Lipoprotein lipase (LPL) plays a crucial role in triglyceride hydrolysis. Rare biallelic variants in the LPL gene leading to complete or near-complete loss of function cause autosomal recessive famili Show more
Lipoprotein lipase (LPL) plays a crucial role in triglyceride hydrolysis. Rare biallelic variants in the LPL gene leading to complete or near-complete loss of function cause autosomal recessive familial chylomicronemia syndrome. However, rare biallelic LPL variants resulting in significant but partial loss of function are rarely documented. This study reports a novel occurrence of such rare biallelic LPL variants in a Chinese patient with hypertriglyceridemia-induced acute pancreatitis (HTG-AP) during pregnancy and provides an in-depth functional characterization. The complete coding sequences and adjacent intronic regions of the LPL, APOC2, APOA5, LMF1, and GPIHBP1 genes were analyzed by Sanger sequencing. The aim was to identify rare variants, including nonsense, frameshift, missense, small in-frame deletions or insertions, and canonical splice site mutations. The functional impact of identified LPL missense variants on protein expression, secretion, and activity was assessed in HEK293T cells through single and co-transfection experiments, with and without heparin treatment. Two rare LPL missense variants were identified in the patient: the previously reported c.809G > A (p.Arg270His) and a novel c.331G > C (p.Val111Leu). Genetic testing confirmed these variants were inherited biallelically. Functional analysis showed that the p.Arg270His variant resulted in a near-complete loss of LPL function due to effects on protein synthesis/stability, secretion, and enzymatic activity. In contrast, the p.Val111Leu variant retained approximately 32.3% of wild-type activity, without impacting protein synthesis, stability, or secretion. Co-transfection experiments indicated a combined activity level of 20.7%, suggesting no dominant negative interaction between the variants. The patient's post-heparin plasma LPL activity was about 35% of control levels. This study presents a novel case of partial but significant loss-of-function biallelic LPL variants in a patient with HTG-AP during pregnancy. Our findings enhance the understanding of the nuanced relationship between LPL genotypes and clinical phenotypes, highlighting the importance of residual LPL function in disease manifestation and severity. Additionally, our study underscores the challenges in classifying partial loss-of-function variants in classical Mendelian disease genes according to the American College of Medical Genetics and Genomics (ACMG)'s variant classification guidelines. Show less
The molecular mechanisms and signaling pathways involved in tooth morphogenesis have been the research focus in the fields of tooth and bone development. However, the cell population in molars at the Show more
The molecular mechanisms and signaling pathways involved in tooth morphogenesis have been the research focus in the fields of tooth and bone development. However, the cell population in molars at the late bell stage and the mechanisms of hard tissue formation and mineralization remain limited knowledge. Here, we used the rat mandibular first and second molars as models to perform single-cell RNA sequencing (scRNA-seq) analysis to investigate cell identity and driver genes related to dental mesenchymal cell differentiation during the late bell hard tissue formation stage. We identified seven main cell types and investigated the heterogeneity of mesenchymal cells. Subsequently, we identified novel cell marker genes, including Pclo in dental follicle cells, Wnt10a in pre-odontoblasts, Fst and Igfbp2 in periodontal ligament cells, and validated the expression of Igfbp3 in the apical pulp. The dynamic model revealed three differentiation trajectories within mesenchymal cells, originating from two types of dental follicle cells and apical pulp cells. Apical pulp cell differentiation is associated with the genes Ptn and Satb2, while dental follicle cell differentiation is associated with the genes Tnc, Vim, Slc26a7, and Fgfr1. Cluster-specific regulons were analyzed by pySCENIC. In addition, the odontogenic function of driver gene TNC was verified in the odontoblastic differentiation of human dental pulp stem cells. The expression of osteoclast differentiation factors was found to be increased in macrophages of the mandibular first molar. Our results revealed the cell heterogeneity of molars in the late bell stage and identified driver genes associated with dental mesenchymal cell differentiation. These findings provide potential targets for diagnosing dental hard tissue diseases and tooth regeneration. Show less
The PICALM::MLLT10 fusion is a rare but recurrent cytogenetic abnormality in acute leukemia, with limited clinicopathologic and outcome data available. Herein, we analyzed 156 acute leukemia patients Show more
