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Acquired renal cysts (ARC) are associated with kidney function decline, necessitating novel dietary pattern (DP) analyses in large cohorts. This UK Biobank prospective cohort study (2006-2010) included participants with ≥2 dietary records, excluding those with severe kidney damage. The constructed comprehensive dietary pattern integration (CDPI) utilized reduced rank regression (RRR) and latent profile analysis (LPA). ARC cases (ICD-10: N28.1) were assessed via Cox regression for risk and dose-response, with NMR metabolites examined as mediators. Among 119,709 participants (median follow-up: 10.57 years), 850 ARC cases were identified. Lipid-rich and hyperglycemic diets increased ARC risk [e.g., HRs for G1.DP1: 1.080 (1.024, 1.139); G1.DP2: 1.144 (1.048, 1.249)], while micronutrient-rich diets showed weak protective effects [G4.DP1: 0.943 (0.892, 0.998)]. LPA confirmed RRR findings, and 7/251 NMR metabolites had significant mediating effects. Diets high in fat (cheese, butter, pizza) and sugar (chocolate, sugary drinks) elevated ARC risk, whereas micronutrient- and fiber-rich diets (vegetables, fruit, lean poultry, nuts, eggs) were protective. Key mediators included branched-chain amino acids, IGF-1, and RBC distribution width. Show less

Early biomarkers are needed to predict the long-term persistence of rheumatical symptoms in patients infected with Chikungunya virus (CHIKV). This nested case-control study aimed to assess immunological factors during the early phases of CHIKV infection to predict the risk of post-CHIK chronic rheumatism (pCHIK-CR) in adult patients of two prospective cohorts. We evaluated 46 febrile patients (median age: 33.5 years; IQR: 19 years; women: 50.0%) with CHIKV infection confirmed during the 2014-2015 outbreak in Santander, Colombia. The participants were classified by a rheumatologist as either cases (pCHIK-CR) or controls (WoRM, without rheumatical manifestations). We quantified serum levels of IL-4, IL-6, IL-8/CXCL-8, IL-27, CCL-2, CXCL-9, CXCL-10, and IgG using Luminex and ELISA assays during the acute and subacute phases of infection. Then, we evaluated the association of these immune factors with the case-control status using piecewise logistic regression adjusted for age and sex. There were non-linear associations between IL-8/CXCL-8, CXCL-9, and CXCL-10 with pCHIK-CR. Increases in the levels of IL-8/CXCL-8 (<35.7 pg/mL), CXCL-9 (≥6000 pg/mL), and CXCL-10 (≥36,800 pg/mL) were significantly associated with a reduced risk of pCHIK-CR (adjusted ORs: 0.85, 0.96, and 0.94, respectively). These results suggest that increases in IL-8/CXCL-8, CXCL-9, and CXCL-10 levels, measured in the early stages of CHIKV infection, may predict a chronic disease risk. This suggests the possibility that an early and strong immune response could contribute to enhancing CHIKV control and potentially reduce the risk of persistent joint symptoms. Given their expression patterns and timing, these three immune factors may be considered promising biomarker candidates for assessing the risk of chronic rheumatologic disease. These findings should be considered as exploratory and validated in additional cohort studies. Show less

Genetic and numerous epidemiologic studies have identified lipoprotein (a) [Lp(a)] as a risk factor for atherothrombotic diseases. The structure of Lp(a) is similar to plasminogen and tissue plasminogen activator and it competes with plasminogen for its binding site, leading to reduced fibrinolysis. Furthermore, since Lp(a) stimulates the secretion of plasminogen activator inhibitor-1, it may lead to thrombogenesis. In this cross-sectional study, we aimed to investigate Lp(a) levels in patients with mechanical prosthetic valve thrombosis (MPVT). Blood samples for Lp(a) determination were obtained from 80 MPVT patients (median age: 48.5 (39-59.75) years; 47 male) and 75 age and sex matched controls (median age: 52 (39-63) years; 44 male) with normally functioning mechanical prosthetic valves. The Lp(a) levels in the PVT group were significantly higher than in the controls [22(16.2-39.4) vs. 6.9(2.9-24.6) mg/dL, p < 0.001]. Elevated Lp(a) levels, recent history of subtherapeutic anticoagulation, history of cerebrovascular accidents (CVA) and a low value of international normalized ratio on admission were found to be the independent predictors of PVT. Lp(a) levels above 19.6 mg/dL predicted PVT with a sensitivity of 65% and a specificity of 71% (AUC:0.767; 95%CI: 0.687 to 0.847; p < 0.001). Lp(a) levels were significantly higher in PVT patients with a history of CVA [42.0 (23.6-53.6) vs. 21.1 (16.1- 36.2) mg/dL, p = 0.012]. Elevated Lp(a) levels may be associated with MPVT. The assessment of plasma Lp(a) levels in patients with prosthetic heart valves may provide additive information regarding the risk of PVT and CVA. 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

