📋 Browse Articles

Aortic valve stenosis (AS) is a progressive valvular disease characterized by fibrocalcific remodeling of the aortic valve leaflets, contributing to significant cardiovascular morbidity and mortality. While valve calcification has been extensively studied, the relationship between valve fibrosis, lipoprotein(a) [Lp(a)], systemic inflammation, sex differences, and valve morphology remains less explored. We prospectively enrolled 45 patients with severe AS undergoing preoperative echocardiography and contrast-enhanced cardiac computed tomography (CT) at Centro Cardiologico Monzino. Aortic valve calcium and fibrosis volumes were quantified using threshold-based segmentation on CT images. Lp(a) was measured by ELISA, while a multiplex Luminex assay measured a panel of 44 cytokines. Patients were stratified by Lp(a) levels (≤ 50 vs. > 50 mg/dL), sex, and valve morphology (bicuspid vs. tricuspid) to explore associations with the fibrocalcific components of stenotic aortic valves. The median Lp(a) level was 34.4 mg/dL (12.6; 93.4). No significant differences in valvular calcium load were observed between low and high Lp(a) groups. However, a modest increase in fibrotic volume was noted in patients with elevated Lp(a), particularly among men (p = 0.075). Several cytokines, including IL-1RA, IL-8, and TGF-α in men, and EGF, GM-CSF, IP-10, and IL-10 in women, were positively correlated with calcium burden. Fibrotic volume was associated with elevated eotaxin and PDGF-AA levels, with sex-specific patterns. Patients with bicuspid valve exhibited higher fibrocalcific volumes but lower circulating levels of several cytokines compared to patients with tricuspid valve morphology. In patients with severe AS, circulating cytokine profiles show sex- and valve-morphology-specific associations with the fibrocalcific composition of the valve. However, Lp(a) was not associated with valvular calcification, and any relationship with fibrosis appeared at most modest, more evident in men. These results support the relevance of inflammatory profiling in assessing AS pathophysiology. Show less

This experiment investigated the response of carcass composition, digestive function, hepatic lipid metabolism, intestinal microbiota, and serum metabolomics to excessive or restrictive dietary energy in Ningxiang pigs. A total of 36 Ningxiang pigs (210 ± 2 d, 43.26 ± 3.21 kg) were randomly assigned to three treatments (6 pens of 2 piglets each) and fed a control diet (CON, digestive energy (DE) 13.02 MJ/kg,), excessive energy diet (EE, 15.22 MJ/kg), and restrictive energy diet (RE, DE 10.84 MJ/kg), respectively. Results showed that EE significantly increased the apparent digestibility of crude protein and total energy ( The findings suggest RE had no obvious negative effect on carcass traits of Ningxiang pigs. Apart from exacerbated body fat deposition, EE promoted fat accumulation in the liver by up-regulating the expression of lipogenic genes. Dietary energy changes affect hepatic bile acid metabolism, which may be mediated through the glycerophospholipid metabolism pathway, as well as disturbances in the gut microbiota. Show less

Tuberculosis (TB) remains a major global health challenge, particularly in resource-limited settings where access to rapid and reliable diagnostics is limited. Conventional diagnostic methods, such as smear microscopy and culture, are either time-consuming or lack adequate sensitivity. This study optimized recombinase polymerase amplification (RPA) using 16 primer combinations targeting IS Show less

Goose foie gras production requires force-feeding with high-energy feed, disrupting hepatic lipid homeostasis and causing excessive lipid accumulation. To investigate the formation mechanism, we collected liver samples from Landes geese at pre-force-feeding (D0), mid-force-feeding (D16), and terminal-force-feeding (D25) stages. Overfeeding shifted liver color from reddish-brown to yellow, significantly increasing size and weight. Histological analysis revealed pronounced lipid droplet accumulation in hepatocytes. Biochemical analysis indicated force-feeding groups (D16, D25) exhibited continuous and significant decreases in liver moisture, crude ash, and crude protein content compared to D0, while crude fat increased substantially. Integrated transcriptomic and lipidomic analyses identified 497 differentially expressed genes (DEGs) and 368 differential lipid molecules (DLMs) between D16 and D0, and 303 DEGs and 172 DLMs between D25 and D16. KEGG enrichment highlighted four pathways associated with fatty liver formation: glycerolipid metabolism, adipocytokine signaling pathway, ErbB signaling pathway, and MAPK signaling pathway. Within these, key genes ( Show less

