Injectable hydrogel implants represent a promising therapeutic approach for ischemic heart failure; but their efficacy is often limited by low bioactivity, poor durability, and inadequate injection te Show more
Injectable hydrogel implants represent a promising therapeutic approach for ischemic heart failure; but their efficacy is often limited by low bioactivity, poor durability, and inadequate injection techniques. Herein, a unique hydrogel incorporating extracellular matrix from fish swim bladder (FSB-ECM), which has distinct advantages over mammalian derived ECM, such as low antigenicity, bioactivity, and source safety, is developed. It consists of collagen, glycoproteins, and proteoglycans, including 13 proteins common in the myocardial matrix and three specific proteins: HSPG, Col12a1, and vWF. This hydrogel enhances cardiac cell adhesion and stretching while promoting angiogenesis and M2 macrophage polarization. In addition, its storage modulus (G') increases over time, reaching about 1000 Pa after 5 min, which facilitates transcatheter delivery and in situ gelling. Furthermore, this hydrogel provides sustained support for cardiac contractions, exhibiting superior longevity. In a rat model of ischemic heart failure, the ejection fraction significantly improves with FSB-ECM treatment, accompanied by increased angiogenesis, reduced inflammation, and decreased infarct size. Finally, RNA sequencing combined with in vitro assays identifies ANGPTL4 as a key protein involved in mediating the effects of FSB-ECM treatment. Overall, this new injectable hydrogel based on FSB-ECM is suitable for transcatheter delivery and possesses remarkable reparative capabilities for treating heart failure. Show less
Hereditary multiple exostoses (HME) is an autosomal dominant skeletal disorder primarily linked with mutations in Exostosin-1 (EXT1) and Exostosin-2 (EXT2) genes. However, not all HME cases can be exp Show more
Hereditary multiple exostoses (HME) is an autosomal dominant skeletal disorder primarily linked with mutations in Exostosin-1 (EXT1) and Exostosin-2 (EXT2) genes. However, not all HME cases can be explained by these mutations, and its pathogenic mechanisms are not fully understood. Herein, utilizing whole-exome sequencing and genetic screening with a family trio design, we identify two novel rare mutations co-segregating with HME in a Chinese family, including a nonsense mutation (c.204G>A, p.Trp68*) in EXT1 and a missense mutation (c.893T>G, p.Phe298Cys) in FUT7. Functional assays reveal that the FUT7 mutation affects the cellular localization of FUT7 protein and regulates cell proliferation. Notably, the simultaneous loss of fut7 and ext1 in a zebrafish model results in severe chondrodysplasia, indicating a functional link between FUT7 and EXT1 in chondrocyte regulation. Additionally, we unveil that FUT7 p.Phe298Cys reduces EXT1 expression through IL6/STAT3/SLUG axis at the transcription level and through ubiquitination-related proteasomal degradation at the protein level. Together, our findings not only identify novel germline mutations in FUT7 and EXT1 genes, but also highlight the critical interaction between these genes, suggesting a potential 'second-hit' mechanism over EXT1 mutations in HME pathogenesis. This insight enhances our understanding of the mechanisms underlying HME and opens new avenues for potential therapeutic interventions. Show less
Yuwen Guo, Huai Bai, Linbo Guan+4 more · 2025 · Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics · added 2026-04-24
To assess the association between the single nucleotide polymorphisms (SNP) rs174575 and rs2845574 of the fatty acid desaturase 2 (FADS2) gene and gestational diabetes mellitus (GDM). A total of 1 514 Show more
To assess the association between the single nucleotide polymorphisms (SNP) rs174575 and rs2845574 of the fatty acid desaturase 2 (FADS2) gene and gestational diabetes mellitus (GDM). A total of 1 514 pregnant women who visited West China Second University Hospital of Sichuan University between January 1, 2013 and December 31, 2021 were enrolled in this study. Among them, 583 were diagnosed with gestational diabetes mellitus (GDM group), and 931 had normal pregnancies (control group). The SNPs rs174575 and rs2845574 of the FADS2 gene were analyzed using Sanger DNA sequencing. Plasma levels of insulin (INS), apolipoprotein A1 (apoA1) and apolipoprotein B (apoB) were measured using enzymatic methods, chemiluminescence and immunoturbidimetry. This study was approved by the Medical Ethics Committee of the West China Second University Hospital of Sichuan University (Ethics No.: 2020-036). The main genotype at the rs174575 C/G and rs2845574 C/T loci were CC in both GDM and control groups. No significant difference was found between the GDM and control groups regarding the genotypic or allelic frequencies of rs174575 