To investigate the impact of 24-h movement behaviors-sleep (SP), sedentary behavior (SB), light physical activity (LPA), and moderate-to-vigorous physical activity (MVPA)-on preschool children's learning ability, with emphasis on inhibitory control as a mediating variable. Data were collected from 328 preschoolers (182 boys and 146 girls) using accelerometers and sleep questionnaires. Inhibitory control was assessed using the Early Years Toolbox, while learning ability was evaluated through the Learning Ability Test. A 15-min daily increase in MVPA, replacing SP, SB, or LPA, was associated with improvements in preschoolers' inhibitory control (0.038, 0.038, and 0.041, respectively) and learning ability (1.93, 1.87, and 2.52, respectively). Conversely, reallocating time in the opposite direction was associated with declines in both measures. Inhibitory control partially mediated the relationship between MVPA and learning ability across various demographic groups. For LPA, inhibitory control fully mediated its effect on learning ability in girls, while it fully mediated the impact of SP and MVPA on learning ability in boys. These findings collectively highlight the importance of 24-h movement behaviors in enhancing learning ability in preschool children through improved inhibitory control. 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

Peripheral arterial disease (PAD) is a global atherosclerotic disease which can lead to acute limb ischemia, chronic limb-threatening ischemia, and limb amputation. It has similar risk factors to coronary artery disease (CAD). Elevated lipoprotein A (Lp[a]) is associated with CAD, myocardial infarction, and PAD. Patients with PAD can have CAD and polyvascular disease. An extensive PubMed and Cochrane library search was performed in April 2025 using the words "Lipoprotein A and PAD", "Elevated lipoprotein A and PAD", and "High Lipoprotein A and PAD" to obtain relevant English articles for this systematic review. An elevated Lp(a) may enhance the risk of PAD. Elevated Lp(a) can amplify the risk of CAD, PAD, and polyvascular disease. It may portend worse outcomes in patients with CAD and PAD. It can increase the risk of acute limb ischemia, coronary revascularization, peripheral revascularization, cardiovascular death, and all-cause mortality. Hence, elevated Lp(a) may serve as a risk factor for patients with CAD who could potentially develop PAD. No currently approved medical therapy aimed at Lp(a) reduction exists; only lipoprotein apheresis is approved to lower Lp(a) levels in these patients. This systematic review discusses the role of an elevated Lp(a) in PAD, clinical research in PAD with elevated Lp(a), and the current treatment for PAD and elevated Lp(a). Show less

Examine whether neonatal neurobehavioral profiles are related to need for pharmacological treatment among infants with prenatal opioid exposure. Prospective cohort study of 217 infants with need for treatment determined using the Finnegan Neonatal Abstinence Tool (FNAST), Neonatal Withdrawal Inventory (NWI), or Eat Sleep Console (ESC). Neurobehavior was assessed with the NeoNatal Neurobehavioral Scale II (NNNS-II). Latent Profile Analysis (LPA) classified infants into neurobehavioral profiles and logistic regression assessed the association between NNNS-II profiles and need for treatment. A 3-profile LPA solution best fit the NNNS-II data comprised of typical (67%), hyper-aroused (19%) and hypo-aroused groups (15%). Infants with atypical NNNS-II profiles were more likely to receive treatment (OR=3.45, 95% CI 1.21-9.81) compared to infants with typical profiles ( Newborn neurobehavioral profiles may aid in early identification of infants requiring pharmacological treatment for opioid withdrawal, reducing length of stay and healthcare costs. Show less

