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Limited identification of insulin resistance-associated loci hinders understanding of its role in cardiometabolic health, impeding therapeutic strategies. We apply three multivariate genome-wide association study approaches on homeostatic model assessment for insulin resistance, insulin resistance index, fasting insulin, and ratio of triglycerides to high-density lipoprotein cholesterol from MAGIC and UK Biobank to develop a comprehensive phenotype ('mvIR'), and identify 217 independent loci, including 24 novel loci. The mvIR is causally associated with higher risks of 17 cardiometabolic diseases and five aging phenotypes, independent of adiposity and sarcopenia. We outline 21 of 2644 druggable genes for insulin resistance by Mendelian randomization and colocalization, where six genes (AKT1, ERBB3, FCGR1A, FGFR1, LPL, NR1H3) encode targets for approved drugs with consistent directions in alleviating insulin resistance, with no significant side effects revealed by phenome-wide association study. This study uncovers novel loci and therapeutic targets to inform strategies promoting insulin resistance-centered cardiometabolic health and longevity. Show less

Tumor fibrosis is recognized as a malignant hallmark in various solid tumors; however, the clinical importance and associated molecular characteristics of tumor fibrosis in liver metastases (LM) from colorectal cancer (CRLM) remain poorly understood. Here we show that patients with CRLM whose liver metastases (LM) exhibited tumor fibrosis (Fibrosis+ LM) had significantly worse progression-free survival (P = 0.025) and overall survival (P = 0.008). Single-cell RNA sequencing revealed that the tumor microenvironment of the Fibrosis+ LM was characterized by T cells with an exhausted phenotype, macrophages displaying a profibrotic and suppressive phenotype and fibrosis-promoting fibroblasts. Further investigation highlighted the pivotal role of VCAN_eCAF in remodeling the tumor fibrosis in the tumor microenvironment of Fibrosis+ LM, emphasizing potential targetable interactions such as FGF23 or FGF3-FGFR1. Validation through multiplex immunohistochemistry/immunofluorescence and spatial transcriptomics supported these findings. Here we present a comprehensive single-cell atlas of tumor fibrosis in LM, revealing the intricate multicellular environment and molecular features associated with it. These insights deepen our understanding of tumor fibrosis mechanisms and inform improved clinical diagnosis and treatment strategies. Show less

Breast cancer (BC) is the most common malignancy among women, with an increasing incidence correlated with age and diverse subtypes exhibiting distinct prognoses. The tumor microenvironment (TME) in BC is complicated. It is now believed that BC may acquire invasive characteristics and even extra proliferative ability from the TME through various mechanisms. However, most studies predominantly focus on the heterogeneity of tumor cells in BC, lacking a comprehensive depiction of intercellular communication within BC. Therefore, the present study aimed to elucidate cellular communication in the TME by integrated bioinformatic analysis of bulk mRNA and single-cell mRNA sequencing, combined with certain validation in clinical samples. We first utilized single-cell sequencing data from GSE176078 to find out the most important cell communication pairs for the tumor microenvironment in BC then we conducted bulk-sequencing analysis to identify the differential expressed genes. Through correlation analysis, we sort out the top five most relevant genes to the most important cell communication pairs. We then validated the expression of the key genes of the aforementioned cell communication pairs and the five differentially expressed genes by qPCR on clinical samples. Furthermore, we analyzed the immunological relevance of these genes via a novel approach at single-cell resolution. The results of single-cell analysis indicated that the CXC12-CXCR4 ligand-receptor pair in the CXCL pathway and the FGF7-FGFR1 ligand-receptor pair in the FGF pathway are the most important cell communication pairs of the TME in BC. Subsequent bulk sequencing analysis showed that CHRDL1, SCARA5, LYVE1, PI16, and SAA2 were the most important differentially expressed genes linked to these cell communication pairs. In addition, we validated the expression of the key genes of the two cell communication pairs and the five genes in clinical samples, observing that the trends fitted the computational results. Finally, we studied the association of these genes with immune cell infiltration at single-cell level and had it cross-validated in bulk sequencing data, finding out that there were significant connections. In the tumor microenvironment of breast cancer, intercellular communication pairs of different cell types and molecules can exacerbate the development of breast cancer. among them, through the present study, we found that CXCL12-CXCR4 and FGF7-FGFR1 are the most important. Also, most significantly differentially expressed genes including CHRDL1, SCARA5, LYVE1, PI16, and SAA2 seemed to play a critical role in these mechanisms and immune cell infiltration, shaping the TME of BC. Show less