and rs2845574 sites (P > 0.05). Among the GDM group, individuals with the GG genotype at the rs174575 site had lower plasma HDL-C levels compared to those with the CC genotype (P < 0.05), and had higher atherogenic indices (AI) compared with the CC and CG genotype (P < 0.05; P < 0.05). Individuals with the TT genotype at the rs2845574 site had higher AI compared with the CT genotype (P < 0.05). Among the control group, individuals with the GG genotype had lower diastolic blood pressure (DBP) compared to those with the CC genotype (P < 0.05). Additional subgroup analysis demonstrated that the rs174575 polymorphism was associated with AI levels in obesity subgroup of GDM, TG levels in non-obese subgroup of control and DBP levels in the obese subgroup of control (P < 0.05; P < 0.05; P < 0.05). The FADS2 rs174575 and rs2845574 polymorphisms in GDM patients are associated wit HDL-C and AI levels, and the FADS2 rs174575 polymorphisms was also associated with DBP levels in normal pregnant women. The AI and DBP levels have a BMI-dependent effect. Show less
Diabetes mellitus (DM) and tuberculosis (TB) are two global health challenges that significantly impact population health, with DM increasing susceptibility to TB infections. However, early risk predi Show more
Diabetes mellitus (DM) and tuberculosis (TB) are two global health challenges that significantly impact population health, with DM increasing susceptibility to TB infections. However, early risk prediction methods for DM patients complicated with TB (DM-TB) are lacking. This study mined transcriptome data of DM-TB patients from the GEO database (GSE181143 and GSE114192) and used differential analysis, weighted gene co-expression network analysis (WGCNA), intersecting immune databases, combined with ten machine learning algorithms, to identify immune biomarkers associated with DM-TB. An early alert model for DM-TB was constructed based on the identified core differentially expressed genes (DEGs) and validated through a prospective cohort study and reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) for gene expression levels. Furthermore, we performed a detailed immune status analysis of DM-TB patients using the CIBERSORT algorithm. We identified 1090 DEGs associated with DM-TB and further pinpointed CETP (cholesteryl ester transfer protein) (AUC = 0.804, CI: 0.744-0.864), TYROBP (TYRO protein tyrosine kinase binding protein) (AUC = 0.810, CI: 0.752-0.867), and SECTM1 (secreted and transmembrane protein 1) (AUC = 0.811, CI: 0.757-0.864) as immune-related biomarkers for DM-TB patients. An early alert model was developed based on these three genes (AUC = 0.86, CI: 0.813-0.907), with a sensitivity of 0.80829 and a specificity of 0.75758 at a Youden index of 0.56587. External validation using the GSE114192 dataset showed an AUC of 0.901 (CI: 0.847-0.955). Population cohort research and RT-qPCR verified the expression levels of these three genes, demonstrating consistency with trends seen in the training set. KEGG enrichment analysis revealed that NF-κB and MAPK signaling pathways play crucial roles in the DM-TB pathogenic mechanism, and immune infiltration analysis showed significant suppression of certain adaptive immune cells and activation of inflammatory cells in DM-TB patients. This study identified three potential immune-related biomarkers for DM-TB, and the constructed risk assessment model demonstrated significant predictive efficiency, providing an early screening strategy for DM-TB. Show less
Podocyte injury is central to diabetic kidney disease (DKD) pathogenesis, however, the mechanisms underlying podocyte loss remain unclear. Emerging evidence underscores the involvement of fibroblast g Show more
Podocyte injury is central to diabetic kidney disease (DKD) pathogenesis, however, the mechanisms underlying podocyte loss remain unclear. Emerging evidence underscores the involvement of fibroblast growth factors (FGFs) in renal pathophysiology. Here we reveal a previously unappreciated role of podocyte-secreted FGF4 in safeguarding renal function. FGF4 expression is downregulated in renal tissues from DKD patients and animal models, correlating with disease severity. Podocyte-specific deletion of Fgf4 exacerbated podocyte loss and accelerated DKD progression in mice. Conversely, treatment with recombinant FGF4 (rFGF4) improved glomerular filtration and reduced renal injury and fibrosis in diabetic male mice. These effects are primary mediated by activating the FGFR1-AMPK-FOXO1 signaling cascade in podocytes, which mitigates oxidative stress, suppresses apoptosis, and fosters podocyte survival. Notably, rFGF4 also restores the morphology and function of human podocytes exposed to high glucose. Our findings establish FGF4 as a critical regulator of podocyte homeostasis and a potential therapeutic target for DKD. 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 strat Show more