To explore the categories of flourishing in patients undergoing postoperative chemotherapy for ovarian cancer and analyse the influencing factors for each category. A cross-sectional survey was conducted with 260 patients who underwent postoperative chemotherapy at the gynaecological oncology ward of a tertiary hospital in Shanxi Province between May 2024 and May 2025. Participants completed the General Information Questionnaire, Flourishing Scale, Learned Helplessness Scale, Index of Autonomous Functioning Scale, and Perceived Social Support Scale. Latent profile analysis (LPA) was used to identify the flourishing profiles. Subsequently, univariate and multivariate logistic regression analyses were conducted to examine the factors associated with profile membership. Among the 237 patients who completed valid questionnaires (recovery rate: 91.2%), the mean age was 59.48 ± 9.70 years. The LPA revealed three distinct latent categories of flourishing: low flourishing group (38.1%, n = 90), moderate flourishing group (34.2%, n = 80), and high flourishing group (27.7%, n = 67). Illness duration, comorbidity burden, learned helplessness, autonomous functioning, and perceived social support were significant factors influencing latent flourishing profiles ( Significant heterogeneity exists in flourishing levels among patients with ovarian cancer undergoing postoperative chemotherapy. Healthcare professionals can tailor interventions based on these distinct flourishing profiles and their key characteristics. This approach aims to promote patient flourishing, thereby improving their quality of life. Show less

High-stakes testing has become increasingly prominent phenomenon in teacher training institutions across the Global South. Despite its psychological implications, limited studies have investigated the stress experiences associated with this phenomenon, thereby constraining the design of appropriate interventions. Guided by the Lazarus and Folkman's Transactional Stress Model, this study examined the examination-related stress patterns and associated factors among pre-service teachers in an exam-oriented high-stakes setting in Ghana. An online survey, using the Perceived Stress Scale (PSS-10), was administered to 984 pre-service teachers at the University of Education, Winneba. The data were analysed using the LPA and multivariate ordinal logistic regression analysis. The results discovered three examination-related stress profiles (i.e., highly stressed, moderately stressed and low-stress groups), with the majority of the pre-service teachers (50.9%) failing into the high-stress cluster. Subsequent analysis revealed that religious affiliation, study level, age, course load (number of registered courses) and the study hours per week were significant predictors of examination-related stress levels. In line with the extended interpretation of the Transactional Stress Model, the study demonstrates how stress appraisal and coping mechanisms are embedded within broader contextual realities, particularly in collectivist cultures where family and community expectations influence academic outcomes. The study concludes that there is a substantial mental health burden associated with examination practices in teacher education programmes under exam-oriented high-stakes testing environment. The findings call for differentiated, culturally responsive interventions to address the specific needs of pre-service teachers with varied stress profiles. Show less

Numerous studies have established lipoprotein(a) [Lp(a)] as an independent and modifiable risk factor for atherosclerotic cardiovascular disease (ASCVD) and calcific aortic valve stenosis (CAVS). As such Lp(a) has become the focus of targeted drug therapy development with the goal of reducing Lp(a) serum concentrations and improving outcomes. This review aims to inform readers on the investigational agents currently in clinical trials and highlight key differences including dosing intervals and routes of administration that may facilitate uptake and retention of a particular potential medication in certain patient populations. Five investigational agents are currently undergoing various stages of clinical trials for the treatment of elevated Lp(a). Three potential therapies are small interfering RNA (siRNA) molecules and a fourth is an antisense oligonucleotide (ASO) all of which are subcutaneously injected. A fifth agent is a small molecule inhibitor that is orally administered. A sixth agent, a cholesteryl ester transfer protein (CETP) inhibitor that is primarily being studied for LDL-C reduction has shown promise for reducing Lp(a). A seventh agent based on gene-editing is currently in the developmental stage. Results have revealed notable reductions in Lp(a) with favorable tolerability and safety. Phase 3 trials will be crucial in determining the viability of lowering Lp(a) with such therapies and improving cardiovascular outcomes. Promising results indicate the potential in the near future to have medications primarily for lowering Lp(a) which has thus far eluded targeted drug therapy. As such advances stand to benefit large segments of the population living with and at risk for ASCVD, future research is vital to validate safety and efficacy in the long-term as well to understand how to optimize uptake and retention among patients with diverse circumstances. Show less

This study investigates the mechanisms by which digital mindfulness training promotes meaning in life among social workers and explores individual heterogeneity in this process. A parallel mediation model was used to test the pathways from digital mindfulness training to meaning in life. Latent Profile Analysis (LPA) was employed to identify distinct subgroups among the participants. All five proposed hypotheses received strong empirical support. Our analysis revealed that social workers who participated in digital mindfulness programs reported a stronger meaning in life. The parallel mediation model identified two distinct pathways: digital mindfulness training was associated with (1) reduced perceived social exclusion and, separately, (2) fewer psychotic-like experiences. Both of these factors, in turn, independently contributed to a greater meaning in life. The LPA identified five distinct subgroups: the "Flourishing Professional," "Socially Isolated yet Resilient," "Typical Practitioner," "Internally Struggling but Connected," and "High-Risk and Distressed." These groups differed significantly in meaning in life, with the "High-Risk and Distressed" category scoring the lowest. Viewed together, these patterns form a coherent explanatory structure that helps clarify how mindfulness interventions may operate. The findings also point to the importance of tailoring program content and delivery to address the particular vulnerabilities and strengths of each subgroup, rather than relying on a single, generic format. Show less