The PICALM::MLLT10 fusion is a rare but recurrent cytogenetic abnormality in acute leukemia, with limited clinicopathologic and outcome data available. Herein, we analyzed 156 acute leukemia patients with PICALM::MLLT10 fusion, including 12 patients from our institutions and 144 patients from the literature. The PICALM::MLLT10 fusion preferentially manifested in pediatric and young adult patients, with a median age of 24 years. T-lymphoblastic leukemia/lymphoma (T-ALL) constituted 65% of cases, acute myeloid leukemia (AML) 27%, and acute leukemia of ambiguous lineage (ALAL) 8%. About half of T-ALL were classified as an early T-precursor (ETP)-ALL. In our institutions' cohort, mediastinum was the most common extramedullary site of involvement. Eight of 12 patients were diagnosed with T-ALL exhibiting a pro-/pre-T stage phenotype (CD4/CD8-double negative, CD7-positive), and frequent CD79a expression. NGS revealed pathogenic mutations in 5 of 6 tested cases, including NOTCH1, and genes in RAS and JAK-STAT pathways and epigenetic modifiers. Of 138 cases with follow-up, pediatric patients (<18 years) had 5-year overall survival (OS) of 71%, significantly better than adults at 33%. The 5-year OS for AML patients was 25%, notably shorter than T-ALL patients at 54%; this distinction was observed in both pediatric and adult populations. Furthermore, adult but not pediatric ETP-ALL patients demonstrated inferior survival compared to non-ETP-ALL patients. Neither karyotype complexity nor transplant status had a discernible impact on OS. In conclusion, PICALM::MLLT10 fusion is most commonly seen in T-ALL patients, particularly those with an ETP phenotype. AML and adult ETP-ALL patients had adverse prognosis. PICALM::MLTT10 fusion testing should be considered in T-ALL, AML, and ALAL patients. Show less
Dual blocker therapy (DBT) has the enhanced antitumor benefits than the monotherapy. Yet, few effective biomarkers are developed to monitor the therapy response. Herein, we investigate the DBT longitu Show more
Dual blocker therapy (DBT) has the enhanced antitumor benefits than the monotherapy. Yet, few effective biomarkers are developed to monitor the therapy response. Herein, we investigate the DBT longitudinal plasma proteome profiling including 113 longitudinal samples from 22 patients who received anti-PD1 and anti-CTLA4 DBT therapy. The results show the immune response and cholesterol metabolism are upregulated after the first DBT cycle. Notably, the cholesterol metabolism is activated in the disease non-progressive group (DNP) during the therapy. Correspondingly, the clinical indicator prealbumin (PA), free triiodothyronine (FT3) and triiodothyronine (T3) show significantly positive association with the cholesterol metabolism. Furthermore, by integrating proteome and radiology approach, we observe the high-density lipoprotein partial remodeling are activated in DNP group and identify a candidate biomarker APOC3 that can reflect DBT response. Above, we establish a machine learning model to predict the DBT response and the model performance is validated by an independent cohort with balanced accuracy is 0.96. Thus, the plasma proteome profiling strategy evaluates the alteration of cholesterol metabolism and identifies a panel of biomarkers in DBT. Show less
Three-dimensional (3D) chromatin architecture frequently altered in cancer. However, its changes during the pathogenesis of hepatocellular carcinoma (HCC) remained elusive. Hi-C and RNA-seq were appli Show more
Three-dimensional (3D) chromatin architecture frequently altered in cancer. However, its changes during the pathogenesis of hepatocellular carcinoma (HCC) remained elusive. Hi-C and RNA-seq were applied to study the 3D chromatin landscapes and gene expression of HCC and ANHT. Hi-C Pro was used to generate genome-wide raw interaction matrices, which were normalized via iterative correction (ICE). Moreover, the chromosomes were divided into different compartments according to the first principal component (E1). Furthermore, topologically associated domains (TADs) were visualized via WashU Epigenome Browser. Furthermore, differential expression analysis of ANHT and HCC was performed using the DESeq2 R package. Additionally, dysregulated genes associated with 3D genome architecture altered were confirmed using TCGA, qRT-PCR, immunohistochemistry (IHC), etc. RESULTS: First, the intrachromosomal interactions of chr1, chr2, chr5, and chr11 were significantly different, and the interchromosomal interactions of chr4-chr10, chr13-chr21, chr15-chr22, and chr16-chr19 are remarkably different between ANHT and HCC, which resulted in the up-regulation of TP53I3 and ZNF738 and the down-regulation of APOC3 and APOA5 in HCC. Second, 49 compartment regions on 18 chromosomes have significantly switched (A-B or B-A) during HCC tumorigenesis, contributing to up-regulation of RAP2A. Finally, a tumor-specific TAD boundary located on chr5: 6271000-6478000 and enhancer hijacking were identified in HCC tissues, potentially associated with the elevated expression of MED10, whose expression were associated with poor prognosis of HCC patients. This study demonstrates the crucial role of chromosomal structure variation in HCC oncogenesis and potential novel biomarkers of HCC, laying a foundation for cancer precision medicine development. Show less
We aimed to evaluate the efficacy, safety, and immunogenicity of a SARS-CoV-2 mRNA vaccine (Omicron BA.5) LVRNA012 given as the booster in immunized but SARS-CoV-2 infection-free adults in China. This Show more