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
Vaccinia-related kinase 1 (VRK1) is involved in numerous cellular processes, including DNA repair, cell cycle and cell proliferation. However, its roles and molecular mechanism underlying the progress Show more
Vaccinia-related kinase 1 (VRK1) is involved in numerous cellular processes, including DNA repair, cell cycle and cell proliferation. However, its roles and molecular mechanism underlying the progression of hepatocellular carcinoma (HCC) are yet largely unexplored. Here, we demonstrated that VRK1 expression is elevated in HCC tumor tissues, which is associated with high tumor stage and poor prognosis in HCC patients. In vitro and in vivo experiments manifested that VRK1 overexpression significantly promotes cell proliferation, colony formation, migration and tumor growth of HCC by inducing epithelial-mesenchymal transition (EMT) program. Mechanistically, immunoprecipitation combined with mass spectrometry analysis determined that VRK1 interacts with CHD1L, which mediates the phosphorylation of CHD1L at serine 122 site. RNA-seq revealed that one of the key downstream target genes of VRK1 is SNAI1, by which VRK1 promotes EMT process and HCC progression. Furthermore, VRK1 upregulates SNAI1 expression through phosphorylating CHD1L. In conclusion, these findings suggested that VRK1/CHD1L/SNAI1 axis acts as a cancer-driving pathway to promote the proliferation and EMT of HCC, indicating that targeting VRK1 may be an attractive therapeutic strategy of HCC. Show less
R-loop is a common chromatin feature consisting of a displaced single-stranded DNA and an RNA-DNA hybrid, and dysregulation of R-loop surveillance results in genomic and transcriptomic instability. Al Show more
R-loop is a common chromatin feature consisting of a displaced single-stranded DNA and an RNA-DNA hybrid, and dysregulation of R-loop surveillance results in genomic and transcriptomic instability. Although the RNA moiety of most R-loops originates from linear transcripts, circular RNAs (circRNAs), outputs from back-splicing, can also hybridize with the complementary strand of a DNA duplex. However, how circRNA-associated R-loops (ciR-loops) are monitored remains elusive. Here, we identify the DEAD-box RNA helicase Brr2 as an evolutionarily-conserved ciR-loop repressor with dual roles in inhibiting circRNA generation and resolving harmful ciR-loops. Accumulation of ciR-loops caused by loss-of-function of this dual-action factor induces antisense transcription and premature transcription termination for many genes and generates significant DNA damage, which further leads to a series of defects in DNA replication, cell division and cell proliferation. We propose that functional integration of multilayered regulation by a single protein can be an efficient double protection against genome instability. Show less
Spontaneous Achilles tendon rupture (SATR) predominantly affects middle-aged and elderly individuals with chronic injuries. However, the exact cause and mechanism of SATR remain elusive, and potential Show more
Spontaneous Achilles tendon rupture (SATR) predominantly affects middle-aged and elderly individuals with chronic injuries. However, the exact cause and mechanism of SATR remain elusive, and potential therapeutic intervention or prevention is still insufficient. The present study aimed to uncover the key pathological molecules by using iTRAQ proteomics. The results identified 2432 candidate proteins in SATR patients using iTRAQ proteomic analysis. A total of 307 differentially expressed proteins (DEPs) were identified and linked to 211 KEGG signaling pathways including Coronavirus disease (COVID-19), focal adhesion, and ribosomes. GO enrichment analysis highlighted significant enrichment in processes such as biological adhesion, ossification, lipid (APOA4) processes, and extracellular matrix (ECM) organization (collagen). PPI network analysis identified hub genes such as serum albumin (ALB), fibronectin (FN1), and actin cytoplasmic 1. The WB analysis confirmed that FN1 and the receptor for activated C kinase (RACK1) were downregulated in the SATR tendon. Immunohistochemical staining revealed that collagen I and III were suppressed, while collagen II and APOA4 expression were higher in the SATR pathological tissue ( Show less
This study evaluated the protective effects of naringin (NG) against intestinal injury in 7-day-old piglets infected with porcine epidemic diarrhea virus (PEDV). Eighteen piglets (Duroc × Landrace × L Show more
This study evaluated the protective effects of naringin (NG) against intestinal injury in 7-day-old piglets infected with porcine epidemic diarrhea virus (PEDV). Eighteen piglets (Duroc × Landrace × Large, body weight = 2.58 ± 0.05 kg) were divided into three treatment groups based on similar body weights and equal numbers of males and females: the blank control group (CON group), the PEDV infection group (PEDV group), and the NG intervention + PEDV infection group (NG + PEDV group) ( Show less
