPR function is shaped by spatiotemporal trafficking of this G protein-coupled receptor (GPCR). While GPCR endocytosis is traditionally associated with β-arrestin, GIPR internalization is only modestly dependent on this pathway. In this study, we demonstrate that GIPR engages a cytoskeletal motor, myosin VI to drive receptor endocytosis. GIPR engages the adaptor-motor complex through a PDZ-binding motif (PBM) at its C-ail. Interestingly, β-arrestin binding to phosphorylated residues upstream of the PBM enhance myosin VI recruitment and activation. GIPR internalization is dependent on both receptor phosphorylation and the PBM site to recruit β-arrestin and myosin VI, respectively. Synergistic engagement of β-arrestin and myosin VI results in desensitization of GIP-stimulated cAMP signaling while activating pERK1/2 from endosomal compartments. Blocking myosin VI activity enhances insulin release in pancreatic beta cells, demonstrating a novel role for this pathway in regulating the physiological effects of GIPR. Our findings highlight the direct convergence of two independent trafficking pathways at the level of the receptor C-tail, with implications for the nuanced regulation of individual GPCRs through the differential engagement of β-arrestin and myosin VI. GIPR has emerged as a frontline drug target in type 2 diabetes and obesity. Cellular effects of GIPR are regulated by receptor internalization and desensitization through mechanisms that are unclear. Here, we identify a novel GIPR trafficking pathway through the engagement of a cytoskeletal motor, myosin VI. Myosin VI and β-arrestin synergistically regulate GIPR endocytosis, signaling and insulin response in pancreatic beta cells. Our study highlights the convergence of two parallel trafficking mechanisms in GPCR function with potential implications in targeting metabolic disorders. Show less

Liver X receptors (LXRα and LXRβ) are nuclear receptors critical for lipid homeostasis and inflammation regulation, making them potential therapeutic targets for atherosclerosis and inflammatory diseases. While LXR agonists hold promise, their use is limited by adverse effects on hepatic lipogenesis. Riccardin C (RC) has shown promise as an LXRα partial agonist/ LXRβ antagonist with cell-type-selective properties. This study investigates the molecular mechanisms behind RC-induced LXRα activation. A series of LXRα/β chimera and point-mutated receptors was generated to identify the domains and residues required for RC-induced transactivation. Functional analysis revealed that mutating alanine-327 of LXRα to LXRβ-type histidine in helix 6 impaired RC-induced association with coactivator peptides, reducing transactivation. Conversely, mutating histidine-341 of LXRβ or the inactive chimera to the LXRα-type alanine partially restored the response to RC, highlighting the significance of the A327H mutation in selective LXRα activation by RC. Furthermore, in vivo experiments revealed that when administered orally to mice, RC selectively induced hepatic and intestinal Abca1 expression without stimulating hepatic lipogenic gene expression, thereby elevating HDL levels without increasing plasma and hepatic triglycerides. These findings offer valuable insights for the development of novel therapeutic agents. Show less

Glucose-dependent insulinotropic polypeptide (GIP) is a gut-derived incretin hormone, and pharmacologic modulation of central GIP receptors (GIPR) improves energy homeostasis. Recent reports have demonstrated that GIPR agonism is also anti-aversive. However, the mechanisms by which GIPR signaling impact food intake and aversion are incompletely understood. Here, we show that GIPR agonism abrogates the aversive and enhances the anorexigenic effects of the pro-inflammatory cytokine interleukin-1β (IL-1β). Aversion-encoding parabrachial calcitonin-gene related peptide (CGRP) neurons were required for IL-1β-induced conditioned taste avoidance (CTA) but not anorexia. Moreover, systemic IL-1β increased Show less

Polycystic ovary syndrome (PCOS) is a complex, multi-system, heritable endocrinopathy that is a common cause of anovulatory infertility in reproductive-aged women. While insulin resistance (IR) is not a diagnostic feature, it is widespread in women with PCOS, and often more severe than in women of similar age and BMI. Conversely, women with rare Mendelian disorders of IR also present with features of PCOS. We hypothesize that PCOS is driven by underlying IR, which can be evaluated through a genetic approach. We curated and stratified 310 genes related to three mechanisms of IR using molecular and clinical criteria. We evaluated protein-altering genetic variation in 102 insulin signaling genes, 29 obesity genes, and 22 dyslipidemia genes from whole-exome sequencing data from 675 PCOS patients. 40 insulin signaling genes, 12 obesity genes, and 10 dyslipidemia genes were significantly enriched for protein-altering variation in PCOS cases compared to healthy population controls. Variants in these 62 significantly enriched genes affected 51% of PCOS cases in our study cohort. The 15 highest ranked genes were selected for follow-up: Show less