We aimed to evaluate the efficacy, safety, and immunogenicity of a SARS-CoV-2 mRNA vaccine (Omicron BA.5) LVRNA012 given as the booster in immunized but SARS-CoV-2 infection-free adults in China. This is a single-center, randomized, double-blind, placebo-controlled phase 3 clinical trial enrolling healthy adult participants (≥18 years) who had completed two or three doses of inactivated COVID-19 vaccines at least 6 months before, in Bengbu, Anhui province, China. Eligible participants were randomly assigned (1:1) to receive a booster intramuscular vaccination with an LVRNA012 vaccine (100ug) or placebo. The primary endpoint was the protective efficacy of a booster dose of the LVRNA012 vaccine or placebo against symptomatic COVID-19 of any severity 14 days after vaccination. Laboratory-confirmed COVID-19 infections were identified from 14 days to 180 days after intervention, with active surveillance for symptomatic illness 8 times per month between 7 to 90 days and at least once per month between 90 to 180 days after intervention. 2615 participants were recruited and randomly assigned in a 1:1 ratio to either the vaccine group (1308) or the placebo group (1307). A total of 141 individuals (46 in the LVRNA012 group and 95 in the placebo group) developed symptomatic COVID-19 infection 14 days after the booster immunization, showing a vaccine efficacy of 51.9% (95% CI, 31.3% to 66.4%). Most infections were detected 90 days after intervention during a period when XBB was prevalent in the community. Adverse reactions were reported by 64% of participants after the LVRNA012 vaccination, but most of them were mild or moderate. The booster vaccination with the LVRNA012 mRNA vaccine could significantly enhance neutralizing antibody titers against the Omicron variant XBB.1.5 (GMT 132.3 [99.8, 175.4]) than did those in the placebo group (GMT 12.5 [8.4, 18.7]) at day 14 for the previously immunized individuals. The LVRNA012 mRNA vaccine is immunogenic, and shows robust efficacy in preventing COVID-19 during the omicron-predominate period. ClinicalTrials.gov, identifier NCT05745545. Show less
A poor prognosis is associated with atherosclerotic plaque rupture (PR) despite after conventional therapy for patients with acute coronary syndrome (ACS). Timely identification of PR improves the ris Show more
A poor prognosis is associated with atherosclerotic plaque rupture (PR) despite after conventional therapy for patients with acute coronary syndrome (ACS). Timely identification of PR improves the risk stratification and prognosis of ACS patients. A derivation cohort of 110 patients with ACS who underwent pre-intervention optical coherence tomography (OCT) were matched 1:1 to the PR and intact fibrous cap (IFC) groups according to traditional risk factors. Candidate PR proteins were identified via mass spectrometry (MS)-based proteomics using unbiased machine learning methods and were further validated by enzyme-linked immunosorbent assay (ELISA) in an external validation cohort of 85 patients with ACS. The performance of candidate biomakers was assessed using the receiver operating characteristic curve analysis. 1121 proteins were identified and 535 filtered proteins were used for analysis. Nine candidate proteins were screened by five machine learning algorithms. Three proteins (APOC3, RAB39A, and KNG1) were significantly different between the PR and IFC in validation cohort. The performance of plasm APOC3, RAB39A, and KNG1 for differentiating PR and IFC was superior to that of the conventional biomarkers and risk factors. The proteins (APOC3, RAB39A, and KNG1) serve as a potential novel diagnostic tool to identify PR in ACS patients. Show less
To investigate the correlation between serum angiopoietin-like protein 4 (ANGPTL4) levels, white matter hyperintensity (WMH), and cognitive impairment (CI) in patients with cerebral small vessel disea Show more
To investigate the correlation between serum angiopoietin-like protein 4 (ANGPTL4) levels, white matter hyperintensity (WMH), and cognitive impairment (CI) in patients with cerebral small vessel disease (CSVD). This cross-sectional study enrolled 171 patients with CSVD who attended the First Affiliated Hospital of Xinxiang Medical University from December 2021 to July 2022. All subjects underwent a 3.0T head magnetic resonance imaging, neuropsychology assessment, and blood sampling. Serum ANGPTL4 levels were detected by enzyme-linked immunosorbent assay and the severity of WMH was assessed by the Fazekas scale. According to the Montreal Cognitive Assessment (MoCA) scale, subjects were divided into normal cognition group (NC, n = 80) and CI group (n = 91). According to the total Fazekas scores, subjects were divided into a mild WMH group (n = 84), a moderate WMH group (n = 70), and a severe WMH group (n = 17). Serum ANGPTL4 levels were significantly higher in the CI group than in the NC group (p < .05) and were negatively correlated with mini-mental state examination scores and MoCA scores (r = -0.26, -0.341, p < .05). Serum ANGPTL4 levels increased significantly in the mild to moderate WMH group but tended to decrease in the severe WMH group. Binary logistic regression analysis showed that ANGPTL4 was an independent influencing factor for CSVD-CI (OR = 2.062, 95% CI (1.591-2.674), p < .001). The area under curve of ANGPTL4 for CSVD-CI was 0.847 (0.791-0.903). ANGPTL4 may be involved in the process of white matter damage and CI in CSVD patients and shows a diagnostic value for CSVD-CI. Show less