Short sleep duraiton is a putative risk for dementia, whereas midlife obesity is an well-known risk factor. Midlife short sleep and obesity share some biological changes such as inflammations or metabolic changes, but their combined impact is not yet fully understood. Our aim is to investigate the associations of short leep obesity with cognitive decline and dementia risk, and to investigate whether these associations are mediated by blood markers. This is an analysis of prospective cohort study of adults who were free of dementia, had data on sleep duration and BMI at baseline in 1997-1999, and were tracked for dementia diagnoses until 2023 via linkage to electronic health records. Participants will be divided into four groups: (1) the reference group (2) short sleep (2) short sleep (≤6 hours) and non-obese weight; (3) normal sleep and obesity (≥30kg/m Show less

Demyelination of corticospinal tract neurons contributes to long-term disability after cortical stroke. Nonetheless, poststroke myelin loss has not been addressed as a therapeutic target, so far. We hypothesized that an antibody-mediated inhibition of the Nogo receptor-interacting protein (LINGO-1, leucine-rich repeat and immunoglobulin domain-containing Nogo receptor-interacting protein) may counteract myelin loss, enhance remyelination and axonal growth, and thus promote functional recovery following stroke. To verify this hypothesis, mice were subjected to photothrombotic stroke and received either an antibody against LINGO-1 (n = 19) or a control treatment (n = 18). Behavioral tests were performed to assess the effects of anti-LINGO-1 treatment on the functional recovery. Seven weeks after stroke, immunohistochemical analyses were performed to analyze the effect of anti-LINGO-1 treatment on myelination and axonal loss of corticospinal tract neurons, proliferation of oligodendrocytes and neurogenesis. Anti-LINGO-1 treatment resulted in significantly improved functional recovery (p < 0.0001, repeated measures analysis of variance), and increased neurogenesis in the hippocampus and subventricular zone of the ipsilateral hemisphere (p = 0.0094 and p = 0.032, t-test). Notably, we observed a significant increase in myelin (p = 0.0295, t-test), platelet-derived growth factor receptor α-positive oligodendrocyte precursor cells (p = 0.0356, t-test) and myelinating adenomatous polyposis coli-positive cells within the ipsilateral internal capsule of anti-LINGO-1-treated mice (p = 0.0021, t-test). In conclusion, we identified anti-LINGO-1 as the first neuroregenerative treatment that counteracts poststroke demyelination of corticospinal tract neurons, presumably by increased proliferation of myelin precursor cells, and thereby improves functional recovery. Most importantly, our study presents myelin loss as a novel therapeutic target following stroke. Show less

Bi-allelic pathogenic variants in A two-month-old infant died from sudden-onset acute heart failure. We performed a full forensic autopsy with detailed histological examination and conducted trio-based whole-exome sequencing (WES) on the proband and parents to identify the genetic etiology. Postmortem examination revealed severe HCM, an atrial septal defect (ASD), and extensive myocardial necrosis and fibrosis. WES identified compound heterozygous pathogenic variants in This "molecular autopsy" established a definitive cause for the infant's death, linking a novel variant to a severe pathological phenotype. Crucially, the diagnosis guided the clinical management of the asymptomatic carrier parents, prompting long-term cardiac surveillance and enabling preimplantation genetic testing (PGT) for future family planning. This case demonstrates how integrating molecular diagnostics with forensic pathology facilitates a systems medicine approach, transforming a fatal index case into actionable preventive care for the entire family. Show less

To investigate the role of pyroptosis in diabetic nephropathy (DN) and identify potential biomarkers for diagnosis. We analyzed the GEO dataset GSE96804 to identify differentially expressed genes (DEGs) related to pyroptosis in DN. The CIBERSORT method was used to assess M1 macrophage infiltration in the samples. Using weighted gene co-expression network analysis (WGCNA), we identified gene modules associated with M1 macrophages. The least absolute shrinkage and selection operator (LASSO) method was then applied to screen for key genes. The intersection of key genes identified by LASSO and the gene modules obtained from WGCNA resulted in the identification of ten hub genes as potential biomarkers for DN. A total of 366 DEGs were identified, with 310 genes associated with pyroptosis. Increased M1 macrophage infiltration was observed in DN patients. Ten hub genes were identified as potential DN biomarkers: ECM1, LRP2BP, ALKBH7, CDH10, DUSP1, HSPA1A, LPL, NFIL3, PDK4, and TMEM150C. This study highlights the importance of pyroptosis in DN pathophysiology and identifies 10 hub genes as potential biomarkers. These findings may contribute to improved diagnosis and treatment of DN. Show less