While most patients with stage I non-small cell lung cancer (NSCLC) remain recurrence-free after resection, some still develop recurrent disease. The surgical curative time window concept, defined as no recurrence through 5-year follow-up, helps identify potentially cured patients, yet predictive clinicopathologic features in stage I invasive NSCLC need clarification. This study sought to identify such features to enable risk-adapted surveillance. We analyzed a prospectively collected dataset of patients with stage I invasive NSCLC who underwent R0 resection between 2008 and 2015. Cox regression analysis was used to evaluate the association between clinicopathologic features and disease recurrence, aiming to identify independent prognostic factors. A total of 1,817 patients met the inclusion criteria. The 5-year cumulative incidence of recurrence was 14.6%. Female sex, tumor size ≤2 cm, lepidic-predominant adenocarcinoma (LPA) histologic type, presence of a ground-glass opacity (GGO) component, and solid component size ≤10 mm were identified as independent prognostic factors. A risk stratification system was subsequently developed, classifying patients into two groups: a low-risk group (with ≥4 factors; n=341) and an elevated-risk group (with <4 factors; n=1,476). Kaplan-Meier analysis revealed statistically significant differences in recurrence-free survival (RFS), overall survival (OS), and lung cancer-specific survival (LCSS) between the two groups (P<0.001). The low-risk group is considered to represent the population within the surgical curative time window. Patients with stage I invasive NSCLC who meet at least four of the following five criteria-female sex, tumor size ≤2 cm, solid component ≤10 mm, presence of a GGO component, and LPA histologic type-may be considered within the "surgical curative time window" and may therefore qualify for reduced surveillance intensity. Show less

(Sb,Bi)(S,Se)(Br,I) pnictogen chalcohalides constitute an emerging family of Van der Waals (VdW) semiconductors with remarkable potential for energy-related applications, including photovoltaics (PV), photocatalysis (PC), and photoelectrocatalysis (PEC). These ternary compounds exhibit a quasi-1D orthorhombic crystalline phase, and an electronic structure analogous to lead-halide perovskites, making them promising candidates for sustainable and high-performance energy devices. This study introduces a new versatile and adaptable synthesis methodology, which combines co-evaporation of binary chalcogenides with reactive annealing under high-pressure halide atmospheres, to fabricate the eight (Sb,Bi)(S,Se)(Br,I) chalcohalides. Comprehensive structural, compositional, and optoelectronic analyses reveal a wide bandgap range (1.2-2.2 eV), high absorption coefficients, and anisotropic properties driven by unique ribbon-like morphology. Theoretical and experimental results highlight their high stability, versatile chemical adaptability, and defect-tolerant characteristics. Moreover, the distinct differences in morphology and crystallization between Sb and Bi-based compounds, as well as the influence of chalcogen and halogen elements on the optical and structural properties are discussed. Demonstrations of functional devices, including photocatalytic systems, underscore the practical viability of these materials. This work establishes a foundation for the development of pnictogen chalcohalides as scalable and eco-friendly alternatives for advanced energy applications. Show less

Single nucleotide polymorphisms (SNPs) located in the genes participating in the steroid hormone metabolism pathway may influence the outcomes of androgen deprivation therapy (ADT) in prostate cancer (PCa) patients, but findings on the Chinese population remain limited. A multicentric cohort of 301 Chinese PCa patients receiving first-line ADT was enrolled. Germline SNPs located in 62 steroid hormone metabolism-related genes were analyzed for associations with time to ADT failure using multivariate Cox regression. Important expression quantitative trait loci (eQTLs) were discovered. Four SNPs were significantly associated with time to ADT failure: rs36119043 in AKR1D1 (hazard ratio, HR = 2.02, 95% confidence interval, 95% CI: 1.44-2.85, p = 5.72 × 10 SNPs in the steroid hormone metabolism pathway can predict time to ADT failure in Chinese PCa patients, supporting their potential role for drug response and pharmacogenomic stratification. Show less