Osteosarcoma is the most prevalent primary malignant bone tumor in children and adolescents. However, its underlying pathogenesis and mechanisms driving metastasis remain poorly understood. Here, we identified a novel super-enhancer-associated long noncoding RNA (SE-lncRNA), Zinc Finger MIZ-Type Containing 1 Antisense RNA 1 (ZMIZ1-AS1), which is highly expressed in osteosarcoma and promoted tumor cell proliferation, migration, and invasion. Mechanistically, the m⁶A demethylase ALKBH5 post-transcriptionally stabilized ZMIZ1-AS1 through m⁶A demethylation. Furthermore, ZMIZ1-AS1 directly bound to the RNA-binding protein Polypyrimidine Tract Binding Protein 1 (PTBP1), facilitating the translocation of PTBP1 from the nucleus to the cytoplasm. The relocalized PTBP1 then bound to and stabilized fibroblast growth factor receptor 1 (FGFR1) mRNA. In nude mouse models, ZMIZ1-AS1 overexpression promoted tumor growth and lung metastasis. Notably, combined inhibition of ALKBH5 (using ALKBH5-IN-5) and FGFR1 (using BGJ398/infigratinib) synergistically suppressed ZMIZ1-AS1-driven oncogenesis in vivo. Our study establishes the ALKBH5/ZMIZ1-AS1/PTBP1/FGFR1 signaling axis as a key driver of osteosarcoma progression and a promising target for therapeutic intervention. Show less

8p11 myeloproliferative syndrome (EMS) is a rare aggressive hematologic malignancy with a poor prognosis that can rapidly develop into acute leukemia. It is characterized by the translocation of fibroblast growth factor receptor-1 (FGFR1), and there is still a lack of effective and reliable treatment methods at present. This report provides a new therapeutic strategy for EMS patients diagnosed with BCR-FGFR1 fusion. This report describes a case of EMS patient with a positive BCR-FGFR1 fusion gene, whose manifestations are similar to those of chronic myeloid leukemia (CML). After diagnosis by fluorescence in situ hybridization (FISH) and RNA sequencing (RNA-seq), olverembatinib, the third-generation tyrosinase inhibitor (TKI) developed in China, was used for treatment. After monotherapy and follow-up for more than one year, partial molecular response (PR) was achieved. During this period, hematologic remission and cytogenetic remission were achieved. The treatment safety of the entire process was excellent. In summary, olverembatinib provides more treatment options for rare diseases such as 8p11 myeloproliferative syndrome. Show less

Patients with inflammatory breast cancer (IBC) have aggressive biology and relatively inferior responses to standard-of-care (SOC) therapies. Understanding the efficacy of SOC therapies in IBC is critical to optimize outcomes. Our objective was to assess the progression-free survival (PFS) of metastatic hormone receptor-positive HER2-negative/low (HR+HER2-) IBC patients treated with CDK4/6 inhibitors (CDKIs) and hormonal therapy (HT). Data from 58 IBC patients with metastatic HR + /HER2- IBC from a single institution were reviewed. The medians (95% confidence intervals) of overall survival (OS), PFS, and time on treatment (ToT) from the time of CDKI initiation were reported via the Kaplan‒Meier method. Differences were tested by the log-rank test. We identified 58 patients (including 16 with de novo stage IV disease). The median OS, PFS, and ToT in the total cohort were 26 (16, 37), 7 (5, 10), and 7 (5, 10) months (mos), respectively. No differences were observed between pre-menopausal patients and postmenopausal patients. The OS, PFS, and ToT rates at the initial diagnosis of Stage III later developing metastatic breast cancer (MBC, N = 42) and de novo IV (N = 16) patients were 19 (15, 34) vs 34 (21, NR), 7 (5, 14) vs 9 (6, NR), and 6 (5, 10) vs 9 (4, NR) mos, respectively (ns). OS, PFS, and ToT in patients receiving CDKI in the first-line vs second-line metastatic setting were 27 (19, 44) vs 17 (12, 39), 7 (5, 15) vs 6 (3, NR), and 7 (5, 15) vs 6 (3, 20) mos, respectively (ns). Among the patients initially diagnosed with stage III disease later progressing to MBC, brain metastases were observed in 12/42 patients. Thirty-eight patients underwent genomic testing either before CDKI treatment (N = 21) or at progression (N = 17). Among the 38 patients who underwent genomic testing, 34 had mutations, most commonly in TP53, PIK3CA, FGFR1, CCND1, and ARID1A. ESR1 mutations were present in 0% of the samples tested prior to CDKI treatment, and 29% of the samples tested at progression. Patients with metastatic HR+HER2- IBC demonstrated a shorter time on treatment suggesting shorter duration of response on CDKI + HT, which is markedly inferior to reported data for non-IBC patients from phase III trials. Show less

