To investigate the associations of monocyte count, lipoprotein(a) [Lp(a)], and monocyte-to-HDL ratio (MHR) with in-stent restenosis (ISR) in coronary heart disease (CHD) patients after drug-eluting st Show more
To investigate the associations of monocyte count, lipoprotein(a) [Lp(a)], and monocyte-to-HDL ratio (MHR) with in-stent restenosis (ISR) in coronary heart disease (CHD) patients after drug-eluting stent (DES) implantation, and to develop a predictive risk model. This study enrolled 190 CHD patients who underwent DES implantation from 2019 to 2024. Based on 1-year coronary angiography, patients were divided into an ISR group ( Compared to the Non-ISR group, ISR patients had higher monocyte count, MHR, and Lp(a) levels (all Monocyte count, Lp(a), and MHR are closely linked to ISR in CHD patients post-DES. Combined assessment enhances risk prediction, offering a basis for early identification and personalized management to reduce restenosis and improve outcomes. Show less
To evaluate the efficacy and safety of inclisiran in the treatment of hypercholesterolemia. Randomized controlled trials comparing inclisiran with a placebo were searched until April 2024. Overall, 8 Show more
To evaluate the efficacy and safety of inclisiran in the treatment of hypercholesterolemia. Randomized controlled trials comparing inclisiran with a placebo were searched until April 2024. Overall, 8 studies involving 4947 patients were included. Inclisiran reduced low-density lipoprotein cholesterol (mean difference [MD]: -46.95 %; 95 % confidence interval [CI]: -53.26 to -40.46; P < 0.05), proprotein convertase subtilisin/kexin type 9 (MD: -70.80 %; 95 % CI: -76.52 to -65.08; P < 0.05), serum total cholesterol (MD: -29.47 %; 95 % CI: -32.56 to -26.39; P < 0.05), non-high-density lipoprotein cholesterol (MD: -40.46 %; 95 % CI: -45.24 to -35.68; P < 0.05), apolipoprotein B (MD: -36.77 %; 95 % CI: -40.94 to -32.61; P < 0.05), and lipoprotein(a) (MD: -20.04 %; 95 % CI: -24.2 to -15.87; P < 0.05) levels but increased high-density lipoprotein cholesterol level (MD: 6.09 %; 95 % CI: 3.63 to 8.55; P < 0.05). The incidences of adverse events, serious adverse events, headache, nasopharyngitis, and muscular adverse reactions were not significantly different between the inclisiran and placebo groups. Inclisiran reduced the incidence of cardiovascular adverse reactions (odds ratio [OR] = 0.79; 95 % CI: 0.65 to 0.96; P = 0.02) and increased the incidence of injection-site reactions (OR = 4.79; 95 % CI: 2.18 to 10.52; P < 0.05). Inclisiran is effective in treating hypercholesterolemia and has a good safety profile. Show less
Myeloid/lymphoid neoplasms with tyrosine kinase gene fusions (MLN-TK) are rare hematologic malignancies characterized by recurrent kinase rearrangements, including
The FGFR1 V561M mutation significantly reduces the efficacy of current FGFR1 inhibitors, creating an urgent need for targeted second-generation therapies. In this study, we developed a comprehensive v Show more
The FGFR1 V561M mutation significantly reduces the efficacy of current FGFR1 inhibitors, creating an urgent need for targeted second-generation therapies. In this study, we developed a comprehensive virtual screening protocol that combines energy-based screening and machine learning techniques, leading to the identification of a novel compound, Show less
Individual differences in immune responses to African swine fever virus (ASFV), whether induced by vaccination or natural infection, may be linked to genetic variation in the genes involved in antigen Show more
Individual differences in immune responses to African swine fever virus (ASFV), whether induced by vaccination or natural infection, may be linked to genetic variation in the genes involved in antigen presentation. A total of nine pigs from the 112-population were selected for RNA-seq analysis. To pinpoint key transcription factors (TFs) regulating gene expression in the lymph nodes, weighted Kendall's Tau rank correlation analysis was performed to link the TF binding potential with the extent of differential expression of target genes. CD8 These mutations may disrupt TFs binding to the ELK4 promoter, potentially reducing ELK4 expression and impairing antigen processing and presentation. Show less
Our aim was to explore the IL-27 effect in sepsis (SP)-related acute hepatic injury (AHI) as well as its possible mechanism. Herein, we utilized both wild-type (WT) and IL-27 receptor (WSX-1)-deficien Show more
Our aim was to explore the IL-27 effect in sepsis (SP)-related acute hepatic injury (AHI) as well as its possible mechanism. Herein, we utilized both wild-type (WT) and IL-27 receptor (WSX-1)-deficient (IL-27R The results revealed that IL-27 exacerbated systemic inflammation and liver damage in AHI mice by promoting M1 macrophage polarization, thereby increasing pro-inflammatory phenotype macrophages (M1). This further exacerbated the inflammatory response and pyroptosis in vivo and in vitro. Additionally, IL-27 down-regulated p-AMPK and SIRT1 protein expression while overexpressing macrophage inflammatory mediators including IL-1β/6 and TNFα. Furthermore, IL-27 promoted increased RAGE and caspase-11 protein expression, aggravating macrophage pyroptosis. Employing CC to block the AMPK pathway further aggravated M1 macrophage polarization and pyroptosis in vitro and in vivo, ultimately worsening liver injury. Here, IL-27 aggravates AHI by promoting macrophage M1 polarization to induce caspase-11-mediated pyroptosis in vitro and in vivo, which may be linked to the AMPK/SIRT1 signaling pathway. Show less