Osteoarthritis (OA) is a degenerative joint disease caused by the deterioration of cartilage. However, the underlying mechanisms of OA pathogenesis remain elusive. Hub genes were screened by bioinform Show more
Osteoarthritis (OA) is a degenerative joint disease caused by the deterioration of cartilage. However, the underlying mechanisms of OA pathogenesis remain elusive. Hub genes were screened by bioinformatics analysis based on the GSE114007 and GSE169077 datasets. The Sprague-Dawley (SD) rat model of OA was constructed by intra-articular injection of a mixture of papain and L-cysteine. Hematoxylin-eosin (HE) staining was used to detect pathological changes in OA rat models. Inflammatory cytokine levels in serum were measured employing the enzyme-linked immunosorbent assay (ELISA). The reverse transcription quantitative PCR (RT-qPCR) was implemented to assess the hub gene expressions in OA rat models. The roles of PDK4 and the mechanism regulating the PPAR pathway were evaluated through western blot, cell counting kit-8 (CCK-8), ELISA, and flow cytometry assays in C28/I2 chondrocytes induced by IL-1β. Six hub genes were identified, of which COL1A1, POSTN, FAP, and CDH11 expressions were elevated, while PDK4 and ANGPTL4 were reduced in OA. Overexpression of PDK4 inhibited apoptosis, inflammatory cytokine levels (TNF-α, IL-8, and IL-6), and extracellular matrix (ECM) degradation protein expressions (MMP-3, MMP-13, and ADAMTS-4) in IL-1β-induced chondrocytes. Further investigation revealed that PDK4 promoted the expression of PPAR signaling pathway-related proteins: PPARA, PPARD, and ACSL1. Additionally, GW9662, an inhibitor of the PPAR pathway, significantly counteracted the inhibitory effect of PDK4 overexpression on IL-1β-induced chondrocytes. PDK4 inhibits OA development by activating the PPAR pathway, which provides new insights into the OA management. Show less
Osteoarthritis is recognized as a common geriatric condition characterized by irregular chronic pain. Its prevalence is steadily increasing, posing significant challenges to global public health, whil Show more
Osteoarthritis is recognized as a common geriatric condition characterized by irregular chronic pain. Its prevalence is steadily increasing, posing significant challenges to global public health, while some studies indicate a trend towards younger individuals being affected. This condition severely impacts patients' quality of life. Using the Gene Expression Omnibus (GEO) database, we downloaded datasets GSE114007, GSE169077, and GSE206848. We utilized R software to screen and confirm differentially expressed genes (DEGs) related to the development of osteoarthritis. A cross-analysis of the three datasets was conducted, with the least overlapping dataset, GSE206848, selected as the validation set. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed on the DEGs from GSE114007 and GSE169077. Weighted Gene Co-Expression Network Analysis (WGCNA) was employed to identify modules closely associated with osteoarthritis, and genes from these intersecting modules were entered into the STRING database to construct Protein-Protein Interaction Networks. The top ten genes by connectivity were identified and validated using GSE206848. Key genes were identified and preliminarily validated using Quantitative Real-Time PCR (QPCR). Subsequent validation of related genes was carried out through Western Blot (WB) analysis. Differentially expressed genes were identified from the GSE114007 and GSE169077 datasets and validated in the GSE206848 dataset, with ANGPTL4 selected as the key gene. QPCR results indicated a significant difference in ANGPTL4 expression levels between normal and osteoarthritic chondrocytes. Western Blot analysis confirmed a significant difference in ANGPTL4 protein expression between normal and osteoarthritic chondrocytes. Based on the experimental findings, ANGPTL4 appears to be a potential key gene in osteoarthritis. Show less
Imbalance in energy regulation is a major cause of insulin resistance and diabetes. Melanocortin-4 receptor (MC4R) signaling at specific sites in the central nervous system has synergistic but non-ove Show more
Imbalance in energy regulation is a major cause of insulin resistance and diabetes. Melanocortin-4 receptor (MC4R) signaling at specific sites in the central nervous system has synergistic but non-overlapping functions. However, the mechanism by which MC4R in the arcuate nucleus (ARC) region regulates energy balance and insulin resistance remains unclear. The MC4R POMC neuron-specific ablation of MC4R in the ARC region promoted food intake, impaired energy expenditure, leading to increased weight gain and impaired systemic glucose homeostasis. Additionally, MC4R ablation reduced the activation of POMC neuron, and is not tissue-specific for peripheral regulation, suggesting the importance of its central regulation. Mechanistically, sequencing analysis and Co-IP assay demonstrated a direct interaction of MC4R with Kir2.1. Knockdown of Kir2.1 in POMC neuron-specific ablation of MC4R restored the effect of MC4R ablation on energy expenditure and systemic glucose homeostasis, indicating by reduced body weight and ameliorated insulin resistance. Hypothalamic POMC neuron-specific knockout of MC4R affects energy balance and insulin sensitivity by regulating Kir2.1. Kir2.1 represents a new target and pathway that could be targeted in obesity. Show less