Uterine corpus endometrial carcinoma (UCEC) is one of the most common gynecologic tumors. Due to the high recurrence and metastasis of UCEC, it is crucial for patients to find new biomarkers for diagnosis and therapy. In this study, R software and the TCGA database were used to screen candidate UCEC predictive markers. Western blot and RT-qPCR were performed to detect protein and mRNA expression of EXT1 in UCEC cell lines. In addition, MTT assay, flow cytometry, transwell assay, and wound healing assay were conducted to assess the cell viability, apoptosis, invasion, and migration in UCEC cells. Overlap-extension PCR technique was employed to construct the vector targeting the deletion of the methylated segment of EXT1. The results showed that a total of 11 candidate genes were obtained and EXT1 was identified as a potential target. The expression and methylation levels of EXT1 were both increased in UCEC tissues and cell lines, as well as elevated EXT1 was closely related to the poor prognosis of patients. Besides, the knockdown of EXT1 significantly inhibited the malignant biological behaviors in UCEC cells. Additionally, the current study also found that the deletion of 1559-2146 bp CpG island segment upregulated EXT1 expression and promoted malignant biological behaviors in UCEC cells. Furthermore, the presence of m7G RNA methylation in UCEC cells also was found. In conclusion, the methylation of EXT1 influenced the gene expression, thereby affecting the malignant biological behaviors in UCEC cells and regulating the pathological progression of UCEC. Show less

Lysophospholipids (LPLs) and host defense peptides (HDPs) are naturally occurring membrane-active agents that disrupt key membrane properties, including the hydrocarbon thickness, intrinsic curvature, and molecular packing. Although the membrane activity of these agents has been widely examined separately, their combined effects are largely unexplored. Here, we use experimental and computational tools to investigate how lysophosphatidylcholine (LPC) and lysophosphatidylethanolamine (LPE), an LPL of lower positive spontaneous curvature, influence the membrane activity of piscidin 1 (P1), an α-helical HDP from fish. Four membrane systems are probed: 75:25 C16:0-C18:1 PC (POPC)/C16:0-C18:1 phosphoglycerol (POPG), 50:25:25 POPC/POPG/16:0 LPC, 75:25 C16:0-C18:1 PE (POPE)/POPG, and 50:25:25 POPE/POPG/14:0 LPE. Dye leakage, circular dichroism, and NMR experiments demonstrate that while the presence of LPLs alone does not induce leakage-proficient defects, it boosts the permeabilization capability of P1, resulting in an efficacy order of POPC/POPG/16:0 LPC > POPE/POPG/14:0 LPE > POPC/POPG > POPE/POPG. This enhancement occurs without altering the membrane affinity and conformation of P1. Molecular dynamics simulations feature two types of asymmetric membranes to represent the imbalanced ("area stressed") and balanced ("area relaxed") distribution of lipids and peptides in the two leaflets. The simulations capture the membrane thinning effects of P1, LPC, and LPE, and the positive curvature strain imposed by both LPLs is reflected in the lateral pressure profiles. They also reveal a higher number of membrane defects for the P1/LPC than P1/LPE combination, congruent with the permeabilization experiments. Altogether, these results show that P1 and LPLs disrupt membranes in a concerted fashion, with LPC, the more disruptive LPL, boosting the permeabilization of P1 more than LPE. This mechanistic knowledge is relevant to understanding biological processes where multiple membrane-active agents such as HDPs and LPLs are involved. Show less

Tumor-agnostic US Food and Drug Administration approvals are transforming oncology. They include larotrectinib/entrectinib/repotrectinib (NTRK fusions), selpercatinib (RET fusions), dabrafenib/trametinib (BRAF Show less