Gastrointestinal (GI) cancers exhibit aberrant lipid metabolism, yet the causal mechanisms remain elusive. Here, we integrated Mendelian randomization (MR) and multi-omics data to dissect metabolic dr Show more
Gastrointestinal (GI) cancers exhibit aberrant lipid metabolism, yet the causal mechanisms remain elusive. Here, we integrated Mendelian randomization (MR) and multi-omics data to dissect metabolic drivers of 20 GI diseases. Focusing on colorectal (CC) and esophageal cancer (EC), we identified five metabolites (e.g., 1,2-di-palmitoyl-sn-glycero-3-phosphocholine) and arachidonic acid ethyl ester as causal drivers. Summary-data-based MR and colocalization analysis (PP.H4 > 0.75) revealed FADS1 as a master regulator of these metabolites, with genetic variants exhibiting tissue-specific lipidomic effects. Functional validation using FADS1-knockout cell lines and mouse models demonstrated that FADS1 inhibition suppresses tumor cell proliferation, migration, and invasion while promoting apoptosis. In vivo, FADS1 deletion reduced chemically induced CC/EC tumor burden by 62-75%, accompanied by decreased Ki-67/MMP-9 expression and inflammatory infiltration. Mechanistically, FADS1 ablation disrupted lipid metabolism (reduced linoleic acid and arachidonic acid) and attenuated PI3K/AKT and MAPK signaling. Multi-omics integration further corroborated FADS1-mediated epigenetic regulation (e.g., mQTL-driven DNA methylation). This study establishes FADS1 as a pivotal orchestrator of GI carcinogenesis via metabolic reprogramming and signaling dysregulation, offering a compelling therapeutic target for precision oncology in CC and EC. Regulatory mechanisms of FADS1 in CC and EC. Show less
Peritoneal metastasis (PM) in gastric cancer (GC) remains a formidable clinical challenge. Although exosomes are critical mediators of tumor-microenvironment communication, their mechanistic role in l Show more
Peritoneal metastasis (PM) in gastric cancer (GC) remains a formidable clinical challenge. Although exosomes are critical mediators of tumor-microenvironment communication, their mechanistic role in linking mesothelial-mesenchymal transition (MMT) to peritoneal dissemination remains poorly understood. This study elucidates a GC-derived exosomal microRNA (miRNA)-driven pathway that orchestrates peritoneal metastasis. Integrated exosomal miRNA sequencing and The Cancer Genome Atlas (TCGA) analysis identified miR-196a-5p as highly enriched in GC-derived exosomes. Functional assays, including in vitro co-culture experiments, and in vivo PM models, demonstrated that GC-derived exosomal miR-196a-5p directly induces MMT in peritoneal mesothelial cells (HMrSV5) and contributed to the formation of metastatic tumors. Mechanistically, miR-196a-5p binds the 3'-untranslated region (UTR) of F-box protein 45 (FBXO45), an E3 ubiquitin ligase, suppressing its expression and thereby stabilizing snail family transcriptional repressor 1 (Snai1)-a key transcription factor in epithelial-mesenchymal transition (EMT). RNA immunoprecipitation sequencing (RIP seq), dual-luciferase reporter assays, co-immunoprecipitation (CO-IP), and rescue experiments validated the miR-196a-5p/FBXO45/Snai1 axis. Notably, miR-196a-5p disrupts FBXO45-mediated Snai1 ubiquitination and degradation, promoting MMT-driven peritoneal niche remodeling and metastatic progression. These findings reveal a novel exosome-mediated mechanism underlying GC dissemination and highlight miR-196a-5p and FBXO45 as promising therapeutic targets for PM. Show less
Ischemic injury induces a partial mesenchymal shift in endothelial cells (ECs), contributing to impaired vascular regeneration. However, the molecular regulators of this transitional state remain poor Show more
Ischemic injury induces a partial mesenchymal shift in endothelial cells (ECs), contributing to impaired vascular regeneration. However, the molecular regulators of this transitional state remain poorly defined. To address this, we performed circular RNA profiling of endothelial cells under ischemic-like conditions and identified a marked upregulation of a circular RNA, named circATXN1. Functional studies revealed that circATXN1 knockdown modulates endothelial phenotype and vascular response after ischemia. Functional studies have shown that knockdown of circATXN1 can regulate the endothelial cell phenotype and vascular response after ischemia. Mechanistically, circATXN1 knockdown enhances the demethylase protein ALKBH5 to reduce the RNA methylation level of the key transcription factor SLUG, thereby stabilizing SLUG. In animal models, suppression of circATXN1 enhances angiogenesis and improves recovery following ischemic injury. Here, we show that circATXN1 regulates partial endothelial-to-mesenchymal transition (EndMT) and angiogenesis by controlling SLUG mRNA methylation dynamics, highlighting its potential as a therapeutic target in ischemic disease. Show less
Long-persistent luminescence (LPL) materials have applications from safety signage to bioimaging; however, existing organic LPL (OLPL) systems do not align with human scotopic vision, which is sensiti Show more