Fasting and refeeding systems can cause significant short-term fluctuations in nutrient and energy levels, triggering adaptive physiological responses in animals. This study examines the effects of fa Show more
Fasting and refeeding systems can cause significant short-term fluctuations in nutrient and energy levels, triggering adaptive physiological responses in animals. This study examines the effects of fasting and refeeding on blood biochemical indicators and transcriptional profiles in the hypothalamus and subcutaneous adipose tissue of geese. Biochemical assays reveal that fasting significantly increases levels of free fatty acids and glucagon, while reducing concentrations of triglycerides, leptin, and insulin. Transcriptomic analyses identify a complex transcriptional response in both the hypothalamus and subcutaneous adipose tissue, affecting several metabolic pathways and key genes associated with feed intake and energy metabolism. In subcutaneous adipose tissue, fasting downregulates genes involved in fatty acid synthesis ( Show less
Lisa A Lansdon, Byunggil Yoo, Ayse Keskus+23 more · 2024 · medRxiv : the preprint server for health sciences · Cold Spring Harbor Laboratory · added 2026-04-24
Gene fusions are common primary drivers of pediatric leukemias and are the result of underlying structural variant (SVs). Current clinical workflows to detect such alterations rely on a multimodal app Show more
Gene fusions are common primary drivers of pediatric leukemias and are the result of underlying structural variant (SVs). Current clinical workflows to detect such alterations rely on a multimodal approach, which often increases analysis time and overall cost of testing. In this study, we used long-read sequencing (lrSeq) as a proof-of-concept to determine whether clinically relevant (cr) SVs could be detected within a small (n = 17) pediatric leukemia cohort. We show that this methodology successfully determined all known crSVs detected through routine clinical testing. We also identified crSVs, such as an ins(11;10)(q23.3;p12p12) forming a KMT2A::MLLT10 fusion, missed by routine clinical approaches, resulting in the classification of leukemia genetic subtypes for four additional patients. This study demonstrates the diagnostic potential of lrSeq as an assay for SV detection in pediatric leukemia and supports lrSeq as a valuable tool for the accurate detection of crSVs. Show less
Acute liver failure (ALF) is a complex syndrome that impairs the liver's function to detoxify bilirubin, ammonia, and other toxic metabolites. Bioartificial liver (BAL) aims to help ALF patients to pa Show more
Acute liver failure (ALF) is a complex syndrome that impairs the liver's function to detoxify bilirubin, ammonia, and other toxic metabolites. Bioartificial liver (BAL) aims to help ALF patients to pass through the urgent period by temporarily undertaking the liver's detoxification functions and promoting the recovery of the injured liver. We genetically modified the hepatocellular cell line HepG2 by stably overexpressing genes encoding UGT1A1, OATP1B1, OTC, ARG1, and CPS1. The resulting SynHeps-II cell line, encapsulated by Cytopore microcarriers, dramatically reduced the serum levels of bilirubin and ammonia, as demonstrated both in vitro using patient plasma and in vivo using ALF animal models. More importantly, we have also completed the 3-dimensional (3D) culturing of cells to meet the demands for industrialized rapid and mass production, and subsequently assembled the plasma-cell contacting BAL (PCC-BAL) system to fulfill the requirements of preclinical experiments. Extracorporeal blood purification of ALF rabbits with SynHeps-II-embedded PCC-BAL saved more than 80% of the animals from rapid death. Mechanistically, SynHeps-II therapy ameliorated liver and brain inflammation caused by high levels of bilirubin and ammonia and promoted liver regeneration by modulating the nuclear factor κB (NF-κB) and signal transducer and activator of transcription 3 (STAT3) pathways. Also, SynHeps-II treatment reduced cerebral infiltration of neutrophils, reduced reactive oxygen species (ROS) levels, and mitigated hepatic encephalopathy. Taken together, SynHeps-II cell-based BAL was promising for the treatment of ALF patients and warrants clinical trials. Show less
Atrial fibrillation is the most common clinical arrhythmia and may be due in part to metabolic stress. Atrial specific deletion of the master metabolic sensor, AMP-activated protein kinase (AMPK), ind Show more
Atrial fibrillation is the most common clinical arrhythmia and may be due in part to metabolic stress. Atrial specific deletion of the master metabolic sensor, AMP-activated protein kinase (AMPK), induces atrial remodeling culminating in atrial fibrillation in mice, implicating AMPK signaling in the maintenance of atrial electrical and structural homeostasis. However, atrial substrate preference for mitochondrial oxidation and the role of AMPK in regulating atrial metabolism are unknown. Here, using LC-MS/MS methodology combined with infusions of [ Show less