This study aimed to develop and apply a novel computational pipeline combining SELFormer, a transformer architecture-based chemical language model, with advanced deep learning techniques to predict na Show more
This study aimed to develop and apply a novel computational pipeline combining SELFormer, a transformer architecture-based chemical language model, with advanced deep learning techniques to predict natural compounds (NCs) with potential in Alzheimer's disease (AD) treatment. The NCs were identified based on activity related to seven AD-specific genes, including acetylcholinesterase (AChE), amyloid precursor protein (APP), beta-secretase 1 (BACE1), and presenilin-1 (PSEN1). We implemented a computational pipeline using SELFormer and deep learning techniques, conducted optimal clustering and quantitative structure-activity relationship (QSAR) analyses, and performed a uniform manifold approximation and projection (UMAP) to categorize compounds based on bioactivity levels. Molecular docking analysis was carried out on selected compounds. To validate the computational predictions, we conducted in vitro studies using nerve growth factor (NGF)-differentiated PC12 cells. Finally, we mapped the relationships between food sources containing the identified compounds and their target proteins. Optimal clustering analysis revealed five distinct groups of NCs, while QSAR analysis highlighted variations in molecular properties across clusters. The UMAP projection identified 17 highly active NCs (pIC This integrated computational and experimental approach offers a promising framework for identifying potential NCs for AD treatment. The results contribute to exploring effective therapeutic strategies against AD. Show less
Parkinson's disease (PD) is a neurodegenerative disorder caused by complex genetic and environmental factors. Genome-edited human pluripotent stem cells (hPSCs) offer a unique experimental platform to Show more
Parkinson's disease (PD) is a neurodegenerative disorder caused by complex genetic and environmental factors. Genome-edited human pluripotent stem cells (hPSCs) offer a unique experimental platform to advance our understanding of PD etiology by enabling the generation of disease-relevant cell types carrying patient mutations along with isogenic control cells. To facilitate this approach, we generated a collection of 65 human stem cell lines genetically engineered to harbor high risk or causal variants in genes associated with PD ( Show less
To investigate the mechanisms underlying sevoflurane-induced POCD, C57BL/6 J mice and SH-SY5Y cells were treated with sevoflurane for model establishment. After the treatment with sevoflurane, CCK-8, Show more
To investigate the mechanisms underlying sevoflurane-induced POCD, C57BL/6 J mice and SH-SY5Y cells were treated with sevoflurane for model establishment. After the treatment with sevoflurane, CCK-8, EdU and flow cytometry were employed to detect cell damage. The levels of N6-methyladenosine (m6A), METTL14 and DUSP6 were determined by qPCR and Western blot. The interaction between METTL14 and DUSP6 was analyzed using RIP-qPCR and Me-RIP methodologies. The cognitive function in mice were assessed by water maze test. After sevoflurane treatment, the cell viability, cell proliferation and METTL14 expression were markedly suppressed, while apoptosis was significantly enhanced. METTL14 overexpression elevated the levels of m6A and DUSP6, increased the binding level of METTL14 to DUSP6 mRNA, reducing damage to cells and cognitive dysfunction of mice. Knockdown of DUSP6 negated the beneficial effects observed with METTL14 overexpression. Sevoflurane induced POCD by regulating METTL14/DUSP6 through m6A methylation. Show less
Sepsis-associated acute lung injury (SA-ALI), a critical complication of sepsis, is characterized by immune dysregulation-induced pulmonary dysfunction. Shenmai Injection (SMI) is a standardized herba Show more