A Genome-wide association study (GWAS) on a European-American cohort identified chr11p11.2 as a neuroblastoma predisposition locus. Combining in-house and public genomic data from neuroblastoma cell lines, this work implicates rs2863002 as the candidate causal variant at the 11p11.2 locus, confirming its cis-regulatory activity through a luciferase reporter assay. The genetic association of rs2863002 with neuroblastoma risk is validated in an Italian case-control cohort. Using ChIP-qPCR, Hi-C, and CRISPR genome editing, this work deciphers the regulatory mechanisms at the risk locus, demonstrating that the rs2863002-C risk allele regulates HSD17B12 expression and reduces GATA3 binding affinity. In vitro functional assays and targeted lipidomic analyses reveal the involvement of the rs2863002-C risk allele in tumorigenicity and modulation of lipid metabolism in neuroblastoma cells through HSD17B12 regulation. This study provides new insights into the genetic basis of neuroblastoma and underscores the importance of post-GWAS functional characterization of risk loci in uncovering relevant biological findings for understanding complex diseases. Show less

Food allergy (FA) is a great public health concern with an increased prevalence in the last decades. The underlying development mechanisms of FA and food sensitization (FS), which represents the first stage of development of FA, are influenced by environmental, epigenetic, and genetic factors. DNA methylation is an important epigenetic mediator of gene-environment interactions and key to understanding these mechanisms. Studies have linked whole-genome DNA methylation profile to FA and FS, but they all use methylation arrays. Methylation sequencing captures target regions of methylome with an extensive coverage. Thus, our objective was to identify CpG sites in genome-wide immune regulatory regions associated with FS and test their association with genetic variants using methylation quantitative trait loci (mQTL) analysis in French-Canadian individuals. In 114 individuals from the Saguenay-Lac-Saint-Jean asthma family cohort, a total of 10 CpG sites out of 5,233,004 CpG sites were associated with the FS status (P < 1 × 10 To our knowledge, this is a unique association study between FS and DNA methylation using targeted bisulfite sequencing across the genome. This approach provides high-resolution assessment of genome-wide functional methylome that yields valuable understandings to this field of research. The results reveal potential relationships between FS, CpG sites, and genetic variants located in genes involved in allergic diseases. This provides potential insights on the underlying effects of DNA methylation and genetic variants on FS and possibly the pathogenesis of FA. Further epigenome-wide studies on larger samples combined with genome-wide genotyping are needed to validate the results and verify the biological potential of these CpG sites. Show less

Stress granules are RNA-protein condensates that form in response to an increase in untranslating mRNPs. Stress granules form by the condensation of mRNPs through a combination of protein-protein, protein-RNA, and RNA-RNA interactions. Several reports have suggested that G-rich RNA sequences capable of forming G-quadruplexes promote stress granule formation. Here, we provide three observations arguing that G-tracts capable of forming rG4s do not promote mRNAs partitioning into stress granules in human osteosarcoma cells. First, we observed no difference in the accumulation in stress granules of reporter mRNAs with and without G-tracts in their 3' UTRs. Second, in U-2 OS cell lines with reduced DHX36 expression, which is thought to unwind G-quadruplexes, the partitioning of endogenous mRNAs was independent of their predicted rG4-forming potential. Third, while mRNAs in stress granules initially appeared to have a higher probability of forming rG4s than bulk mRNAs, this effect disappeared when rG4 motif abundance was standardized by mRNA length. However, we observe that in a G3BP1/2 double knockout cell line, reducing DHX36 expression rescued stress granule-like foci formation. This indicates that DHX36 can limit stress granule formation, potentially by unwinding trans rG4s, or limiting other intermolecular RNA-RNA interactions that promote stress granule formation. Show less

High-grade serous ovarian cancer (HGSOC) is the most lethal type of gynecological cancer, and platinum-resistance is a serious challenge in its treatment. Long non-coding RNAs (lncRNAs) play critical regulatory roles in the occurrence and development of cancers. Here, using RNA sequencing of tumor small extracellular vesicles (sEVs) from HGSOC patients, the lncRNA CATED is identified as significantly upregulated in both tumors and tumor-derived sEVs in platinum-resistant HGSOC, and low CATED levels correlate with good prognosis. Functionally, CATED enhances cisplatin resistance by promoting cell proliferation and inhibiting apoptosis in vitro and in vivo. These effects could be transferred via CATED-overexpressing sEVs from donor cells and HGSOC tumor sEVs. Mechanistically, CATED binds to and upregulates DHX36 via PIAS1-mediated SUMOylation at the K105 site, and elevated DHX36 levels increase downstream RAP1A protein levels by enhancing RAP1A mRNA translation, consequently activating the MAPK pathway to promote platinum-resistance in HGSOC. Antisense oligonucleotide mediated knockdown of CATED reverse platinum-resistance in sEV-transmitted mouse models via the DHX36-RAP1A-MAPK pathway. This study newly identifies a sEV-transmitted lncRNA CATED in driving HGSOC platinum-resistance and elucidates the mechanism it regulates the interacting protein through SUMOylation. These findings also provide a novel strategy for improving chemotherapy in HGSOC by targeting CATED. Show less