Long-persistent luminescence (LPL) materials have applications from safety signage to bioimaging; however, existing organic LPL (OLPL) systems do not align with human scotopic vision, which is sensitive to blue light. We present a strategy to blueshift the emissions in binary OLPL systems by upconverting the charge-transfer (CT) to a locally excited (LE) singlet state. Through rigorous steady-state and time-resolved photoluminescence spectroscopy and wavelength-resolved thermoluminescence measurements, we provide the direct experimental evidence for this upconversion in OLPL systems featuring small energy offsets between the lowest-energy CT and LE singlet states. These systems exhibited strong room temperature LPL, particularly when extrinsic electron traps are added. Importantly, the developed OLPL system achieved Class A (ISO 17398) LPL, matching well with human scotopic vision. The findings not only elucidate the role of small energy offsets in modulating LPL but also provide potential avenues for enhancing the efficiency and applicability of OLPL materials. Show less
DHAV-3 is one of the main causative agents of duck viral hepatitis (DVH), an acute and highly lethal infectious disease in duck industry. However, the understanding of the pathogenesis of this virus i Show more
DHAV-3 is one of the main causative agents of duck viral hepatitis (DVH), an acute and highly lethal infectious disease in duck industry. However, the understanding of the pathogenesis of this virus in ducklings is limited. To dissect the molecular characteristics associated with pathobiology of ducklings to DHAV-3, we applied single-cell RNA-sequencing approach to profile the transcriptome of 1.4 million cells from 14 livers of DHAV-3 susceptible (S) and resistant (R) ducklings during viral infection and 4 uninfected healthy controls. We found that infected S ducks exhibited the activation of type I and II interferon pathways with elevated expression of interferon-stimulated genes (ISGs) compared to infected R ducks and healthy controls. DHAV-3 promoted proinflammatory phenotype and inhibited the cell apoptosis pathway of Kupffer cells of S ducks. Furthermore, we observed the elevated expression of host factor PLAC8 in S ducks and validated its ability to facilitate the infection of DHAV-3. We identified significant dysregulation of various genes in complement and coagulation cascades in hepatocytes2 exclusive to S ducks, together with over-secretion of ANGPTL4 from endothelial cells in S ducks which is confirmed to promote cellular migration, suggesting etiology of coagulopathic complications in ducks with severe DVH. Collectively, this study provides a rich resource for understanding the inflammatory immune signatures and cell communications underlying the pathogenesis of DHAV-3 infection, which may accelerate the development of better diagnostic methods and strategies for controlling this disease. Show less
The embryos of lotus (Nelumbo nucifera Gaertn.) is a famous traditional Chinese medicine used to treat insomnia, memory decline, and dementia for a long time. However, the underlying material basis an Show more
The embryos of lotus (Nelumbo nucifera Gaertn.) is a famous traditional Chinese medicine used to treat insomnia, memory decline, and dementia for a long time. However, the underlying material basis and mechanisms of this medicine are still unclear. Isoliensinine (IL) is a major alkaloid derived from lotus embryos. Our previous research has demonstrated that IL can exert strong anti-inflammatory and neuroprotective effects in vitro. To reveal the underlying therapeutic effect and mechanism of IL on Alzheimer's disease (AD)-like mice induced by AlCl The AD-like mice were modeled by intragastric injection (i.g.) of AlCl IL (1, 3, and 10 mg/kg) treatment effectively ameliorated cognitive impairment in AD-like model mice. IL inhibited the decrease of brain index and body weight in AD-like mice and alleviated neuronal damage in the cortex and hippocampus (DG, CA1, and CA3). IL decreased the levels of Ca IL has a significant therapeutic effect on pathological alterations and cognitive impairment in AlCl Show less
Oxidative deterioration of fish oil in aquafeeds poses a significant challenge to fish health and aquaculture sustainability, making it crucial to mitigate this issue through healthy and green nutriti Show more
Oxidative deterioration of fish oil in aquafeeds poses a significant challenge to fish health and aquaculture sustainability, making it crucial to mitigate this issue through healthy and green nutritional strategies. This study examined the potential of stevia chlorogenic acid (SCGA), a bioactive byproduct of stevia processing, to alleviate intestinal injury, gut microbiota dysbiosis, and lipid metabolism disorders induced by oxidized fish oil in turbot. Four diets with equal nitrogen and lipid contents were formulated: a control diet (PC) containing 5 % fresh fish oil, an oxidized fish oil diet (OFO) comprising 5 % oxidized fish oil, and two additional OFO diets supplemented with 200 mg/kg (OFO200) or 400 mg/kg (OFO400) of SCGA. Each dietary treatment was randomly assigned to three replicates, each containing 40 fish weighing approximately 16.99 ± 0.01 g, and administered over a 10-week period. Fish fed the OFO diet exhibited significantly compromised growth performance, as indicated by decreased WGR and SGR, along with reduced serum immune indices (IgM, C3, and C4) and lipid parameters (TC, HDL, LDL), and elevated serum D-LA levels (P < 0.05). Moreover, dietary OFO markedly suppressed antioxidant enzyme activities (serum SOD; intestinal SOD, GSH-Px, and CAT) and elevated MDA concentrations (P < 0.05). Additionally, OFO reduced intestinal expression of tight junction-associated genes (Claudin-4, Claudin-7, Occludin) while increasing expression levels of MLCK, Keap1, inflammatory mediators (IL-6, IL-1β, TNF-α2, NF-κB, IFN-γ), and Caspase7 (P < 0.05). Notably, the TLR signaling pathway-related genes were upregulated, accompanied by pronounced shifts in gut microbiota composition (P < 0.05). In hepatic tissue, lipogenesis-associated genes (FAS, ACC) were significantly increased, while key genes involved in lipid transport and β-oxidation (CD36, LPL, ACOX1, PPARγ) exhibited reduced expression (P < 0.05). Dietary supplementation with 200 and 400 mg/kg SCGA effectively mitigated these detrimental impacts. SCGA restored growth performance, serum immune parameters, and antioxidant enzyme activities to levels comparable to the PC group. It also normalized gene expression related to intestinal barrier function, inflammation, apoptosis, and hepatic lipid metabolism. Furthermore, SCGA supplementation modulated gut microbiota structure by increasing beneficial genera and decreasing potential pathogens. In conclusion, SCGA effectively improves growth performance, alleviates OFO-induced intestinal injury and microbial dysbiosis, and regulates lipid metabolism in turbot. These findings provide theoretical insights and technical support for the application of SCGA in aquaculture. Show less
The intact tendon-bone interface (TBI) consists of four histological layers-tendon, fibrocartilage, calcified fibrocartilage, and bone-that gradually merge into each other, making complete structural Show more
The intact tendon-bone interface (TBI) consists of four histological layers-tendon, fibrocartilage, calcified fibrocartilage, and bone-that gradually merge into each other, making complete structural restoration after injury challenging. Osteoporosis poses a significant risk for rotator cuff tears (RCTs) and re-tears after arthroscopic rotator cuff repair (ARCR). Activating Leptin receptor (Lepr) mediated Stat3 signaling transduction facilitates the transcription of Runx2 and Sox9, respectively, and promotes osteogenesis and chondrogenesis. Sixty-five female Sprague Dawley rats were used. Animal models-ovariectomy (OVX) and rotator cuff tear and repair (RC)-were employed to simulate typical tendon-bone healing and TBI reconstruction under deficient bone-forming capability. And, grip strength, transcriptome, ELISA, histochemistry, and qPCR were performed to reveal the distinct functional recovery between RC and OVX + RC rats, as well as pathophysiologic exhibition in the TBI at 2-week and 8-week. RC rats exhibited better functional recovery during the proliferative phase of TBI reconstruction, i.e., 2-week, compared to OVX + RC rats, while both RC and OVX + RC rats showed a lower grip strength in the upper limbs during the remodeling phase, i.e., 8-week. In RCTs, where adipogenesis was suppressed in RCT healing, the osteoblast-derived Leptin (Lep) and Angiopoietin like 4 (Angptl4), the Lepr ligands, facilitate osteogenesis and chondrogenesis, resulting in an obvious mineralized band in the reconstructed TBI and a transit cartilage band during the proliferative phase in RC rats. In osteoporosis-comorbid RCTs, where osteogenesis was suppressed while adipogenesis was activated, the adipocyte-derived Lep and Angptl4, particularly Angptl4, facilitated Stat3 phosphorylation and nucleus transfer, Sox9 transcription, and chondrogenesis, which was observed in OVX + RC rats and led to excessive cartilage regeneration. This study demonstrated the role of Lep and Angptl4 in TBI reconstruction, via activating Lepr-mediated Stat3-Sox9 and Stat3-Runx2 signaling pathways, differentially regulating osteogenesis and chondrogenesis, and leading to the distinct clinical outcomes post-ARCR in RCTs and osteoporosis-comorbid RCTs. This study provides fundamental support for increasing Angptl4 in situ for chronogenesis in RCTs and lowering Angptl4 to Lep ratio for osteogenesis in RCTs with osteoporosis comorbidity. Show less
As one of the most common malignant tumors in men, prostate cancer (PCa) still lacks convenient, non-invasive and highly specific diagnostic markers. The advantages of Extracellular vesicle (EV) DNA i Show more
As one of the most common malignant tumors in men, prostate cancer (PCa) still lacks convenient, non-invasive and highly specific diagnostic markers. The advantages of Extracellular vesicle (EV) DNA in tumor diagnosis have gradually attracted the attention of researchers. However, methylation detection, which is more advantageous than mutation detection in tumor diagnosis, has not been widely practiced in EV DNA, and its value in PCa diagnosis also remains underexplored. This study aims to establish and optimize an EV DNA methylation detection system and evaluate its diagnostic and classification potential for PCa. We characterized EV DNA biological properties, optimized pretreatment strategies, validated its correlation with genomic DNA methylation, and explored urine EV DNA methylation targets in 86 benign prostatic hyperplasia (BPH) and 109 PCa patients across three cohorts (screening: 30 BPH/33 PCa; training: 27 BPH/30 PCa; validation: 29 BPH/46 PCa). Heterogeneous biological characteristics were observed among DNA from different subtypes of EV, but methylation profiles remained consistent across subtypes and post-DNase I treatment. EV DNA accurately reflected the methylation state of source cell genomic DNA. By combining our screening results with data from the TCGA database and previously reported, we developed a panel consisting of 667 PCa-specific methylation targets for detection. Among these, six methylation sites (MACF1、LINC01359-1、LINC01359-2、ADCY4、GAPLINC、C19orf25) demonstrated high diagnostic value for PCa, enabling construction of PCa and aggressive PCa differential diagnosis model with AUCs up to 0.74 and 0.91 respectively. The diagnostic value of these six markers was further confirmed using methylight PCR in the validation cohort which also displayed promising performance as a tool for diagnosing PCa. This study highlights the potential of urine EV DNA methylation as a novel diagnostic marker for PCa and lays a foundation for future EV DNA research. Show less