Sepsis-associated acute lung injury (SA-ALI), a critical complication of sepsis, is characterized by immune dysregulation-induced pulmonary dysfunction. Shenmai Injection (SMI) is a standardized herbal preparation consisting of Panax ginseng C.A.Mey (Hongshen) and Ophiopogon japonicus (Thunb.) Ker Gawl (Maidong), traditionally used for qi-replenishing, collapse-stabilizing, and lung-moistening therapy. Although clinically utilized in the management of SA-ALI, the specific mechanisms by which it acts against SA-ALI necessitate further investigation. The present study endeavors to comprehensively determine the therapeutic efficacy of SMI against SA-ALI through an integrated approach combining network pharmacology, metabolomics, metagenomic sequencing, and experimental validation. In this study, murine SA-ALI was established using lipopolysaccharide (LPS) and Poly(I:C). Results indicated that SMI administration significantly attenuated pulmonary inflammation, restored blood-gas barrier integrity, reduced serum pro-inflammatory cytokines and suppressed NF-κB pathway activation in SA-ALI mice. Network pharmacology elucidated the multi-targeted mechanism of SMI in modulating steroid hormone biosynthesis. Integrated metabolomics and target analysis revealed that ophiopogonin A/B and luteolin in SMI alleviates metabolic dysregulation by targeting key enzymes, including AKR1C3, HSD17B1/2, and SULT1E1. Metagenomic profiling demonstrated SMI-mediated gut microbiota remodeling, marked by suppression of pathogenic Chlamydiaceae (particularly Chlamydia abortus) and enrichment of commensal Lactobacillaceae. Correlation analysis showed that intestinal androstenedione and androsterone levels during SMI treatment recovery were negatively correlated with Chlamydia abortus abundance. In conclusion, SMI enhances the recovery from sepsis-associated SA-ALI by dual modulation of gut microbial ecology and host metabolic homeostasis, thereby establishing its potential as a multi-mechanistic therapeutic candidate for sepsis-related organ injury. Show less
The objective of this study was to assess the correlation between the ApoB/ApoA ratio and the recurrence of kidney stones in a Chinese adult population. We collected electronic records of patients wit Show more
The objective of this study was to assess the correlation between the ApoB/ApoA ratio and the recurrence of kidney stones in a Chinese adult population. We collected electronic records of patients with kidney stones who underwent surgical treatment at our hospital from March 2016 to March 2022. These patients were followed up and categorized into groups based on the recurrence of kidney stones. Parameters related to routine blood and biochemical tests, as well as the history of hypertension and diabetes mellitus, were gathered. Multiple imputation was applied for missing data. Subsequently, differences between the recurrence and non-recurrence groups were assessed using the chi-square test, independent samples t test, or Wilcoxon rank sum test. Logistic regression analysis, subgroup analysis, and propensity-matched analysis were conducted to evaluate the relationship between the ApoB/ApoA ratio and kidney stone recurrence. The study included a total of 923 participants aged > 18 years, among whom 296 experienced kidney stone recurrence during the follow-up period. An elevated ApoB/ApoA ratio was identified as a risk factor for kidney stone recurrence (adjusted OR = 2.48, 95% CI 1.04, 5.92). Propensity-matched analyses further supported the association, showing that elevated ApoB/ApoA ratios were linked to a higher risk of renal stone recurrence (OR = 3.37, 95% CI 1.24-9.17). The dose-response curve illustrated a positive linear correlation between the ApoB/ApoA ratio and the risk of kidney stone recurrence. Increased ApoB/ApoA ratios are positively correlated with the risk of kidney stone recurrence. This association remains significant, although a causal relationship cannot be definitively established. Show less
Coronary heart disease (CHD) and type 2 diabetes (T2D) represent a significant global comorbidity burden, with shared yet incompletely understood molecular mechanisms. This study aimed to identify sha Show more
Coronary heart disease (CHD) and type 2 diabetes (T2D) represent a significant global comorbidity burden, with shared yet incompletely understood molecular mechanisms. This study aimed to identify shared diagnostic biomarkers and elucidate core pathways linking CHD and T2D pathogenesis. Integrated bioinformatics of CHD/T2D transcriptomes identified shared differentially expressed genes (DEGs) and co-expression modules via Weighted Gene Co-expression Network Analysis (WGCNA). Receiver operating characteristic (ROC) analysis selected CPD, GGCT, SUZ12, and ZMYM2 as top diagnostic biomarkers. These predictions were validated using C57BL/6 and ApoE Bioinformatics revealed 328 shared DEGs, with CPD, GGCT, SUZ12, and ZMYM2 showing high diagnostic efficacy. T2D mice exhibited persistent hyperglycemia. Aortic histopathology confirmed disease-specific changes: atherosclerotic plaques in CHD and vascular basement membrane thickening in T2D. Critically, all four biomarkers showed concurrent upregulation in diseased vessels at both protein (immunofluorescence, Western blot) and mRNA (RT-qPCR) levels. This study establishes CPD, GGCT, SUZ12, and ZMYM2 as shared CHD/T2D diagnostic biomarkers. Their validated co-upregulation highlights their dual-disease diagnostic and therapeutic potential. Show less