Diabetes mellitus (DM) is a major metabolic disease endangering global health, with diabetic nephropathy (DN) as a primary complication lacking curative therapy. Sporoderm-broken spores of
Essential thrombocythemia (ET) and prefibrotic primary myelofibrosis (pre-PMF) are Philadelphia chromosome-negative myeloproliferative neoplasms. These conditions share overlapping clinical presentati Show more
Essential thrombocythemia (ET) and prefibrotic primary myelofibrosis (pre-PMF) are Philadelphia chromosome-negative myeloproliferative neoplasms. These conditions share overlapping clinical presentations; however, their prognoses differ significantly. Current morphological diagnostic methods lack reliability in subtype differentiation, underlining the need for improved diagnostics. The aim of this study was to investigate the multi-omics alterations in bone marrow biopsies of patients with ET and pre-PMF to improve our understanding of the nuanced diagnostic characteristics of both diseases. We performed proteomic analysis with 4D direct data-independent acquisition and microbiome analysis with 2bRAD-M sequencing technology to identify differential protein and microbe levels between untreated patients with ET and pre-PMF. Laboratory and multi-omics differences were observed between ET and pre-PMF, encompassing diverse pathways, such as lipid metabolism and immune response. The pre-PMF group showed an increased neutrophil-to-lymphocyte ratio and decreased high-density lipoprotein and cholesterol levels. Protein analysis revealed significantly higher CXCR2, CXCR4, and MX1 levels in pre-PMF, while APOC3, APOA4, FABP4, C5, and CFB levels were elevated in ET, with diagnostic accuracy indicated by AUC values ranging from 0.786 to 0.881. Microbiome assessment identified increased levels of Mycobacterium, Xanthobacter, and L1I39 in pre-PMF, whereas Sphingomonas, Brevibacillus, and Pseudomonas_E were significantly decreased, with AUCs for these genera ranging from 0.833 to 0.929. Our study provides preliminary insights into the proteomic and microbiome variations in the bone marrow of patients with ET and pre-PMF, identifying specific proteins and bacterial genera that warrant further investigation as potential diagnostic indicators. These observations contribute to our evolving understanding of the multi-omics variations and possible mechanisms underlying ET and pre-PMF. Show less
There is a decline in the quality and nutritive value of eggs in aged laying hens. Fruit pomaces with high nutritional and functional values have gained interest in poultry production to improve the p Show more
There is a decline in the quality and nutritive value of eggs in aged laying hens. Fruit pomaces with high nutritional and functional values have gained interest in poultry production to improve the performance. The performance, egg nutritive value, lipid metabolism, ovarian health, and cecal microbiota abundance were evaluated in aged laying hens (320 laying hens, 345-day-old) fed on a basal diet (control), and a basal diet inclusion of 0.25%, 0.5%, or 1.0% fermented The results show that 0.5% FAMP reduced the saturated fatty acids (such as C16:0) and improved the healthy lipid indices in egg yolks by decreasing the atherogenicity index, thrombogenic index, and hypocholesterolemia/hypercholesterolemia ratio and increasing health promotion index and desirable fatty acids ( Overall, FAMP improved the nutritive value of eggs in aged laying hens by improving the liver-blood-ovary function and cecal microbial and metabolite composition, which might help to enhance economic benefits. Show less
Despite centuries of traditional use of silymarin for hepatoprotection, current randomized controlled trial (RCT) studies on the effectiveness of silymarin in managing metabolic dysfunction-associated Show more
Despite centuries of traditional use of silymarin for hepatoprotection, current randomized controlled trial (RCT) studies on the effectiveness of silymarin in managing metabolic dysfunction-associated steatotic liver disease (MASLD) are limited and inconclusive, particularly when it is administered alone. The low bioavailability of silymarin highlights the possible influence of gut microbiota on the effectiveness of silymarin; however, no human studies have investigated this aspect. To determine the potential efficacy of silymarin in improving MASLD indicators and to investigate the underlying mechanisms related to gut microbiota. In this 24-week randomized, double-blind, placebo-controlled trial, 83 patients with MASLD were randomized to either placebo (n = 41) or silymarin (103.2 mg/d, n = 42). At 0, 12, and 24 weeks, liver stiffness and hepatic steatosis were assessed using FibroScan, and blood samples were gathered for biochemical detection, while faecal samples were collected at 0 and 24 weeks for 16S rRNA sequencing. Silymarin supplementation significantly reduced liver stiffness (LSM, -0.21 ± 0.17 vs. 0.41 ± 0.17, P = 0.015) and serum levels of γ-glutamyl transpeptidase (GGT, -8.21 ± 3.01 vs. 1.23 ± 3.16, P = 0.042) and ApoB (-0.02 ± 0.03 vs. 0.07 ± 0.03, P = 0.023) but had no significant effect on the controlled attenuation parameter (CAP), other biochemical indicators (aminotransferases, total bilirubin, glucose and lipid parameters, hsCRP, SOD, and UA), physical measurements (DBP, SBP, BMI, WHR, BF%, and BMR), or APRI and FIB-4 indices. Gut microbiota analysis revealed increased species diversity and enrichment of Oscillospiraceae in the silymarin group. These findings suggest that silymarin supplementation could improve liver stiffness in MASLD patients, possibly by modulating the gut microbiota. The trial was registered at the Chinese Clinical Trial Registry (ChiCTR2200059043). Show less