Depression is a pervasive mental illness that has a significant impact on public health globally. This study aimed to identify risk factors for depression and elucidate their causal relationships. Usi Show more
Depression is a pervasive mental illness that has a significant impact on public health globally. This study aimed to identify risk factors for depression and elucidate their causal relationships. Using data from the National Health and Nutrition Examination Survey (NHANES) and Genome-Wide Association Studies (GWAS). Serum ApoB was log-transformed and further divided into 4 groups. Multifactorial logistic regression analysis was used to assess the relationship between serum ApoB and depression. Subgroup analyses and interaction tests were used to observe the stability of the association between them. Smooth curve fitting was used to investigate nonlinear correlations. The causal effect of serum ApoB on depression was assessed using Mendelian randomization (MR) analysis. A total of 6531 participated in the study. After adjusting for all covariates, serum ApoB levels were positively associated with depression after adjustment for all covariates (OR = 1.40, 95 % CI = 1.06-1.84; P = 0.0176). Unfortunately, there was no significant causal relationship between serum ApoB and depression (OR = 0.9985,95 % CI = 0.9962-1.0008; P = 0.1923). Sensitivity analysis verified the reliability of the results. Serum ApoB was positively associated with an increased risk of depression, but MR analysis did not show a genetic causal relationship between ApoB and depression. Based on the results of the current study, no indication maintaining high levels of ApoB contributes to the management of depression. The main limitation of this study is the inconsistency of the cross-sectional study and the MR population. Show less
Kidney Yang Deficiency (KYD) is a metabolic disorder associated with kidney damage. Its slow progression means that causative factors and effective therapeutic agents remain unclear. Extensive evidenc Show more
Kidney Yang Deficiency (KYD) is a metabolic disorder associated with kidney damage. Its slow progression means that causative factors and effective therapeutic agents remain unclear. Extensive evidence links KYD to gut microbiome metabolic diseases and the Hypothalamic-Pituitary-Thyroid (HPT) axis. CDG was extracted from both raw and processed CD and analyzed via HPLC. Propylthiouracil-induced KYD rats were used to assess pharmacological effects, including serum levels of T Fecal non-targeted metabolomics identified 98 metabolites associated with KYD, while 16S rRNA sequencing revealed 13 key intestinal microbiotas linked to KYD. CDG therapy effectively alleviated KYD symptoms by modulating the gut microbiota, improving metabolic and microbial imbalances in KYD. RG/WG significantly improves KYD rats mainly through the relationship between the intestinal microbiota and arachidonic acid metabolism. The key bacterial genera This integrative approach of gut microbiome and fecal metabolomics not only provides a scientific basis for CDG's preventive effects on KYD via the HPT axis but also elucidates the potential mechanisms underlying CDG's action against KYD. Show less
Obesity is a major public health crisis associated with high mortality rates. Previous genome-wide association studies (GWAS) investigating body mass index (BMI) have largely relied on imputed data fr Show more
Obesity is a major public health crisis associated with high mortality rates. Previous genome-wide association studies (GWAS) investigating body mass index (BMI) have largely relied on imputed data from European individuals. This study leveraged whole-genome sequencing (WGS) data from 88,873 participants from the Trans-Omics for Precision Medicine (TOPMed) Program, of which 51% were of non-European population groups. We discovered 18 BMI-associated signals (P < 5 × 10 Show less
Familial hypertrophic cardiomyopathy (HCM) is the most common genetic cardiovascular disease (CVD). Related mutations contributing to hypercontractility and poor relaxation in HCM are not completely u Show more
Familial hypertrophic cardiomyopathy (HCM) is the most common genetic cardiovascular disease (CVD). Related mutations contributing to hypercontractility and poor relaxation in HCM are not completely understood. This study aimed to explore and verify a novel variant of cardiac myosin-binding protein C (cMyBP-C, encoded by MYBPC3) in an HCM family. Clinical information and cardiac parameters were collected in the pedigree. Genomic DNA was extracted from peripheral blood and second-generation sequencing technology was used to investigate the proband and his family members. Subsequent sequence analysis was performed with DNAMAN software. The cardiac expression levels of MYBPC3 mRNA and cMyBP-C protein were assessed using RT-qPCR and Western blot analysis, respectively. Typical interventricular septal thickening was detected in all four HCM patients without left ventricular outflow tract obstruction. The c.1042₁₀₄₃insCGGCA mutation in MYBPC3 was verified in the proband and family members. In silico analysis of the mutation revealed that c.1042₁₀₄₃insCGGCA led to a shift in the sequence of nucleotides, creating a premature stop codon at the new reading frame. RT-qPCR analysis of MYBPC3 mRNA revealed a marked reduction in HCM heart compared to the normal controls (P < 0.05). Consistently, Western blot analysis showed significantly reduced expression of cMyBP-C in the pedigree in comparison with the controls (P < 0.05). The novel c.1042₁₀₄₃insCGGCA MYBPC3 mutation is a genetic basis for HCM due to c-MyBP-C haploinsufficiency. 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 Show more