Microtubule actin crosslinking factor 1 (MACF1), is a cytoskeletal protein that functions as a crosslinker between microtubules and actin filaments, with early studies expanding the role of this spectraplakin protein to the central nervous system and Wnt signaling. In the early 2000's, genetic alterations of MACF1 were identified in several cancers suggesting that this cytoskeletal crosslinker was involved in tumor development and progression, while preclinical studies provided evidence that MACF1 is a potential diagnostic and prognostic biomarker and therapeutic target in glioblastomas, a central nervous system cancer derived from astrocytes and neural progenitor stem cells. Furthermore, investigations in glioblastomas demonstrated that genetic inhibitory targeting of this spectraplakin protein alone and in combination with DNA damaging agents had synergistic antitumorigenic effects. The established role of MACF1 in Wnt signaling, a known mechanistic driver of central nervous system development and pro-tumorigenic cell behavior in glioblastomas, provide a premise for addressing the potential of this spectraplakin protein as a novel oncoprotein in cancers with origins in the nervous system. The present review provides a summary of the role and function of MACF1 in the central nervous system, Wnt signaling and cancer development, specifically as an oncoprotein that underlie the transformation and oncogenic properties of glioblastomas. Show less

Gut brain axis can affect the incidence of Alzheimer's disease (AD). Probiotics restore the homeostasis of gut dysbiosis and prevent AD. Here, we evaluated the impact of Saccharomyces boulardii on rats with lipopolysaccharide (LPS)-induced amyloidogenesis. Rats were classified into four groups: (1) Control (saline), (2) LPS 250 µg/kg (saline + LPS), (3) S. boulardii (10 Show less

In recent years, the discovery of IL-12 family cytokines, which includes IL-12, IL-23, IL-27, IL-35, and IL-39, whose biological functions directly or indirectly affect various autoimmune diseases. In autoimmune diseases, IL-12 family cytokines are aberrantly expressed to varying degrees. These cytokines utilize shared subunits to influence T-cell activation and differentiation, thereby regulating the balance of T-cell subsets, which profoundly impacts the onset and progression of autoimmune diseases. In such conditions, IL-12 family members are aberrantly expressed to varying degrees. By exploring their immunomodulatory functions, researchers have identified varying therapeutic potentials for each member. This review examines the physiological functions of the major IL-12 family members and their interactions, discusses their roles in several autoimmune diseases, and summarizes the progress of clinical studies involving monoclonal antibodies targeting IL-12 and IL-23 subunits currently available for treatment. Show less

Cancer-targeted therapies are progressively pivotal in oncological care. Observational studies underscore the emergence of cancer therapy-related cardiovascular toxicity (CTR-CVT), impacting patient outcomes. We aimed to investigate the causal relationship between different types of cancer-targeted therapies and cardiovascular disease (CVD) outcomes through a two-sample Mendelian randomization (MR) study. This genome-wide association study was conducted using a two-sample Mendelian randomization framework. Genetic instruments for drug target gene expression were extracted from the eQTLGen consortium (31684 individuals, 37 cohorts). Genome-wide association study (GWAS) summary statistics for 19 cardiovascular diseases were derived from the FinnGen database. Primary analysis was carried out using the summary-data-based MR (SMR) method, with sensitivity analysis for validation. Colocalization analysis identifies shared causal variants between exposure eQTLs and CVD-associated single-nucleotide polymorphisms (SNPs). Among the 39 drug target genes, 8 were identified with detectable cis-eQTLs and were subsequently validated through positive control analysis for further investigation. In the SMR and sensitivity analyses, genetically proxied VEGFA inhibition showed significantly strong association with stroke (odds ratio [OR] = 1.17, 95% confidence interval [CI] = 1.09-1.26, p = 1.33 × 10 This genetic association study revealed evidence supporting the genetic association between the use of VEGFA inhibitors and increased stroke risk, highlighting the need for enhanced pharmacovigilance. These findings underscore the delicate balance between cardiovascular toxicity risk and the benefits of cancer-targeted therapy. Show less