Endothelial-mesenchymal transition (EndMT) disrupts vascular endothelial integrity and induces atherosclerosis. Active integrin β1 plays a pivotal role in promoting EndMT by facilitating TGFβ/Smad sig Show more
Endothelial-mesenchymal transition (EndMT) disrupts vascular endothelial integrity and induces atherosclerosis. Active integrin β1 plays a pivotal role in promoting EndMT by facilitating TGFβ/Smad signaling in endothelial cells. Here, we report a novel anthraquinone compound, Kanglexin (KLX), which prevented EndMT and atherosclerosis by activating MAP4K4 and suppressing integrin β1/TGFβ signaling. First, KLX effectively counteracted the EndMT phenotype and mitigated the dysregulation of endothelial and mesenchymal markers induced by TGFβ1. Second, KLX suppressed TGFβ/Smad signaling by inactivating integrin β1 and inhibiting the polymerization of TGFβR1/2. The underlying mechanism involved the activation of FGFR1 by KLX, resulting in the phosphorylation of MAP4K4 and Moesin, which led to integrin β1 inactivation by displacing Talin from its β-tail. Oral administration of KLX effectively stimulated endothelial FGFR1 and inhibited integrin β1, thereby preventing vascular EndMT and attenuating plaque formation and progression in the aorta of atherosclerotic Apoe Show less
The Butuo Black Sheep (BBS) is well-known for its ability to thrive at high altitudes, resist diseases, and produce premium-quality meat. Nonetheless, there is insufficient data regarding its genetic Show more
The Butuo Black Sheep (BBS) is well-known for its ability to thrive at high altitudes, resist diseases, and produce premium-quality meat. Nonetheless, there is insufficient data regarding its genetic diversity and population-specific Single nucleotide polymorphisms (SNPs). This paper centers on the genetic diversity of (BBS). The investigation conducted a whole-genome resequencing of 33 BBS individuals to recognize distinct SNPs exclusive to BBS. The inquiry utilized bioinformatic analysis to identify and explain SNPs and pinpoint crucial mutation sites. The findings reveal that reproductive-related genes (GHR, FSHR, PGR, BMPR1B, FST, ESR1), lipid-related genes (PPARGC1A, STAT6, DGAT1, ACACA, LPL), and protein-related genes (CSN2, LALBA, CSN1S1, CSN1S2) were identified as hub genes. Functional enrichment analysis showed that genes associated with reproduction, immunity, inflammation, hypoxia, PI3K-Akt, and AMPK signaling pathways were present. This research suggests that the unique ability of BBS to adapt to low oxygen levels in the plateau environment may be owing to mutations in a variety of genes. This study provides valuable insights into the genetic makeup of BBS and its potential implications for breeding and conservation efforts. The genes and SPNs identified in this study could serve as molecular markers for BBS. Show less
To evaluate the potential of zinc finger protein 1 (ZPR1) as a diagnostic biomarker and explore the underlying role for esophageal squamous cell carcinoma (ESCC). A human proteome microarray was custo Show more
To evaluate the potential of zinc finger protein 1 (ZPR1) as a diagnostic biomarker and explore the underlying role for esophageal squamous cell carcinoma (ESCC). A human proteome microarray was customized to identify anti-ZPR1 autoantibody, and enzyme-linked immunosorbent assay (ELISA) was adopted to assess the diagnostic performance of anti-ZPR1 autoantibody in 294 patients with ESCC and 294 normal controls. The expression of ZPR1 protein was measured by immunohistochemistry. The effect of ZPR1 on the proliferation, migration, and invasion of ESCC cells was investigated through CCK-8, wound healing, and Transwell assays. The expression level of anti-ZPR1 autoantibody (fold change = 2.77) in ESCC patients was higher than that in normal controls. The receiver operating characteristic (ROC) analysis manifested anti-ZPR1 autoantibody achieved area under the ROC curve (AUC) of 0.726 and 0.734 to distinguish ESCC from normal controls with sensitivity of 50.0% and 42.3%, and specificity of 91.0% and 92.0% in the test group and validation group, respectively. The positive rate of ZPR1 protein was significantly higher in ESCC tissues (75.5%, 80/106) than paracancerous tissues (9.4%, 5/53). Compared with the human normal esophageal cell line, the expression level of ZPR1 mRNA and protein in ESCC lines (KYSE150, Eca109, and TE1) had an increased trend. The knockdown or overexpression of ZPR1 reduced and enhanced the proliferation, migration, and invasion of ESCC cell, respectively. ZPR1 was a potential immunodiagnostic biomarker for noninvasive detection and could be a promotional factor in tumor progression of ESCC. Show less