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
Integration of human genomics and other omics across different ancestries provides novel, affordable, and systematic approach for target identification. We used Mendelian randomization approaches to u Show more
Integration of human genomics and other omics across different ancestries provides novel, affordable, and systematic approach for target identification. We used Mendelian randomization approaches to unravel causal associations between 2,940 circulating proteins and 19 CVD. We found 218 proteins that impacted risk of one or more CVDs through forward MR (106 and 182 using cis-pQTLs only and cis- + trans-pQTLs, respectively), among which 107 were previously reported as associated with CVD or CVD-related traits. There were 102 proteins replicated (FDR < 5%, 53 with cis-pQTLs only and 88 with cis- + trans-pQTLs) using the FinnGen Olink data. BTN3A2 was highlighted as a novel candidate gene for ischemic stroke, suggesting a crosstalk between immune modulation and stroke pathogenesis. Single cell integration prioritized PAM for stable angina pectoris and ventricular arrhythmia and LPL for peripheral artery disease, whose transcriptional expressions were enriched in cardiomyocytes. Forward and reverse MR found largely non-overlapping proteins (only 2 overlapped: LGALS4 and MMP12), suggesting distinct proteomic causes and consequences of CVD. Our study provides human genetics-based evidence of novel candidate genes, a foundational step towards full-scale causal human biology-based drug discovery for CVD. Show less
Previous studies have shown that astrocytes can transfer healthy mitochondria to dopaminergic (DA) neurons, which may serve as an intrinsic neuroprotective mechanism in Parkinson's disease (PD). LRRK2 Show more
Previous studies have shown that astrocytes can transfer healthy mitochondria to dopaminergic (DA) neurons, which may serve as an intrinsic neuroprotective mechanism in Parkinson's disease (PD). LRRK2 G2019S is the most common pathogenic mutation associated with PD. In this study, we explored whether mitochondrial transfer is influenced by genetic and environmental factors and whether dysfunction in this process is one of the mechanisms of the pathogenic LRRK2 G2019S mutation. DA neurons and astrocytes were differentiated from induced pluripotent stem cells generated from the peripheral blood of a healthy individual and a PD patient carrying the LRRK2 G2019S mutation. A coculture system of astrocytes and DA neurons was established to explore the pathogenic mechanisms of LRRK2 G2019S. Exposure to the environmental toxin rotenone impaired mitochondrial transfer from astrocytes to DA neurons. Compared with the co-culture system from the healthy participant, the co-culture system harboring the LRRK2 G2019S mutation experienced more pronounced damage. Specifically, STX17 was colocalized with the mitochondrial outer membrane marker TOM20, and its knockdown caused damage to mitochondrial transfer. Drp1 interacted with STX17. LRRK2 G2019S-mutant astrocytes exhibited markedly increased phosphorylation of Drp1 at Ser616 upon rotenone exposure. Moreover, the degree of colocalization of STX17 with TOM20 decreased. The Drp1 phosphorylation inhibitor DUSP6 restored the colocalization of STX17 and TOM20, as well as the mitochondrial transfer efficiency and neuronal survival. The impairment of mitochondrial transfer is a potential pathogenic mechanism associated with LRRK2 G2019S mutation. The molecular mechanisms of mitochondrial transfer were observed to occur through a Drp1-STX17-dependent pathway. Notably, inhibitors for Drp1 Ser616 phosphorylation may offer neuroprotection through mitigating mitochondrial transfer impairments. This study provides novel insights into the pathogenesis of PD and the development of new therapeutic targets. Show less
To optimize livestock production of integrated farms, dietary crude fat levels are often increased, making efficient fat utilization crucial. Bile acids are known to improve fat utilization, but their Show more
To optimize livestock production of integrated farms, dietary crude fat levels are often increased, making efficient fat utilization crucial. Bile acids are known to improve fat utilization, but their impact on growth performance and breast muscle development in Zhijiang ducks remains unclear. In this study, a total of 360 twenty-day-old Zhijiang ducks with similar body weights were divided into three groups: the control group (CN) received a basal diet; the high-fat group (FA) received the basal diet plus 1.25 % rapeseed oil; and the high-fat plus bile acids compound (BA) group (FB) received the FA diet supplemented with 250 mg/kg BA for 30 days. Results indicated that the addition of rapeseed oil and BA significantly increased (P < 0.05) average daily gain (ADG) and reduced (P < 0.05) feed conversion ratio (FCR). Slaughter data showed that BA significantly enhanced (P < 0.05) breast muscle weight and percentage while decreasing (P < 0.05) abdominal fat weight. Additionally, BA increased (P < 0.05) the cross-sectional area of breast muscle fibers, total bile acid content, and levels of insulin-like growth factors 1/2 (IGF1/2). Transcriptomic analysis further revealed that BA significantly upregulated (P < 0.05) the levels of PPARα, CPT1α, NR1H4, and CETP in breast muscle. 