For decades, platinum chemotherapy was the mainstay of treating metastatic urothelial carcinoma (mUC). More recently, checkpoint inhibitors (CPI) were an important addition to the armamentarium capable of inducing durable responses for a minority of patients. Management of mUC has changed significantly with the advent of antibody-drug conjugate (ADC) therapies and fibroblast growth factor receptor inhibitors (FGFRi). Enfortumab vedotin, a Nectin-4 targeting ADC, is now the first line therapy of choice in combination with pembrolizumab. Erdafitinib, a pan FGFR1-4 inhibitor, is approved for patients with susceptible FGFR3 alterations. There are multiple other agents in development within both therapeutic classes that hold promise. But most patients will still succumb to their disease, either via primary or secondary resistance. This review looks critically at the approved and pipeline ADC and FGFR-targeting agents of interest in mUC as well as known mechanisms of resistance by which their efficacy is dampened. We propose strategies for overcoming resistance including combination strategies, tumor microenvironment modification, and drug structure modification to maximize efficacy. The progress to date in mUC has been remarkable, but there is still significant work to do in this deadly disease and this review highlights the gap between current available therapeutics and cure that so desperately needs to be closed. Show less

Fibroblast growth factor receptor 1 (FGFR1) is crucial in the progression of various cancers, participating in the processes of cell proliferation, survival, and differentiation. FGFR1 plays a role in the resistance to immune checkpoint inhibitors (ICIs) such as pembrolizumab and nivolumab. Therefore, using monoclonal antibodies and tyrosine kinase inhibitors to target FGFR1 and enhancing ICIs by modifying the tumor microenvironment and combating immune suppression represents a potential therapeutic strategy. Based on the FGFR1-related research and the active targeting strategy, we believe that modifying the surface of nanomedicines with anti-FGFR1 antibodies (such as OM-RCA-01) is an effective targeted treatment method for tumors with high expression of FGFR1. Although there have been relevant studies confirming the feasibility of this approach, there are challenges in clinical application, especially in terms of maintaining uniform quality during large-scale production. Therefore, we suggest conducting further optimization studies in the future to accelerate the clinical application of such drug delivery systems and provide more efficient and cost-effective options for tumor treatment. Show less

Molecular analysis of Each participating institution was requested to apply its own diagnostic testing strategy on 8 sections obtained from artificial reference specimens built to harbor Overall, cell resuspension yielded higher amounts of DNA and RNA (SNU16 61.5 ng/µl, 38100.0 pg/µl; RT112 118.0/µl, 2140.0 pg/µl, respectively) in comparison with SNU16+ RT112 mixing cell block (0.7 ng/µl DNA and 412.0 pg/µl RNA). Moreover, FFPE samples showed a higher fragmentation index (DIN 1.2 and RIN not calculated) compared with cell line resuspension (DIN 2.2 and 9.5 for SNU16 and RT112; RIN 3.9 and 6.8 for SNU16 and RT112). All participating institutions identified NGS represents the most suitable approach in molecular profiling of Show less

Basal cell carcinoma (BCC) is the most common skin cancer, predominantly affecting sun-exposed areas. It typically grows slowly and rarely metastasizes, though untreated cases can cause significant tissue destruction and morbidity. Its pathogenesis primarily involves dysregulation of the Hedgehog (HH) signaling pathway, mainly through mutations in Show less

H3 K27-altered diffuse midline gliomas (DMGs) are a rare form of primary CNS tumors. In this retrospective single-center case study, DMGs were reviewed for clinical and imaging findings, surgical approaches and challenges, and molecular diagnosis. Four cases of adult DMG, H3 K27-altered, located among midline structures of the thalamus, brainstem, and spinal cord are presented here. All tumors exhibited heterogeneous presentations on imaging. Symptoms ranged from unspecific back pain and vertigo to focal neurological deficits. Surgery was complicated by high vascularization, infiltrative growth, and proximity to eloquent areas. Diagnostic accuracy was increased by epigenetic DNA methylation-based classification. Three cases were rapidly progressive and resulted in death within 1 year of diagnosis. One case had an exceptionally long overall survival of > 5 years, which was associated with a FGFR1 p.N546K hotspot mutation. DMGs are rare but imitate other pathologies due to variable clinical and radiological characteristics. Surgery is complicated by location and high vascularization. Although DMGs are rare, they should be considered as a differential diagnosis in intracranial and spinal masses in adults. As the FGFR1 p.N546K hotspot mutation is associated with prolonged survival, it may justify more radical surgery in eloquent regions. https://thejns.org/doi/10.3171/CASE25357. Show less