Percutaneous coronary intervention (PCI) is a practical and effective method for treating coronary heart disease (CHD). This study aims to explore the influencing factors of major cardiovascular events (MACEs) and hospital readmission risk within one year following PCI treatment. Additionally, it seeks to assess the clinical value of Apolipoprotein B/Apolipoprotein A-I (ApoB/ApoA-I) in predicting the risk of one-year MACEs and readmission post-PCI. A retrospective study included 1938 patients who underwent PCI treatment from January 2010 to December 2018 at Shandong Provincial Hospital affiliated with Shandong First Medical University. Patient demographics, medications, and biochemical indicators were recorded upon admission, with one-year follow-up post-operation. Univariate and multivariate Cox proportional hazards regression models were utilized to establish the relationship between ApoB/ApoA-I levels and MACEs/readmission. Predictive nomograms were constructed to forecast MACEs and readmission, with the accuracy of the nomograms assessed using the concordance index. Subgroup analyses were conducted to explore the occurrence of MACEs and readmission. We observed a correlation between ApoB/ApoA-I and other lipid indices, including total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) (P < 0.001). Univariate and multivariate Cox regression analyses demonstrated that ApoB/ApoA-I is an independent risk factor for MACEs in post-PCI patients (P = 0.038). Within one year, the incidence of MACEs significantly increased in the high-level ApoB/ApoA-I group (ApoB/ApoA-I ratio ≥ 0.824) (P = 0.038), while the increase in readmission incidence within one year was not statistically significant. Furthermore, a nomogram predicting one-year MACEs was established (Concordance Index: 0.668). Subgroup analysis revealed that ApoB/ApoA-I was associated with the occurrence of both MACEs and readmission in male patients, those using CCB/ARB/ACEI, those without multivessel diseases, or those with LDL-C < 2.6 mmol/L. The ApoB/ApoA-I ratio serves as an independent risk factor for one-year MACEs in post-PCI patients and correlates closely with other blood lipid indicators. ApoB/ApoA-I demonstrates significant predictive value for the occurrence of MACEs within one year.Trial registration Chinese clinical trial registry: No.ChiCTR22000597-23. Show less

Preclinical studies suggest that a triglyceride (TG)-independent proinflammatory action of apolipoprotein C-III (apoCIII) exists. We aimed to investigate the relationship between circulating apoCIII levels and subclinical inflammation markers across different cohorts with distinctive inflammatory patterns: patients with metabolic disorders (MDs), patients with rheumatoid arthritis (RA), and controls. Specifically, we assessed the associations of apoCIII with acute inflammation biomarkers (e.g., high sensitivity C-reactive protein (hsCRP)) and novel systemic inflammation biomarkers (e.g., glycosylated proteins: Glyc-A, Glyc-B, Glyc-F), aiming to understand the role of apoCIII beyond its traditional function in TG metabolism. This cross-sectional study involved 1242 participants: 906 patients with MD (metabolic syndrome, type 2 diabetes (T2DM) and/or obesity), 192 patients with RA, and 144 controls. ApoCIII and hsCRP levels were measured via immunoturbidimetric assays, and glycosylated proteins were quantified via 1 H-NMR spectroscopy. Correlation and multivariate linear regression analyses were conducted. ApoCIII levels were significantly and positively associated with Glyc-A, Glyc-B, and Glyc-F levels across all cohorts. Most of these associations remained significant in the MD group after adjusting for TG levels. Conversely, negative associations were detected between apoCIII and hsCRP patients with MD and RA, which were maintained after including TG in the models. In patients with MD and RA, circulating apoCIII levels were positively associated with glycoproteins and negatively with hsCRP, in a TG-independent manner. Our results suggest that apoCIII is associated with the low-grade inflammatory profile represented by glycoproteins, independent of triglyceride levels. Additionally, we observed a negative association with hsCRP, which, while seemingly paradoxical, has been reported in previous studies. Show less

The dysregulation of T cell differentiation was associated with cognitive impairment. Recently, the peripheric β-secretase (BACE1) has been suggested as a regulator of T cell differentiation, which was increased in both cognitive impairment (CI) and type 2 diabetes mellitus (T2DM) in CI patients. However, the relationship between T cell dysfunction and CI remains unclear. To address this question, we measured T cell subtypes and BACE1 enzyme activity in a clinical cohort and 5xFAD mice. We found that both IFNγ+ Th1 and Tc1 cells were increased in the CI and T2DM-CI groups, which were associated with worsening cognitive function. The elevated IFNγ + Th1 and Tc1 cells were also observed in 8-month-old 5xFAD mice. The elevated BACE1-mediated INSR cleavage was associated with increased IFNγ + Th1 and Tc1 cells. These findings demonstrate the potential role of elevated BACE1 in IFNγ+ T cells and CI. Show less