16S rRNA analysis showed a significant increase (P < 0.05) in the relative abundances of genera Enorma, [Eubacterium nodatum group], Rikenellaceae RC9 gut group, and SP3-e08. Additionally, the Spearman correlation suggested a positive correlation between the genera Olsenella, SP3-e08, Enorma, Rikenellaceae_RC9_gut_group, and [Eubacterium_nodatum_group] with PPARα, CETP, NR1H4, and CPT1α. In contrast, the genera Christensenellaceae_R₇_group and Sutterella exhibited negative correlations with PPARα. These findings provide new insights into the role of BA in promoting growth performance and skeletal muscle development in Zhijiang ducks fed a high-fat diet, with this effect potentially linked to changes in the gut microbiota. Show less
CD11c+ microglia are a functionally specialized subpopulation of microglia that play a crucial role in the pathophysiological processes of various central nervous system diseases. This review synthesi Show more
CD11c+ microglia are a functionally specialized subpopulation of microglia that play a crucial role in the pathophysiological processes of various central nervous system diseases. This review synthesizes compelling evidence that CD11c+ microglia exhibit unique transcriptomic and phagocytic characteristics. These characteristics distinguish them from homeostatic microglia and support their specialized functions. During development, CD11c+ microglia are crucial for the maturation of oligodendrocytes and the integrity of white matter, particularly in regions such as the corpus callosum and cerebellum. In preclinical models of neurodegenerative diseases (such as Alzheimer's disease and amyotrophic lateral sclerosis) and central nervous system injuries (such as stroke and spinal cord injury), they are consistently associated with neuroprotective phenotypes. CD11c+ microglia exhibit enhanced phagocytic capacity near amyloid plaques and damaged neurons, helping to clear pathological protein aggregates and cell debris, thereby reducing neurotoxicity and promoting a repair environment. The current consensus is that specific microenvironmental cues, particularly hazard signaling molecules (DAMPs) and cytokines (such as interferon-γ), are the main drivers of the differentiation and activation of CD11c+ microglia. Among these, the TREM2-APOE signaling axis is a key and widely accepted regulatory pathway for their survival, proliferation, and functional status. The plasticity of CD11c+ microglia is regulated by multiple signaling pathways, including CSF1R, SIRPα-CD47, IFN-γ, and the complement cascade. Emerging therapeutic strategies aim to regulate their activities through gene targeting, metabolic intervention, and immune regulation using TREM2 agonists, CSF1R inhibitors, or nanopharmacological methods. However, challenges remain in defining specific CD11c+ biomarkers, understanding environment-dependent functions, and achieving targeted delivery. Future prospects depend on clearly addressing individual developmental issues, deciphering the molecular switches that control phenotypic plasticity, and developing highly specific therapeutic strategies to leverage their beneficial functions, thereby paving the way for new intervention methods for neurological diseases. Show less
The microtubule actin crosslinking factor 1 ( Trios-based whole-exome sequencing was performed on a cohort with generalised epilepsy from the China Epilepsy Gene 1.0 project. The spatial-temporal expr Show more
The microtubule actin crosslinking factor 1 ( Trios-based whole-exome sequencing was performed on a cohort with generalised epilepsy from the China Epilepsy Gene 1.0 project. The spatial-temporal expression, single-cell sequencing and genotype-phenotype correlation were analysed to explore the role of Two de novo heterozygous and eight biallelic Show less
Does preconception mental health status in either partner affect fertility and infertility, and is this association modified by socioeconomic status (SES)? Preconception mental health problems in both Show more
Does preconception mental health status in either partner affect fertility and infertility, and is this association modified by socioeconomic status (SES)? Preconception mental health problems in both partners are associated with lower couple fertility, with the synergistic impact being most pronounced among couples with low SES status. Mental health problems are rising among young adults, and fertility rates are declining. Women's preconception mental health has been linked to lower fertility, but few studies have examined the combined impact of both partners' mental health. The modifying role of SES in these associations is also poorly understood. This couple-based prospective cohort study included 966 preconception couples who sought preconception care and were followed for 12 months in the Shanghai Birth Cohort between 2013 and 2015. The couples' mental health status was evaluated at enrolment using the Center for Epidemiological Studies-Depression Scale, Zung Self-Rating Anxiety Scale, and Perceived Stress Scale. The outcomes included couple fecundability (measured by the TTP) and infertility (i.e. TTP >12 menstrual cycles). In the partner-specific model, Cox proportional hazards models and logistic regression were used to evaluate the associations between each partner's depression, anxiety, and stress levels and couples' fertility. In the couple-based model, cross-classification and quantile