Accelerated population aging and rising incidence of bone defects have intensified the need for advanced bone regeneration strategies. While tissue-engineered scaffolds fabricated via 3D printing offe Show more
Accelerated population aging and rising incidence of bone defects have intensified the need for advanced bone regeneration strategies. While tissue-engineered scaffolds fabricated via 3D printing offer promising alternatives to conventional grafts, most techniques fail to replicate the multi-scale fibrous architecture of native bone extracellular matrix, limiting their biofunctionality. To address this, we developed a hybrid manufacturing strategy integrating low-temperature thermally induced phase separation with extrusion-based 3D printing of polylactic acid (PLA) scaffolds. By optimizing solvent ratios (THF: DMF = 3:1) and freezing temperatures (-196 °C-4 °C), we produced scaffolds with tunable micro-nano fibrous surfaces and macroporous structures. Key findings revealed that scaffolds processed at -196 °C (PLA-196) exhibited the highest porosity (pore size: 6.01 ± 2.06 μm), superior hydrophilicity, and enhanced compressive modulus. These scaffolds significantly promoted BMSC adhesion, proliferation, and osteogenic differentiation via activation of Show less
The mediation effect of 24-hour physical activities on the association between type 2 diabetes and mortality is unclear. Additionally, Little evidence was found on the isotemporal substitution effect Show more
The mediation effect of 24-hour physical activities on the association between type 2 diabetes and mortality is unclear. Additionally, Little evidence was found on the isotemporal substitution effect of 24-hour physical activities components on changing Life expectancy among patients with type 2 diabetes diagnosed. To address the abovementioned research gap, the study has a two-fold aims: first, to examine the mediation effect of 24-hour physical activities in type 2 diabetes and mortality; and second, to address how reallocating time on different daily activities would affect life expectancy. Analysis was conducted on the accelerometer data of 103,359 participants in the UK Biobank, with a median age of 57 years (range 39 to 70). Compositional mediation cox model was conducted to analyze the mediating effects of 24-hour physical activities. Additionally, the cohort Life table method was utilized to estimate the changes of Life-years over the next 10 years resulting from the substitution effect of different physical activities. During a mean follow-up of 13.95 (range 2.95-16.28) years, 2,649 deaths were recorded. Diabetes was significantly associated with increased time spent engaging in sedentary behavior (SB), and reduced time spent on moderate-to-vigorous physical activity (MVPA) and light-intensive physical activity (LPA), thereby demonstrating an association with higher mortality risk. The indirect effect of physical activity (HR = 1.27, 95% CI 1.23-1.30) accounted for 41.9% of the total effect of diabetes on mortality. Furthermore, the Life expectancy gains with a maximum of 1.32 years over the next 10 years was found when reallocating SB time to MVPA. The results revealed that 24-hour physical activities might mediate the association between diabetes and mortality. Therefore, promoting participation in MVPA and reducing sedentary activities among diabetes patients was expected to have a positive effect on Life expectancy over the next 10 years. Show less
Our previous investigations identified miR-30a-3p as a differentially expressed miRNA in ovine mammary tissue across sheep breeds with distinct lactation performance and different physiological stages Show more
Our previous investigations identified miR-30a-3p as a differentially expressed miRNA in ovine mammary tissue across sheep breeds with distinct lactation performance and different physiological stages. However, its regulatory mechanisms controlling mammary gland development and lactation remain unexplored. In this study, the effect of miR-30a-3p on the proliferation of ovine mammary epithelial cells (MECs) and the target genes of miR-30a-3p were investigated. The regulatory effects of miR-30a-3p on the expression of the target genes and the content of triglycerides in ovine MECs were also analyzed. The transfection of miR-30a-3p mimic was found to promote cell viability and the number of proliferated ovine MECs using CCK8 and Edu assays. On the contrary, the miR-30a-3p inhibitor showed the opposite results with the miR-30a-3p mimic. These results suggest that miR-30a-3p promotes the proliferation of ovine MECs. The dual luciferase assay revealed that Phosphatase and Tensin Homolog ( Show less
To investigate the risk factors associated with coronary heart disease (CHD) in patients with metabolic-associated fatty liver disease (MAFLD) and develop a nomogram prediction model. This study inclu Show more