Antipsychotic medications are essential when treating schizophrenia spectrum and other psychotic disorders, but the efficacy and tolerability of these medications vary from person to person. This interindividual variation is likely mediated, at least in part, by epigenomic processes that have yet to be fully elucidated. Herein, we systematically identified and evaluated 65 studies that examine the influence of antipsychotic drugs on epigenomic changes, including global methylation (9 studies), genome-wide methylation (22 studies), candidate gene methylation (16 studies), and histone modification (18 studies). Our evaluation revealed that haloperidol was consistently associated with increased global hypermethylation, which corroborates with genome-wide analyses, mostly performed by methylation arrays. In contrast, clozapine seems to promote hypomethylation across the epigenome. Candidate-gene methylation studies reveal varying effects post-antipsychotic therapy. Some genes like Glra1 and Drd2 are frequently found to undergo hypermethylation, whereas other genes such as SLC6A4, DUSP6, and DTNBP1 are more likely to exhibit hypomethylation in promoter regions. In examining histone modifications, the literature suggests that clozapine changes histone methylation patterns in the prefrontal cortex, particularly elevating H3K4me3 at the Gad1 gene and affecting the transcription of genes like mGlu2 by modifying histone acetylation and interacting with HDAC2 enzymes. Risperidone and quetiapine, however, exhibit distinct impacts on histone marks across different brain regions and cell types, with risperidone reducing H3K27ac in the striatum and quetiapine modifying global H3K9me2 levels in the prefrontal cortex, suggesting antipsychotics demonstrate selective influence on histone modifications, which demonstrates a complex and targeted mode of action. While this review summarizes current knowledge, the intricate dynamics between antipsychotics and epigenetics clearly warrant more exhaustive exploration with the potential to redefine our understanding and treatment of psychiatric conditions. By deciphering the epigenetic changes associated with drug treatment and therapeutic outcomes, we can move closer to personalized medicine in psychiatry. Show less

Characterized by social communication deficits and the presence of restricted and repetitive behaviors, autism spectrum disorder (ASD) is a significant neurodevelopmental condition. Genetic studies have revealed a strong association between ASD and numerous mutations that alter the function of key proteins, either through activation or inactivation. These alterations are widely hypothesized to affect neuronal morphogenesis; however, a comprehensive understanding of the specific molecular cascades driving these cellular and symptomatic changes remains lacking. In this study, we report for the first time that signaling through the atypical Rho family guanine-nucleotide exchange factor (GEF) Dock7 and ErbB2, an activator acting upstream of Dock7, drives the excessive elongation of neuronal processes observed in association with the ASD- and intellectual disability (ID)-linked semaphorin-5A (Sema5A) Arg676Cys variant (p.Arg676Cys). Knockdown of Dock7 using short hairpin RNA or inhibition of ErbB2 kinase signaling with a specific chemical inhibitor reduced this excessive process elongation in primary cortical neurons. Similar results were obtained in the N1E-115 cell line, a neuronal cell model that undergoes neuronal morphological differentiation. Moreover, inhibition of ErbB2-Dock7 signaling specifically decreased the overactivation of the downstream molecules Rac1 and Cdc42. These findings indicate that the ErbB2-Dock7 signaling axis plays a role in mediating the aberrant neuronal morphology associated with the ASD- and ID-linked Sema5A p.Arg676Cys. Targeting this pathway may therefore offer a potential approach to addressing the molecular and cellular developmental challenges observed in ASD. Show less

The association between obesity and cholelithiasis has been identified. However, the causal relationship between age-specific childhood obesity and adult cholelithiasis remains unclear. In addition, the biological basis for the association between childhood obesity and adult cholelithiasis is poorly understood, which poses a challenge for preventing adult cholelithiasis in specific biological pathways. Summary statistics of genome-wide association studies (GWASs) of childhood age-specific body mass index (BMI) at 12 time points and adult cholelithiasis derived from FinnGen were used in this study, with the former covering data from birth to 8 years. Linkage disequilibrium score regression (LDSC) analyses were used to assess the genetic correlations of age-specific childhood BMI to cholelithiasis. Two-sample Mendelian randomization (MR) and multivariable Mendelian randomization (MVMR) analyses were utilized to explore the causal associations. As downstream analyses, summary-based Mendelian randomization (SMR) analyses, transcriptome-wide association studies (TWAS), and Bayesian colocalization were conducted to discover the shared transcriptomic signals. The GWAS summary statistics of cholelithiasis from the UK Biobank were used for sensitivity analyses. LDSC analyses revealed significant genetic correlations between 11 age-specific childhood BMIs and adult cholelithiasis (except for birth BMI). Two-sample MR and MVMR analyses indicated causal relationships between birth BMI and BMI at 8 months, 1.5 years, 7 years, and 8 years after birth and adult cholelithiasis. SMR, TWAS, and colocalization analyses identified MLXIPL as the strongest overlapping signal between age-specific BMI and adult cholelithiasis. This study provides new evidence on the relationships between childhood obesity and adult cholelithiasis, highlighting the role of early intervention for obesity in childhood at key time points. MLXIPL gene expression was identified as a potential biological pathway, suggesting potential therapeutic targets and precise intervention strategies for childhood obesity and adult cholelithiasis. Show less