The 3-hydroxybutyrate dehydrogenase 1 (BDH1) mainly participates in the regulation of milk fat synthesis and ketone body synthesis in mammary epithelial cells. In our previous study, BDH1 was identified as a key candidate gene regulating lipid metabolism in mammary glands of dairy goats by RNA-seq. This study aimed to investigate the effect of BDH1 on lipid metabolism in mammary epithelial cells of dairy goats (GMECs). The results suggest that BDH1 plays a significant role in reducing triacylglycerol content and lipid droplet accumulation in GMECs (p < 0.05). Overexpression of BDH1 significantly decreased the expression of lipid metabolism-related genes (SREBF1 and GPAM) and reduced the levels of C14:0 and C17:1, while increasing FABP3 expression and C10:0 concentration (p < 0.05). Interference with BDH1 significantly increased the expression of SREBF1 and GPAM and the concentration of C14:0, C15:1, and C20:1, but significantly decreased FABP3 and C18:0 (p < 0.05). Treatment of GMECs with β-hydroxybutyric acid (R-BHBA) significantly decreased the expression of FASN, ACACA, LPL, SREBF1, FABP3, ACSL1, GPAM, DGAT1, and triacylglycerol content, while significantly increasing the expression of BDH1 (p < 0.05). Interference with BDH1 rescued the reduction of cellular TAG content and the expression of FASN, LPL, SREBF1, ACSL1, and GPAM in BHBA-treated GMECs. In conclusion, BDH1 negatively regulates lipid metabolism in mammary glands of dairy goats. Furthermore, it may mitigate the inhibitory effect of R-BHBA on lipid metabolism in GMECs. Show less

Metabolism alteration is a common complication of rheumatic arthritis (RA). This work investigated the reason behind RA-caused triglyceride (TG) changes. Fresh RA patients' whole blood was transfused into NOD-SCID mice. Metabolism-regulatory tissues were examined after sacrifice. To verify the findings, tissues of the rats with long-lasting adjuvant-induced arthritis (AIA) were analyzed. Some rats were injected with human plasma and GPIHBP1, and their blood TG was monitored. Various cells were stimulated by cytokines or rheumatic subjects' serum. Some pre-adipocytes were cultured by human serum or in the presence of HUVEC cells and GPIHBP1. TG decrease occurred in blood and white adipose tissues (WAT) of the RA blood-transfused NOD-SCID mice and chronic AIA rats. Fatty acids (FA) oxidation in muscles was accelerated a bit, while TG catabolism status in their livers was varied. TNF-α, IL-1β, IL-6 and RA/AIA serum promoted expression of TG utilization-related enzymes and FA uptake transporters in pre-adipocytes, but barely affected LPL. Mild IL-6 stimulus promoted GPIHBP1 release of HUVEC cells. GPIHBP1 was increased in RA serum. This change can decrease blood TG in rats, which was overshadowed by an injection of excessive GPIHBP1. RA serum slightly inhibited LPL secretion in pre-adipocytes. Both HUVEC cells co-culture and GPIHBP1 supplement reduced LPL distribution on pre-adipocytes, and eliminated LPL activity difference between normal and RA serum-treated cells. No TG uptake difference was observed in these circumstances. RA-associated inflammation induces GPIHBP1 secretion of endothelial cells, which facilitates blood TG hydrolysis and uptake to compensate the loss in WAT. Show less

Autism Spectrum Disorder (ASD) is a complex condition with a multifactorial aetiology including both genetic and epigenetic factors. MicroRNAs (miRNAs) play a role in ASD and may influence metabolic pathways. Glycosylation (the glycoconjugate synthesis pathway) is a necessary process for the optimal development of the central nervous system (CNS). Congenital Disorders of Glycosylation (CDGs) (CDGs) are linked to over 180 genes and are predominantly associated with neurodevelopmental disorders (NDDs) including ASD. From a literature search, we considered 64 miRNAs consistently deregulated in ASD patients (ASD-miRNAs). Computational tools, including DIANA-miRPath v3.0 and TarBase v8, were employed to investigate the potential involvement of ASD-miRNAs in glycosylation pathways. A regulatory network constructed through miRNet 2.0 revealed the involvement of these miRNAs in targeting genes linked to glycosylation. Protein functions were further validated through the Human Protein Atlas. A total of twenty-five ASD-miRNAs were identified, including nine miRNAs that were differentially expressed in cells or brain tissue in ASD patients and associated with glycosylation pathways, specifically protein N- and O-glycosylation and glycosaminoglycan biosynthesis (heparan sulfate). A number of CDG genes and/or ASD-risk genes, including Show less