g-computation were first applied to identify couples' joint exposure to specific psychological conditions in relation to fertility. Latent profile analysis (LPA) was then conducted to characterize distinct latent profiles of couples' overall mental health statuses, followed by Cox proportional hazards models and logistic regression to examine the corresponding associations. Key symptoms in the couples' depression, anxiety, and stress scales were determined by elastic net regression and least absolute shrinkage and selection operator. To assess the potential effect modification of SES on the association between couples' mental health and fertility, we conducted stratified analyses by male and female partner education levels and household income. In the female partner-specific model, a 1 SD increase in depression score was associated with 10% lower fecundability (FOR = 0.90, 95% CI: 0.82, 0.99). Likewise, a 1 SD increase in the stress score was associated with 13% lower fecundability (FOR = 0.87, 95% CI: 0.79, 0.96). Male anxiety was associated with a higher risk of infertility (OR = 1.19, 95% CI: 1.01, 1.42). Stratified analyses showed that depression, anxiety, and stress were significantly associated with lower fecundability among males with an education level Show less
Despite the critical role of e-Health literacy (eHL) in modern healthcare, current research predominantly concentrates on conditions such as cancer and diabetes, as well as outpatient care settings. H Show more
Despite the critical role of e-Health literacy (eHL) in modern healthcare, current research predominantly concentrates on conditions such as cancer and diabetes, as well as outpatient care settings. However, there remains a significant gap in studies specifically addressing the eHL needs of patients with maintenance hemodialysis (MHD). This study aims to explore the latent categories of eHL among MHD patients and its impact on health-promoting lifestyle (HPL). A survey was conducted using a convenience sampling method involving 500 MHD patients from three tertiary hospitals in Baoding. Data were analyzed using latent profile analysis (LPA) and a mixed regression model. This study showed that MHD patients could be classified into low (23.17%), middle (49.78%), and high (27.05%) eHL groups, with the three-class model showing optimal fit (AIC = 2321.213, BIC = 2271.168, entropy = 0.967). MHD Patients in the high literacy group scored significantly higher in all dimensions of e-HL and overall HPL (119.58 ± 13.86) compared to those in the low literacy group (91.82 ± 11.73) (all The findings suggest a heterogeneous stratification of eHL among MHD patients, closely linked to HPL. Stratified intervention strategies should be developed for different patient groups to potentially improve their health behaviors. The study provides evidence-based support for personalized health management. Show less
As a chronic lipid driven arterial disease, dyslipidemia is one of the most critical risk factors for atherosclerosis (AS). The gut microbiota plays an important role in regulating host lipid metaboli Show more
As a chronic lipid driven arterial disease, dyslipidemia is one of the most critical risk factors for atherosclerosis (AS). The gut microbiota plays an important role in regulating host lipid metabolism disorders. Studies have shown that the herb "Gualou-Xiebai" (GLXB) can effectively regulate the blood lipid levels of ApoE Show less
The competency of specialist nurse clinical educators is crucial for the effectiveness of specialist nurse training programmes. However, variability in teaching competency and training needs among edu Show more
The competency of specialist nurse clinical educators is crucial for the effectiveness of specialist nurse training programmes. However, variability in teaching competency and training needs among educators remains insufficiently studied, especially in the context of rapidly evolving healthcare education in China. This study aimed to identify distinct core competency profiles among clinical educators for specialist nurses, examine associated socio-demographic factors, and explore differences in training needs across profiles. A cross-sectional online survey was conducted with 3,945 specialist nurse clinical educators from 30 Chinese regions. The Chinese version of the Nurse Educator Core Competency Scale (NECCS) and a self-developed training needs questionnaire were used. Latent Profile Analysis (LPA) identified competency subgroups, while multinomial logistic regression and Kruskal-Wallis tests examined associated variables and training needs. Latent Profile Analysis identified three competency profiles: foundational (8.6%), intermediate (43.0%), and advanced (48.4%), with mean scores of 43.89, 68.24, and 91.68, respectively. Educators without prior training were significantly more likely to belong to the foundational (OR = 3.195, p < 0.001) and intermediate (OR = 1.676, p < 0.001) groups compared to those with training experience. Advanced-competency educators showed the highest demand for curriculum design training, with 75% rating it as highly necessary. In contrast, educators in the intermediate group identified clinical teaching methods and techniques as their top training need (58.7%). Those in the foundational group prioritised common pedagogical methods and instructional technologies (54.7%). Clinical educator competencies vary by background characteristics and training exposure. Tailored, competency-based training is needed to address these gaps and enhance the quality of specialist nursing education. Show less