Diabetes is a leading cause of death, affecting nearly half a billion adults worldwide. With projections indicating a significant increase in prevalence, understanding the genetic factors that contribute to diabetes, particularly type 2, is crucial. This study investigated the association of specific polymorphisms with type 2 diabetes (T2D) in the Uzbek population. A total of 165 individuals, including 125 patients with T2D and 40 controls, were genotyped for variants located in the The analysis revealed significant associations between these polymorphisms and T2D under various genetic models. The distribution of the genotype frequencies was consistent with the Hardy-Weinberg equilibrium. The findings of this study underscore the importance of ethnic and geographical diversity in genetic studies and contribute to the understanding of T2D in the Uzbek population. Further research is needed to explore the clinical implications of these genetic associations. Show less

Cerebrotendinous xanthomatosis is a rare autosomal recessive lipid storage disorder involving bile acid biosynthesis. Reduced mitochondrial cytochrome P450 enzyme activity leads to abnormal lipid accumulation in various tissues, especially tendons, lenses, and the central and peripheral nervous systems. This condition manifests with systemic symptoms such as neurological disorders, atherosclerosis, tendon xanthomas, and cataracts. Cerebrotendinous xanthomatosis typically presents in individuals with homozygous or compound heterozygous mutations in the CYP27A1 gene because of its autosomal recessive inheritance pattern. However, the phenotypic expression in heterozygous carriers remains uncertain. We report a 53-year-old Japanese man who was clinically diagnosed with familial hypercholesterolemia. He presented with marked Achilles tendon xanthomas and refractory hyper-low-density-lipoprotein cholesterolemia. Initiation of intensified lipid-lowering therapy, including inclisiran, resulted in improvement of hyper-low-density-lipoprotein cholesterolemia. Genetic testing revealed heterozygous mutations in CYP27A1 (p.Arg405Gln) and apolipoprotein B (APOB) (p.Pro955Ser). He had no neurological symptoms, cataracts, or other features suggestive of cerebrotendinous xanthomatosis without Achilles tendon xanthomas. This case highlights a rare presentation of a potential CYP27A1 heterozygous mutation-related phenotype. The APOB (p.Pro955Ser) variant is associated with reduced low-density-lipoprotein receptor activity, contributing to hyper-low-density-lipoprotein cholesterolemia and Achilles tendon xanthomas. However, this patient's Achilles tendon xanthoma was thicker than those reported in previous cases with APOB (p.Pro955Ser) gene mutations, suggesting a potential contribution from the CYP27A1 mutation. Although the patient did not exhibit elevated serum cholestanol levels or other cerebrotendinous xanthomatosis features, the marked Achilles tendon thickening raises the possibility that the combination of a heterozygous CYP27A1 gene mutation and an APOB gene mutation contributed to the condition. Show less

Lipoprotein kinetics are a crucial factor in understanding lipoprotein metabolism because a prolonged time in circulation can contribute to the atherogenic character of B-lps (ApoB-containing lipoproteins). We developed a genetically encoded B-Lp reporter, LipoTimer, in which the zebrafish endogenous By quantifying the red population of ApoB-Dendra2 over time, we found that B-lp turnover in wild-type larvae becomes faster as development proceeds. Mutants with impaired B-lp uptake or lipolysis present with increased B-lp levels and half-life. In contrast, mutants with impaired B-lp triglyceride loading display slightly fewer and smaller B-lps, which have a significantly shorter B-lp half-life. Furthermore, we showed that chronic high-cholesterol feeding is associated with a longer B-lp half-life in wild-type juveniles but does not lead to changes in B-lp half-life in lipolysis-deficient In conclusion, the new LipoTimer reporter allows for direct in vivo examination of B-lp kinetics, which can be used to better understand the role of lipoprotein modifier genes and environmental factors (eg, diet) on B-lp lifetime. Show less