Physical activity (PA), including sedentary behavior, is associated with many diseases, including Alzheimer's disease and all-cause dementia. However, the specific biological mechanisms through which PA protects against disease are not entirely understood. To address this knowledge gap, we first assessed the conventional observational associations of three self-reported and three device-based PA measures with circulating levels of 2,911 plasma proteins measured in the UK Biobank (n Show less

MicroRNA (miRNA), a conservatively evolved single-stranded non-coding RNA, exerts pivotal control over the appearance of target genes and several biological processes. This study conducted a comprehensive screening of candidate microRNAs (miRNAs) associated with Lipoprotein Lipase (LPL) in the large yellow croaker (Larimichthys crocea), utilizing sophisticated bioinformatics techniques across the species' muscular and hepatic tissues. The bioinformatics analysis facilitated the compilation and examination of miRNA datasets specific to these tissues. The investigation culminated in the identification of miR-84a and miR-1231-5p as key miRNAs that modulate fat hydrolysis, highlighting their potential roles in lipid metabolism. Subsequent in-depth analysis further implicated these miRNAs, along with miR-891a, as prospective targets of LPL, suggesting their integral involvement in the regulation of this critical enzyme. Validation of these bioinformatics predictions was conducted through the construction of double luciferase reporters concealing the LPL 3' untranslated region (3'UTR), substantiating that miR-84a and miR-1231-5p can modulate LPL expression via the LPL 3'UTR. Conversely, miR-891a was not concerned with this regulatory mechanism. Site-directed mutagenesis experiments elucidated the specificity of the interaction sequences. Quantitative PCR assays suggested that miR-84a and miR-1231-5p might influence LPL expression during the starvation phase, intimating the regulatory role of miRNA in fatty acid metabolism within hepatic and muscular tissue under starvation. These findings offer a nuanced understanding of LPL's molecular functionality under stress conditions in fish, emphasizing the regulatory dynamics of miRNA during metabolic stress. Show less

An association has been observed between alcohol and cheese intake and the onset of inflammatory bowel disease (IBD), necessitating further exploration from a genetic structural perspective. The present analysis was focused on the intake of alcohol and cheese in conjunction with IBD genome-wide association study (GWAS) data, with the objective of exploring genetic correlations and identifying common loci. Initially, overall genetic correlations were assessed employing two methodologies: linkage disequilibrium score regression (LDSC) and genetic covariance analyzer (GNOVA). Subsequently, local correlations were examined through the SUPERGNOVA method. A genetic overlap analysis between various traits was then conducted based on the statistical theory of conditional/conjunctional false discovery rate (cond/conjFDR). Ultimately, shared loci between the two traits were identified via conjFDR analysis and multi-trait analysis of GWAS (MTAG). Substantial overall correlations were noted at the genome-wide level between alcohol and cheese intake and both IBD and Crohn's disease (CD), whereas the association with ulcerative colitis (UC) was of lesser significance. In the local genetic analysis, chromosome 16 emerged as a key region implicated in the relationship between alcohol and cheese intake and IBD (including both CD and UC). The conjFDR analysis confirmed the genetic overlap between the two diseases. Furthermore, both conjFDR and MTAG analyses identified multiple shared genetic loci, with nine genes ( The present study provides genetic evidence supporting the comorbidity of alcohol and cheese intake with IBD, offering novel insights into potential strategies for the prevention and treatment of IBD through the modulation of alcohol and cheese consumption. Show less

Tetralogy of Fallot (TOF) is the most common cyanotic heart defect in neonates. While there is compelling evidence of genetic contribution to the etiology of TOF, the contribution of noncoding variants to the development of the defect remains unexplored. Potentially damaging noncoding de novo variants (NC DNVs) were detected from 141 Chinese nonsyndromic TOF trios (CHN-TOF) and compared with those detected in the Pediatric Cardiac Genomics Consortium (PCGC). Bioinformatic analyses on noncoding and previously detected coding DNVs were performed to identify developmental pathways affected in TOF. Chinese but not PCGC-TOF patients showed a notably increased burden of putative damaging NC DNVs (n = 249). In Chinese, NC and coding DNVs were predominantly associated with cardiomyocyte differentiation and with chamber/valve/aorta development, respectively, producing a combined enrichment in NOTCH signaling (p = 1.1 × 10 Show less