The rapid detection of drug resistance in Mycobacterium tuberculosis is essential for managing drug-resistant tuberculosis (DR-TB). This study evaluated the performance of molecular assays compared to phenotypic drug susceptibility testing (pDST) and targeted next-generation sequencing (T-NGS). We retrospectively analyzed 40 presumptive pulmonary DR-TB cases in Rio de Janeiro from 2018 to 2022. Xpert MTB/RIF Ultra (Xpert Ultra) and Line Probe Assay (LPA; MTBDRplus = LPA-1, MTBDRsl = LPA-2) were performed directly on clinical respiratory specimens, with pDST serving as the reference standard. T-NGS was used to identify resistance mutations and clarify discordant results. Most samples (92.5%) were smear-positive. Xpert Ultra and LPA-1 demonstrated high sensitivity for detecting resistance to rifampicin (91.7% and 89.3%, respectively). However, LPA-1 exhibited lower sensitivity for isoniazid (81.5%). The performance of LPA-1 decreased in samples with cycle threshold (Ct) values ≥16, indicating low bacterial load (p = 0.001). T-NGS detected resistance to fluoroquinolones (22.5%) and injectables (15-20%) that was missed by LPA-2 and MGIT. Mixed infections were identified in 17.5% of samples and accounted for 27.8% of discordant results. Isoniazid heteroresistance was detected in 32.5% of samples by LPA-1 and in 7.5% by T-NGS. Xpert Ultra and LPA-1 are effective for the rapid detection of rifampicin resistance but have limitations for isoniazid and second-line drugs. T-NGS improved the detection of low-level resistance, heteroresistance, and mixed infections, supporting its implementation in reference laboratories for comprehensive DR-TB diagnosis. Show less

Oocyte maturation-coupled mRNA post-transcriptional regulation is essential for the establishment of developmental potential. Previously, oocyte mRNA translation efficiencies focused on the trans-regulation of key RNA-binding protein (RBPs), rarely related to RNA structure. RNA G-quadruplexes (rG4s) are four-stranded RNA secondary structures involved in many different aspects of RNA metabolism. In this study, we have developed a low-input technique for rG4 detection (G4-LACE-seq) in mouse oocytes and found that rG4s were widely distributed in maternal transcripts, with enrichment in untranslated regions, and they underwent transcriptome-wide removal during meiotic maturation. The rG4-selective small-molecule ligand BYBX stabilized rG4s in the oocyte transcriptome and impaired spindle assembly and meiotic cell cycle progression. The proteomic spectrum results revealed that rG4 accumulation weakened the binding of a large number of RBPs to mRNAs, especially those associated with translational initiation. Ribosomal immunoprecipitation and translational reporter assays further proved that rG4s in the untranslated regions negatively affected the translational efficiency of key maternal mRNAs. Overexpression DEAH/RHA family helicase-36 partially reverses BYBX-induced oocyte developmental defects, suggesting its importance in rG4 regulation. Collectively, this study describes the distribution, dynamic changes, and regulation of rG4s in the mouse maternal transcriptome. Before meiosis resumption, a large number of rG4s in oocytes are necessary to maintain the translatome at a low level, and DHX36-mediated rG4 removal promotes a translational switch and is required for successful maternal-to-zygotic transition. Show less

The Mpox virus (MPXV) has emerged as a formidable orthopoxvirus, posing an immense challenge to global public health. An understanding of the regulatory mechanisms of MPXV infection, replication and immune evasion will benefit the development of novel antiviral strategies. Despite the involvement of G-quadruplexes (G4s) in modulating the infection and replication processes of multiple viruses, their roles in the MPXV life cycle remain largely unknown. Here, we found a highly conservative and stable G4 in MPXV that acts as a positive regulatory element for viral immunodominant protein expression. Furthermore, by screening 42 optically pure chiral metal complexes, we identified the Λ enantiomer of a pair of chiral helical compounds that can selectively target mRNA G4 and enhance expression of the 39-kDa core protein encoded by the MPXV Show less