Alzheimer's Disease (AD) is a progressive neurodegenerative disorder and the leading cause of cognitive decline in older adults. Several biomarkers of AD have been identified, but its pathogenesis has not yet been completely elucidated. One of the most relevant hypotheses proposed to explain the cognitive impairment caused by this disease is the cholinergic hypothesis, which postulates that loss of cholinergic neurons is one of its causes and that the subsequent reduction of acetylcholine levels in the synaptic cleft can be compensated through the inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Another well-known hypothesis is the amyloid-beta hypothesis, which explains the disease as being caused by the formation and accumulation of amyloid plaques in a cascade of enzymatic events starting with the cleavage of an amyloid precursor protein (APP) by beta-secretase 1 (BACE-1). Previous studies have shown that silodosin has the structural requirements for the inhibition of those three enzymes (AChE, BuChE, and BACE-1), which suggests that it can be useful as a multitarget candidate to treat Alzheimer patients. This study aims to assess the effect of silodosin on cellular viability, measure the inhibitory activity against AChE, BuChE, and BACE-1, and evaluate the molecular behavior of all three inhibitor-enzyme systems by molecular dynamics (MD) simulations. Cell viability assays through the MTT method showed that silodosin concentrations of less than 10 μM are safe to be used. Enzymatic assays revealed AChE inhibitory activity at high micromolar levels (IC50 >500.0 μM) but inhibited BuChE at low micromolar levels (IC50 = 3.02 ± 0.05 μM). BACE-1 inhibition assays have shown significant reduction at three micromolar. MD simulations demonstrated that silodosin promotes late stabilization of the AChE complex, but the simulations involving BuChE and BACE-1 revealed that the compound promotes system stabilization at early stages and has the structural requirements to inhibition. Show less

The Interaction of Person-Affect-Cognition-Execution (I-PACE) model offers a framework for understanding the interplay between cognitive, affective, and behavioral factors in internet addiction (IA). Our study aims to explore the heterogeneity of IA, identify bridge connectors, and compare the efficacy of cognitive behavioral therapy combined with mindfulness-based intervention (CBT+MBI) versus CBT alone in reducing IA levels among Chinese college students. In study 1, 1,030 Chinese college students completed assessments of IA, automatic thoughts, self-control, and anxiety. Latent profile analysis (LPA) was employed to identify distinct symptom profiles of IA across individuals. Network analysis (NA) identified bridge connectors for targeted intervention. In study 2, 36 participants randomly selected from the high IA and low IA groups of study 1 were randomly assigned to CBT+MBI, CBT alone, or a control group. The CBT+MBI group received an 8-week dual-modality intervention and the CBT alone received an 8-week CBT intervention, both designed to target the bridge connectors identified via NA in Study 1, while the control group only completed basic questionnaires. In study 1, LPA identified four subgroups: regular, at-risk, low IA, and high IA groups. NA pinpointed automatic thoughts and anxiety as bridge connectors. In study 2, targeted interventions significantly reduced college students' levels of IA. CBT+MBI resulted in greater and more sustained improvements compared to CBT alone, with effects maintained for six-month post-intervention. Our study not only reinforces the I-PACE model but also provides actionable strategies for designing evidence-based, multidimensional interventions to reduce addictive behaviors among college students. Show less

Familial hypercholesterolaemia (FH) is a hereditary disorder characterised by elevated low-density lipoprotein cholesterol (LDL-C) levels, substantially increasing the risk of atherosclerotic cardiovascular disease. Proprotein convertase subtilisin/kexin type 9 (PCSK9) targeting therapies, including monoclonal antibodies and small interfering RNA (siRNA) agents, have emerged as effective lipid lowering therapies. To assess the efficacy and safety of PCSK9-targeting therapy on lipid biomarkers and adverse events in patients with FH, compared with placebo on the background of standard lipid-lowering therapy. A systematic review and meta-analysis were conducted, incorporating data from 23 randomised controlled trials involving adult and paediatric FH patients treated with PCSK9 inhibitors (PCSK9i) or siRNA, including alirocumab, bococizumab, evolocumab, tafolecimab and inclisiran. Eligible studies reported changes in LDL-C, apolipoprotein B (ApoB), lipoprotein a (Lp(a)), triglycerides (TGL) and adverse effects. Pooled mean differences (MDs) and ORs with 95% CIs were calculated using random-effects models, and heterogeneity was assessed with I² statistic. This meta-analysis was registered on PROSPERO (CRD42025631510). A total of 4282 patients were included. PCSK9-targeting therapies significantly reduced LDL-C levels compared with control therapies (MD=-46.64%; 95% CI -50.77% to -42.52%; p<0.00001) and TGL (MD=-15.18%; 95% CI -19.34% to -11.03%; p<0.00001). Significant reductions were also observed for ApoB (MD=-34.94%; 95% CI -40.89% to -28.99%; p<0.00001) and Lp(a) (MD=-22.7%; 95% CI -25.95% to -19.44%; p<0.00001). LDL-C, TGL and ApoB reduction were more significant in heterozygous FH patients than in homozygous patients. The safety profile of these therapies was favourable, with adverse event rates comparable to those of the controls. PCSK9i and Inclisiran demonstrate significant and sustained reductions in LDL-C, ApoB, Lp(a) and TGL in FH patients, especially in heterozygous FH patients. These agents are generally well-tolerated and represent effective treatment options for FH patients inadequately controlled by standard lipid-lowering therapies. Show less