To investigate the risk factors associated with coronary heart disease (CHD) in patients with metabolic-associated fatty liver disease (MAFLD) and develop a nomogram prediction model. This study included 394 patients with MAFLD who underwent coronary angiography at The Affiliated Hospital of Qingdao University between December 2019 and December 2024. The study cohort was divided in a 7:3 ratio into training and validation sets comprising 277 and 117 cases, respectively. The training group was further divided into the MAFLD-only ( Of the 394 MAFLD cases, 313 had CHD-related complications. Of the 277 patients in the training set, 220 had CHD, and of the 117 patients in the validation set, 93 had CHD. LASSO regression analysis revealed that the following variables were associated with the risk of CHD: sex, lipoprotein(a) (Lp[a]), low-density lipoprotein cholesterol, white blood cell count (WBC), glycated triglyceride-glucose index (TyG), and atherosclerosis index (AIP). Multivariate logistic regression analysis revealed that sex, Lp(a), WBC, TyG, and AIP were independent risk factors for CHD in MAFLD cases. A nomogram was constructed and an ROC curve was plotted, based on which the optimal cutoff value was determined as 0.698. The area under the curve of the nomogram in the training and validation cohorts was 0.860 (95% CI = 0.807-0.913) and 0.843 (95% CI = 0.757-0.929), respectively. Calibration curves for CHD risk probability showed good agreement between the nomogram's predicted probabilities and the observed event rates. DCA demonstrated the net clinical benefit of the constructed nomogram. Sex, Lp(a), WBC, TyG, and AIP emerged as independent risk factors for CHD in patients with MAFLD and the nomogram prediction model constructed using these factors could effectively predict CHD occurrence. Show less
Nolan Priedigkeit, Beth Harrison, Robert Shue+27 more · 2025 · Clinical cancer research : an official journal of the American Association for Cancer Research · added 2026-04-24
Inflammatory breast cancer (IBC) is a rare and clinically distinct form of breast cancer associated with poor outcomes. The biological mechanisms driving IBC remain poorly understood, partly due to li Show more
Inflammatory breast cancer (IBC) is a rare and clinically distinct form of breast cancer associated with poor outcomes. The biological mechanisms driving IBC remain poorly understood, partly due to limited large-scale genomic studies that directly compare IBC with non-IBC cases. We conducted a retrospective analysis of 140 patients with IBC (68 primary tumors and 72 metastatic tumors) and 2,317 patients with non-IBC (700 primary tumors, 65 local recurrences, and 1,552 metastases). We compared clinicopathologic features, single-nucleotide variants, copy-number variants, tumor mutational burden, and exploratory survival outcomes between IBC and non-IBC tumors. The most frequent somatic alterations in IBC were detected in TP53 (72%), ERBB2 (32%), PIK3CA (24%), CCND1 (12%), MYC (9%), FGFR1 (8%), and GATA3 (8%). Multivariate logistic regression revealed a significant enrichment of TP53 single-nucleotide variants in IBC, particularly in HER2+ and hormone receptor-positive disease. Tumor mutational burden did not differ between IBC and non-IBC cases. In HER2+ disease, a pathway analysis revealed an enrichment of NOTCH pathway alterations. TP53, CCND1, and RB1 alterations were associated with poor outcomes in IBC. This study provides a comprehensive resource of somatic alterations in a large cohort of patients with metastatic IBC and non-IBC, highlighting genomic features associated with worse outcomes. Our findings reveal a significant enrichment of TP53 mutations, reinforcing its critical role in IBC pathogenesis. Few other distinct differences in IBC were observed, suggesting further investigations-beyond bulk sequencing of the somatic genome-are required to better understand the biology driving this aggressive disease. Show less
Hypertrophic cardiomyopathy (HCM) is a common inherited heart condition. Traditional genetic testing is typically conducted on the proband only, with family members undergoing Sanger sequencing, which Show more