Skeletal muscle is the largest tissue in mammals, and it plays a crucial role in metabolism and homeostasis. Skeletal muscle development and regeneration consist of a series of carefully regulated changes in gene expression. Leiomodin2 (LMOD2) gene is specifically expressed in the heart and skeletal muscle. But the physiological functions and mechanisms of LMOD2 on skeletal muscle development are unknown. In this study, we examined the expression levels of the LMOD2 in porcine tissues and C2C12 cells. LMOD2 is mainly expressed in the heart, followed by skeletal muscle. The expression level of LMOD2 gradually decreased with skeletal muscle growth, but increased after injury. LMOD2 expression levels increased gradually with C2C12 cells proliferation and differentiation. In terms of function, the muscle fiber types were altered after LMOD2 was knocked out in C2C12 cells, MyHC-I and MyHC-2b were inhibited, whereas MyHC-2a and MyHC-2x were promoted. LMOD2 knockout has different effects on LMOD family, LMOD1 expression level was promoted, while LMOD3 was inhibited. Loss of LMOD2 suppressed cell viability and PAX7 protein expression. At the transcriptome level, proliferation-related genes and muscle contraction-related genes were respectively inhibited after LMOD2 knockout. In terms of molecular networks, a series of experiments have shown that MyoG is a transcription factor for LMOD2, while miR-335-3p can negatively regulate LMOD2 expression. We screened ACTC1 as a candidate interacting protein for LMOD2 using protein prediction software and RNA-seq, and Co-IP experiments confirmed the relationship between LMOD2 and ACTC1. In vivo, Lentivirus-mediated LMOD2 knockdown reduces muscle mass. LMOD2 knockdown inhibited MyHC-I mRNA expression, but had no effect on MyHC-2b. The protein expression of MyHC-I, MyHC-2x, and MyHC-2b was suppressed after LMOD2 knockdown. Collectively, our data indicates that LMOD2 knockout inhibits myoblast proliferation and alters muscle fiber types. MyoG is a transcription factor for LMOD2, while miR-335-3p can negatively regulate LMOD2 expression. Moreover, LMOD2 and ACTC1 interact to regulate myogenic differentiation. Our study provides a new target for skeletal muscle development. Show less

The transition of smooth muscle cells (SMCs) from a contractile to a synthetic phenotype is a key contributor to cardiovascular disease (CVD) pathologies, such as atherosclerosis and in-stent restenosis. We previously reported that loss of leiomodin 1 (LMOD1), a coronary artery disease risk gene highly expressed in SMCs, promotes SMC phenotypic switching in vitro. However, the in vivo role of LMOD1 and the molecular mechanisms driving this transition remain unknown. In this study, we found that Lmod1 heterozygous mice subjected to carotid artery ligation developed larger neointimal lesions. Histopathological analyses attributed this phenotype to increased SMC proliferation. RNA sequencing studies of LMOD1-deficient SMCs revealed a significant upregulation of genes associated with increased cell proliferation, particularly those involved in the G1/S phase transition. Further analysis identified cyclin-dependent kinase 6 (CDK6) as a potential mediator of this hyperproliferative response. Notably, the knockdown of CDK6 in LMOD1-deficient cultured SMCs restored SMC proliferation to near baseline levels, indicating that the observed phenotype is reversible in vitro. Collectively, these findings indicate that LMOD1 deficiency promotes SMC proliferation by upregulating CDK6 expression and provide mechanistic insight into how reduced LMOD1 expression may contribute to increased neointimal lesion size and vascular remodeling. Show less

Low-carbohydrate, high-fat diets under eucaloric conditions are associated with several health-beneficial metabolic effects in humans, particularly in the liver. We recently observed that apolipoprotein A-IV (apoA-IV), a highly abundant apolipoprotein, was among the most upregulated proteins in circulation after six weeks of consuming a high-fat diet in humans. However, the impact of dietary changes in regulating apoA-IV, and the potential effects of apoA-IV on regulation of glucose- and lipid metabolism remain to be fully established. We investigated the regulation of circulating fasting concentrations of apoA-IV in humans in response to diets enriched in either fat or carbohydrates. Moreover, to study the whole-body and tissue-specific glucose and lipid metabolic effects of apoA-IV, we administrered apoA-IV recombinant protein to mice and isolated pancreatic islets. We demonstrate that in healthy human individuals high-fat intake increased fasting plasma apoA-IV concentrations by up to 54%, while high-carbohydrate intake suppressed plasma apoA-IV concentrations. In mice, administration of apoA-IV acutely lowered blood glucose levels both in lean and obese mice. Interestingly, this was related to a dual mechanism, involving both inhibition of hepatic glucose production and increased glucose uptake into white and brown adipose tissues. In addition to an effect on hepatic glucose production, the apoA-IV-induced liver proteome revealed increased capacity for lipoprotein clearance. The effects of apoA-IV in the liver and adipose tissues were concomitant with increased whole-body fatty acid oxidation. Upon glucose stimulation, an improvement in glucose tolerance by apoA-IV administration was related to potentiation of glucose-induced insulin secretion, while apoA-IV inhibited glucagon secretion ex vivo in islets. We find that apoA-IV is potently increased by intake of fat in humans, and that several beneficial metabolic effects, previously associated with high fat intake in humans, are mimicked by administration of apoA-IV protein to mice. Show less