DEAH-box helicases, which share a structurally conserved ATPase core, function in all facets of eukaryotic gene expression. While most helicases are highly specialized for their substrates, DHX36 (DEAH-box helicase 36) resolves both DNA and RNA G-quadruplexes. To elucidate the molecular basis of this versatility, we have determined cryo-electron microscopy structures of bovine DHX36 bound to a three-tier RNA G-quadruplex and a six-tier DNA G-quadruplex at 2.6 and 3.4 Å resolution, respectively. Kinetic and smFRET characterizations of structure-guided mutants indicate a key role for the RecA2 domain of the helicase core in DNA vs. RNA discrimination. Furthermore, our structures show that a sequence-divergent RecA2 domain surface loop synergizes with a DHX36-specific N-terminal extension to orthogonally recognize features that specify G-quadruplexes over other nucleic acid structures. Our analysis suggests that recognizing their folded substrates by DEAH-box helicases may generally involve ornamentations of their structural cores acting synergistically with specialized peripheral elements. Show less

Obesity is the principal driver of insulin resistance, and lipodystrophy is also linked with insulin resistance, emphasizing the vital role of adipose tissue in glucose homeostasis. The quality of adipose tissue expansion is a critical determinant of insulin resistance predisposition, with individuals suffering from metabolic unhealthy adipose expansion exhibiting greater risk. Adipocytes are pivotal in orchestrating metabolic adjustments in response to nutrient intake and cell intrinsic factors that positively regulate these adjustments are key to prevent Type-2 diabetes. Employing unique genetic mouse models, we established the critical involvement of heparan sulfate (HS), a fundamental element of the adipocyte glycocalyx, in upholding glucose homeostasis during dietary stress. Genetic models that compromise adipocyte HS accelerate the development of high-fat diet-induced hyperglycemia and insulin resistance, independent of weight gain. Mechanistically, we show that perturbations in adipocyte HS disrupts endogenous FGF1 signaling, a key nutrient-sensitive effector. Furthermore, compromising adipocyte HS composition detrimentally impacts FGF1-FGFR1-mediated endocrinization, with no significant improvement observed in glucose homeostasis. Our data establish adipocyte HS composition as a determinant of Type 2 diabetes susceptibility and the critical dependency of the endogenous adipocyte FGF1 metabolic pathway on HS. Show less

Taurine is an amino acid widely present in animal tissues. Recent research has highlighted the importance of including taurine in the diet of various commercially relevant species. This study evaluated the impact of taurine supplementation in the diet of Seriola rivoliana on the activity of antioxidant enzymes, lysozyme, and the expression of metabolic-related genes in different tissues. Three experimental diets were designed with 0% (Control), 1%, and 2% of taurine concentrations, administered over 60 days. The results indicated that taurine supplementation significantly improved the activity of antioxidant enzymes such as catalase (CAT), superoxide dismutase (SOD), and myeloperoxidase (MPO) in the liver and plasma. Additionally, an increase in lysozyme (LZM) activity was observed in mucus and plasma of the fish. Regarding gene expression, the 2% taurine supplementation significantly increased the expression of critical genes involved in carbohydrates and lipid metabolism, such as glucokinase (gck), hexokinase (hk1), and acetyl-CoA carboxylase (acoa1) in the liver, as well as lipase (lpl), cholecystokinin (cck), and trypsin (try1) in the intestine. These results suggest that taurine not only enhances the antioxidant and immune capacity of the fish but also optimizes their energy metabolism and digestion, which could contribute to improved aquaculture diets, promoting more excellent resistance to oxidative stress and better overall health of fish raised under intensive conditions. Show less

Patients born with congenital porto-systemic shunts have been shown to have a high risk of benign and malignant liver tumors in otherwise healthy livers. This study aimed to evaluate the genetic landscape of liver tumors in patients with congenital porto-systemic shunts (CPSS) and correlate genotype with histological findings. Nodules from patients with CPSS and sporadic pediatric focal nodular hyperplasia (FNH) or FNH-like nodules were evaluated histologically and sequenced for a panel of 50 genes using next-generation sequencing. Thirty-eight nodules from 17 patients with CPSS were histologically classified as hepatoblastomas ( CPSS is strongly associated with nodules containing variants in Show less