Infantile epileptic spasms syndrome is a severe epilepsy of infancy that is often associated with focal malformations of cortical development. This study aimed to elucidate the genetic landscape and histopathologic aetiologies of infantile epileptic spasms syndrome due to focal malformations of cortical development requiring surgery. Fifty-nine children with a history of infantile epileptic spasms syndrome and focal malformations of cortical development on MRI were studied. Genetic testing of resected brain tissue was performed by high-coverage targeted panel sequencing or exome sequencing. Histopathology and MRI were reviewed, and integrated clinico-pathological diagnoses were established. A genetic diagnosis was achieved in 47 children (80% of cohort). Germline pathogenic variants were identified in 27/59 (46%) children, in Show less

Many factors involved in heparan sulfate (HS) biosynthesis and metabolism have been reported to play roles in viral infection. However, the detailed mechanisms are still not fully understood. In this study, we report that exostosin glycosyltransferase 1 (EXT1), the HS polymerase, is a critical regulatory factor for Zika virus (ZIKV) infection. Knocking out EXT1 dramatically restricts ZIKV infection, which is not due to the inhibition of virus entry resulting from HS deficiency, but mediated by the downregulation of autophagy. Induction of autophagy promotes ZIKV infection, and attenuated autophagy is found in distinct EXT1 knockout (EXT1-KO) cell lines. Induction of autophagy by rapamycin can relieve the ZIKV production defect in EXT1-KO cells. While over-expressing EXT1 results in the reduction of ZIKV production by targeting the viral envelope (E) protein and non-structural protein NS3 in a proteasome-dependent degradation manner. The different roles of EXT1 in ZIKV infection are further confirmed by the data that knocking down EXT1 at the early stage of ZIKV infection represses viral infection, whereas the increase of ZIKV infection is observed when knocking down EXT1 at the late stage of viral infection. This study discovers previously unrecognized intricate roles of EXT1 in ZIKV infection. Show less

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by cognitive decline, anxiety-like behavior, β-amyloid (Aβ) accumulation, and tau hyperphosphorylation. BACE1, the enzyme critical for Aβ production, has been a major therapeutic target; however, direct BACE1 inhibition has been associated with adverse side effects. This study investigates the therapeutic potential of RA-PR058, a novel ramalin derivative, as a multi-targeted modulator of AD-related pathologies. The effects of RA-PR058 were evaluated Show less

Lymphoplasmacytic lymphoma (LPL) is a B-cell lymphoproliferative disorder typically involving the bone marrow with infiltration by small lymphocytes and plasma cells. Studies have identified MYD88 L265P mutation as a diagnostic marker to distinguish LPL from other small B-cell lymphomas. Detection rates for this mutation have varied depending on the analytic methodology, with previous data suggesting that routine next-generation sequencing (NGS) does not demonstrate the required sensitivity to reliably detect MYD88 L265P. NGS has become part of routine clinical testing because it allows detection of variants across multiple genes. To study the utility of NGS in the detection of MYD88 L265P, we performed droplet digital PCR (ddPCR) and routine NGS on a cohort of 34 cases of lymphoid neoplasms (22 LPL, 4 CLL, 1 MCL, 1 MGUS, 2 plasma cell myeloma, and 4 negative bone marrow cases). We utilized manual review and BAMtools to assess MYD88 L265P in NGS cases. Limit of detection for ddPCR was determined to be 0.4 % variant allele frequency (VAF) with 10 ng DNA input. MYD88 L265P VAF detection by NGS and ddPCR was comparable down to 0.5 % VAF (R Show less

The fibroblast growth factor receptor family members, FGFR1-4, are frequently overexpressed in various solid tumors, including breast cancer and sarcomas. This overexpression highlights the potential of the family of FGFRs as promising targets for cancer therapy. However, conventional FGFR kinase inhibitors often encounter challenges such as limited efficacy or drug resistance. In this study, we pursue an alternative strategy by designing a conjugate of the FGFR ligand FGF1 with the radioisotope Show less