Metabolic-associated fatty liver disease (MAFLD) is a common chronic condition that poses a significant threat to human health. Mitochondrial dysfunction, particularly involving the mitochondrial Ca
Is there a relationship between serum uric acid and fructose levels in polycystic ovary syndrome (PCOS)? Elevated serum uric acid levels in women with PCOS positively correlate with serum fructose lev Show more
Is there a relationship between serum uric acid and fructose levels in polycystic ovary syndrome (PCOS)? Elevated serum uric acid levels in women with PCOS positively correlate with serum fructose levels, and elevated serum fructose levels are an independent risk factor for hyperuricemia in women with PCOS. Our previous study suggested a link between elevated serum fructose levels and PCOS. Fructose is unique as it generates uric acid during metabolism, and high uric acid levels are associated with metabolic disorders and an increased risk of anovulation. However, the relationship between serum uric acid and fructose levels in women with PCOS remains unclear. In a case-control study of 774 women (482 controls and 292 patients with PCOS) between May and October 2020 at the Shengjing Hospital of China Medical University, the relationship between uric acid and fructose levels in women with PCOS was examined. Participants were divided into subgroups based on various factors, including BMI, insulin resistance, dyslipidemia, metabolic syndrome, and hyperuricemia. Serum uric acid concentrations were measured using enzymatic assays, and serum fructose levels were determined using a fluorescent enzyme immunoassay. Dietary fructose data were collected through a validated food-frequency questionnaire of 81 food items. We applied restricted cubic splines to a flexibly model and visualized the linear/nonlinear relationships between serum uric acid and fructose levels in PCOS. Multivariate logistic analysis was executed to assess the association between serum fructose levels and hyperuricemia in PCOS. Human granulosa cell and oocyte mRNA profile sequencing data were downloaded for mapping uric acid and fructose metabolism genes in PCOS. Further downstream analyses, including Gene Ontology, Kyoto Encyclopedia of Genes and Genomes analysis, and protein-protein interactions were then carried out on the differentially expressed genes (DEGs). The correlation between uric acid and fructose metabolism genes was calculated using the Pearson correlation coefficient. The GeneCards database was used to identify DEGs related to uric acid and fructose metabolism in PCOS, and then several DEGs were confirmed by quantitative real-time PCR. Both serum fructose and uric acid levels were significantly increased in women with PCOS compared with the control women (P  <  0.001), and there was no statistically significant difference in dietary fructose intake between PCOS and controls, regardless of metabolic status. There was a positive linear correlation between serum uric acid and fructose levels in women with PCOS (Poverall < 0.001, Pnon-linear = 0.30). In contrast, no correlation was found in control women (Poverall = 0.712, Pnon-linear = 0.43). Additionally, a non-linear association was observed in the obese subgroup of patients with PCOS (Poverall < 0.001, Pnon-linear = 0.02). Serum uric acid levels were linearly and positively associated with serum fructose levels in patients with PCOS with insulin resistance, dyslipidemia, and metabolic syndrome. Furthermore, even after adjusting for confounding factors, elevated serum fructose levels were an independent risk factor for hyperuricemia in patients with PCOS (P  =  0.001; OR, 1.380; 95% CI, 1.207-1.577). There were 28 uric acid and 25 fructose metabolism genes which showed a significant correlation in PCOS. Seven upregulated genes (CAT, CRP, CCL2, TNF, MMP9, GCG, and APOB) related to uric acid and fructose metabolism in PCOS ovarian granulosa cells were ultimately successfully validated using quantitative real-time PCR. Due to limited conditions, more possible covariates (such as smoking and ethnicity) were not included, and the underlying molecular mechanism between fructose and uric acid levels in women with PCOS remains to be further investigated. The results of this study and our previous research indicate that the high uric acid status of PCOS may be mediated by fructose metabolism disorders, highlighting the importance of analyzing fructose metabolism, and especially its metabolic byproduct uric acid, during the clinical diagnosis of PCOS. These results suggest the adverse effects of high uric acid in PCOS, and the importance of taking early interventions regarding uric acid levels to reduce the occurrence and development of further clinical signs, such as metabolic disorders in women with PCOS. This work was supported by: the National Natural Science Foundation of China (No. 82371647, No. 82071607, and No. 32100691); LiaoNing Revitalization Talents Program (No. XLYC1907071); Fok Ying Tung Education Foundation (No. 151039); and Outstanding Scientific Fund of Shengjing Hospital (No. 202003). No competing interests were declared. N/A. Show less