Hypertrophic cardiomyopathy (HCM) is a common inherited heart condition. Traditional genetic testing is typically conducted on the proband only, with family members undergoing Sanger sequencing, which may overlook other pathogenic variants. This study explores the gene sequencing strategy in a three-generation family based on genetic carrier status and examines the relationship between phenotypic characteristics and genotype. High-throughput second-generation sequencing was performed on the proband to analyze HCM-related pathogenic genes. Subsequently, the identified pathogenic variants were validated by Sanger sequencing in the proband and family members. Clinical, electrocardiographic, and echocardiographic assessments were conducted for family members. Second-generation sequencing of the proband (III7) revealed a pathogenic variant MYBPC3-P453Lfs. Initially, no HCM-related pathogenic variants were detected in another patient (III11), prompting additional sequencing of III11, which identified the MYH7-G823E pathogenic variant. Both patients had severe left ventricular outflow tract obstruction. Sanger sequencing showed that five family members carried both mutations. Among them, three died suddenly before age 40, one required an implantable cardioverter defibrillator for arrhythmias, and one developed HCM before adulthood. Cardiac magnetic resonance imaging (MRI) of patients carrying both mutations showed myocardial fibrosis of 32.75%, significantly higher than the 6.98% observed in patients carrying only one mutation. In families with varying HCM phenotypes, second-generation sequencing should be considered for all members. In this family, carrying one variant led to outflow tract obstruction, while carrying both variants resulted in severe disease, including sudden death and early onset. Cardiac MRI is crucial for assessing the severity of the disease within the family. Show less
The genetic foundations underlying the observed disease resistance in certain indigenous pig breeds, notably the Min pigs of China, present a compelling underexplored subject of study. Exploring the m Show more
The genetic foundations underlying the observed disease resistance in certain indigenous pig breeds, notably the Min pigs of China, present a compelling underexplored subject of study. Exploring the mechanisms of disease resistance in these breeds could lay the groundwork for genetic improvements in pig immunity, potentially augmenting overall pig productivity. In this study, whole blood samples were collected from pre- and post- swine fever vaccinated Min and Large White pigs for transcriptome sequencing. The mRNA and lncRNA in both pig breeds were analyzed, and intra-group and inter-group comparisons were also conducted. The results indicated that a greater number of immune-related pathways such as the JAK-STAT and PI3K-AKT signaling were enriched in Min pigs. Furthermore, genes involved in inflammation and antiviral responses, including IL16, IL27, USP18, and DHX58, were upregulated in post-vaccination Min pigs compared to post-vaccination Large White pigs. This heightened immune responsiveness could contribute to the observed differences in disease resistance between Min pigs and Large White pigs. Show less
Although light-intensity physical activity (LPA) has been suggested to be associated with a lower risk of mortality, the minimal and optimal volumes of LPA remain unclear. We aimed to examine the mini Show more
Although light-intensity physical activity (LPA) has been suggested to be associated with a lower risk of mortality, the minimal and optimal volumes of LPA remain unclear. We aimed to examine the minimal and optimal volumes of LPA associated with the risks of mortality and disease incidence (i.e., cardiovascular diseases and cancer). Data were derived from the population-based UK Biobank cohort study, including 69,492 adults aged 43-78 years. Accelerometer-measured LPA was defined using a validated, published machine learning-based Random Forest activity method, which was categorized into 4 quartile groups. All-cause and cause-specific mortality (cardiovascular disease- and cancer-specific) were determined according to the International Classification of Diseases, 10th version codes. Disease incidence was defined based on primary care, hospitalization, or death records. During a median follow-up period of 8.04 years, 2024 adults died from all causes, 539 from cardiovascular disease, and 1175 from cancer. For all-cause mortality, compared with participants in the lowest quartile of LPA (<3.9 h/day), the hazard ratios (HRs) and 95% confidence intervals (95%CIs) were 0.82 (95%CI: 0.73‒0.93) for those with 3.9 to <5.0 h/day, 0.75 (95%CI: 0.66‒0.85) for those with 5.0 to <6.1 h/day, and 0.77 (95%CI: 0.68‒0.88) for those with ≥6.1 h/day, respectively. There was an inverse non-linear dose-response association between LPA and all-cause mortality, with an optimal dose of 5.72 h/day (95%CI: 5.45‒6.41; HR = 0.63, 95%CI: 0.56‒0.71) and a minimal dose of 3.59 h/day (95%CI: 3.53-8.56; HR = 0.81, 95%CI: 0.78‒0.86), with the 5th percentile as the reference. Similar patterns were observed for cause-specific mortality and disease incidence (cardiovascular disease and cancer). Engaging in LPA for ∼3.5 h/day was conservatively associated with lower risk of mortality and disease incidence, with further risk reductions observed up to an optimal dose of ∼6.0 h/day. These findings suggest that sufficient LPA offers important health benefits, which can inform the development of future PA guidelines. Show less