The role of biomarkers in diagnosing pulmonary hypertension (PH) and distinguishing between pre- and post-capillary PH remains poorly understood. We aimed to identify biomarkers with a strong association with mean pulmonary arterial pressure, mPAP (PH diagnosis) and pulmonary vascular resistance, PVR (pre-capillary component), but not with pulmonary arterial wedge pressure, PAWP (post-capillary component). Blood samples were collected in patients undergoing right heart catheterization within a prospective cross-sectional study. Biomarkers measured included BMP10, NT-proBNP, ANG2, ESM1/endocan, FGF23, GDF15, IGFBP7, IL6, MyBPC3, proC3, and proC6/endotrophin. Primary outcomes were mPAP, PVR, and PAWP, while secondary outcomes included PH diagnosis (mPAP > 20 mmHg) and elevated PVR (> 2 Wood units). Multivariable linear and logistic regression models were used to assess the relationship between biomarkers and outcomes. Of the 127 patients included (age 66 ± 13 years, 54% female), 73% were diagnosed with PH. BMP10, NT-proBNP, ANG2, MyBPC3, and FGF23 showed a strong association with mPAP (p < 0.001). BMP10 and NT-proBNP were strongly associated with PVR (p < 0.001), while NT-proBNP and ANG2 were strongly associated with PAWP (p < 0.001). NT-proBNP had the strongest association with the diagnosis of PH (area under the curve = 0.76). BMP10 was the only biomarker associated with elevated PVR (OR 1.60, 95%CI 1.01-2.54, p = 0.04) but not with PAWP (p = 0.86). Several biomarkers were strongly associated with mPAP, PAWP, and PVR. BMP10 was the only biomarker strongly associated with mPAP and PVR, but not with PAWP, thus reflecting the pre-capillary PH component. Measurement of BMP10 along with NT-proBNP may aid in diagnosing PH. Show less

Congenital heart disease (CHD) is a prevalent condition characterized by defective heart development, causing premature death and stillbirths among infants. Genome-wide association studies (GWASs) have provided insights into the role of genetic variants in CHD pathogenesis through the identification of a comprehensive set of single-nucleotide polymorphisms (SNPs). Notably, 90-95% of these variants reside in the noncoding genome, complicating the understanding of their underlying mechanisms. Here, we developed a systematic computational pipeline for the identification and analysis of CHD-associated SNPs spanning both coding and noncoding regions of the genome. Initially, we curated a thorough dataset of SNPs from GWAS-catalog and ClinVar database and filtered them based on CHD-related traits. Subsequently, these CHD-SNPs were annotated and categorized into noncoding and coding regions based on their location. To study the functional implications of noncoding CHD-SNPs, we cross-validated them with enhancer-specific histone modification marks from developing human heart across 9 Carnegie stages and identified potential cardiac enhancers. This approach led to the identification of 2,056 CHD-associated putative enhancers (CHD-enhancers), 38.9% of them overlapping with known enhancers catalogued in human enhancer disease database. We identified heart-related transcription factor binding sites within these CHD-enhancers, offering insights into the impact of SNPs on TF binding. Conservation analysis further revealed that many of these CHD-enhancers were highly conserved across vertebrates, suggesting their evolutionary significance. Utilizing heart-specific expression quantitative trait loci data, we further identified a subset of 63 CHD-SNPs with regulatory potential distributed across various cardiac tissues. Concurrently, coding CHD-SNPs were represented as a protein interaction network and its subsequent binding energy analysis focused on a pair of proteins within this network, pinpointed a deleterious coding CHD-SNP, rs770030288, located in C2 domain of MYBPC3 protein. Overall, our findings demonstrate that SNPs have the potential to disrupt gene regulatory systems, either by affecting enhancer sequences or modulating protein-protein interactions, which can lead to abnormal developmental processes contributing to CHD pathogenesis. Show less

Hypertrophic cardiomyopathy (HCM) is often characterized by augmented cardiac contractility, which frequently remains undetectable in its early stages. Emerging evidence suggests that hypercontractility is linked to mitochondrial defects that develop early in HCM progression. However, imaging markers for identifying these early alterations in myocardial function are lacking. We used cardiac magnetic resonance feature tracking (CMR-FT) to assess myocardial strain in a Show less

BackgroundGenome-wide association studies (GWAS) have identified numerous genetic variants associated with Alzheimer's disease (AD), but their functional implications remain unclear. Transcriptome-wide association studies (TWAS) offer enhanced statistical power by analyzing genetic associations at the gene level rather than at the variant level, enabling assessment of how genetically-regulated gene expression influences AD risk. However, previous AD-TWAS have been limited by small expression quantitative trait loci (eQTL) reference datasets or reliance on AD-by-proxy phenotypes.ObjectiveTo perform the most powerful AD-TWAS to date using summary statistics from the largest available brain and blood Show less

Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiac disorder characterized by progressive fibrofatty replacement of the myocardium. In the Japanese population, variants of the desmoglein-2 ( A 6-year-old asymptomatic girl was diagnosed with ACM based on abnormal electrocardiogram findings, including epsilon waves, and T-wave inversions in leads V This case illustrates the potential for severe pediatric ACM associated with compound heterozygous This case underscores the genetic heterogeneity and phenotypic variability in inherited cardiomyopathies. It emphasizes the importance of comprehensive genetic testing and close monitoring of affected individuals and their families. Show less