Apolipoprotein A-IV (apoA-IV) is an abundant lipid-binding protein in blood plasma. We previously reported that apoA-IV, as an endogenous inhibitor, competitively binds platelet αIIbβ3 integrin from its N-terminal residues, reducing the potential risk of thrombosis. This study aims to investigate how the apoA-IV Show less

Lysophosphatidic acid (LPA) is a bioactive phospholipid that mediates a variety of biological actions through binding to G protein-coupled receptors known as LPA receptors (LPARs). In mammals, six LPAR subtypes (LPAR1-6) have been identified. This study aimed to determine the expression of LPAR4 in the developing mouse brain. Brains samples were prepared from mice in various stages of development and biochemical and immunohistochemical analyses were conducted using anti-LPAR4. Western blot analysis detected two LPAR4-immunoreactive species at ∼50 kDa and ∼42 kDa from embryonic day 16.5 (E16.5). The ∼50 kDa molecule increased during development, reaching a peak at postnatal day 3 (P3), and then gradually decreased through P22. In contrast, the ∼42 kDa molecule continued to increase up to P22. Immunohistochemical analyses demonstrated strong LPAR4 expression in neural cells in the intermediate zone and cortical plate of the E15.5 cerebral cortex, whereas neural progenitors in the ventricular and subventricular zones exhibited weaker expression. At P15, fiber-like staining resembling the apical dendrites of cortical neurons and hippocampal pyramidal cells was also observed. This study demonstrated dynamic, spatiotemporal changes of LPAR4 expression in the brain from embryonic to postnatal stages. These findings support a potential role for LPAR4 in neural development. Show less

Early diagnosis of Alzheimer's disease (AD), particularly during its preclinical and prodromal phases, remains a major challenge. Plasma biomarkers such as phosphorylated tau at threonine 217 (p-tau217), amyloid-β (Aβ) isoforms, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) show promise for early detection; however, their relationships with medial temporal lobe (MTL) subfield atrophy and potential inter-biomarker pathways remain unclear. This study aimed to address this gap by investigating the associations between plasma biomarkers and MTL subfield atrophy, and by assessing potential mediation pathways. We conducted a cross-sectional study using data from 330 participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI), including cognitively normal (CN) and mild cognitive impairment (MCI) groups. High-resolution coronal T2-weighted MRI quantified MTL subfield volumes using the ASHS protocol. Plasma biomarkers were measured using ultrasensitive immunoassays. The cohort included 209 CN participants (mean age [SD] = 69.3 [6.9] years; 64.2% women; 24.4% APOE ε4 carriers) and 121 MCI participants (mean age [SD] = 71.3 [7.3] years; 48.8% women; 27.9% APOE ε4 carriers). MCI individuals showed significantly higher plasma concentrations of p-tau217, p-tau217/Aβ Show less

Macrophage-like phenotype switching of vascular smooth muscle cells (VSMCs) is a crucial mechanism driving atherogenesis. Inhibition of a phenotype switch to macrophage-like cells is a promising strategy to prevent atherosclerosis (AS), and targeted nanotherapeutics represent one approach for implementing this strategy. To this end, we designed immunosuppressive oligodeoxynucleotide A151 functionalized selenium nanoparticles with a spearhead LacNAc (LN-A151-SeNPs) that target macrophage-like VSMCs. Nano characterization showed that the uniformity and stability of nanoparticles were optimized by modification with LacNAc and A151, resulting in an average diameter of 88.90 ± 1.45 nm, Zeta potentials of -21.1 ± 1.5 mV, a A151:Se molar ratio of 1:60 and mass ratio of 1.68:1. The effects of LN-A151-SeNPs on inhibiting VSMCs phenotype switching and attenuation of AS were investigated using [Image: see text] The online version contains supplementary material available at 10.1186/s12951-025-03925-7. Show less