Previous studies show that spinal cord ischemia and hypoxia is an important cause of spinal cord necrosis and neurological loss. Therefore, the study aimed to identify genes related to ischemia and hy Show more
Previous studies show that spinal cord ischemia and hypoxia is an important cause of spinal cord necrosis and neurological loss. Therefore, the study aimed to identify genes related to ischemia and hypoxia after spinal cord injury (SCI) and analyze their functions, regulatory mechanism, and potential in regulating immune infiltration. The expression profiles of GSE5296, GSE47681, and GSE217797 were downloaded from the Gene Expression Omnibus database. Gene ontology and Kyoto Encyclopedia of Genes and Genomes analyses were performed to determine the function and pathway enrichment of ischemia- and hypoxia-related differentially expressed genes (IAHRDEGs) in SCI. LASSO model was constructed, and support vector machine analysis was used to identify key genes. The diagnostic values of key genes were evaluated using decision curve analysis and receiver operating characteristic curve analysis. The interaction networks of miRNAs-IAHRDEGs and IAHRDEGs-transcription factors were predicted and constructed with the ENCORI database and Cytoscape software. CIBERSORT algorithm was utilized to analyze the correlation between key gene expression and immune cell infiltration. There were 27 IAHRDEGs identified to be significantly expressed in SCI at first. These genes were mostly significantly enriched in wound healing function and the pathway associated with lipid and atherosclerosis. Next, five key IAHRDEGs (Abca1, Casp1, Lpl, Procr, Tnfrsf1a) were identified and predicted to have diagnostic value. Moreover, the five key genes are closely related to immune cell infiltration. Abca1, Casp1, Lpl, Procr, and Tnfrsf1a may promote the pathogenesis of ischemic or hypoxic SCI by regulating vascular damage, inflammation, and immune infiltration. 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 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
Triple-negative breast cancer (TNBC) represents a highly aggressive subset of breast malignancies characterized by its challenging clinical management and unfavorable prognosis. While TFAP2A, a member Show more
Triple-negative breast cancer (TNBC) represents a highly aggressive subset of breast malignancies characterized by its challenging clinical management and unfavorable prognosis. While TFAP2A, a member of the AP-2 transcription factor family, has been implicated in maintaining the basal phenotype of breast cancer, its precise regulatory role in TNBC remains undefined. In vitro assessments of TNBC cell growth and migratory potential were conducted using MTS, colony formation, and EdU assays. Quantitative PCR was employed to analyze mRNA expression levels, while Western blot was utilized to evaluate protein expression and phosphorylation status of AKT and ERK. The post-transcriptional regulation of TFAP2A by miR-8072 and the transcriptional activation of SNAI1 by TFAP2A were investigated through luciferase reporter assays. A xenograft mouse model was employed to assess the in vivo growth capacity of TNBC cells. Selective silencing of TFAP2A significantly impeded the proliferation and migration of TNBC cells, with elevated TFAP2A expression observed in breast cancer tissues. Notably, TNBC patients exhibiting heightened TFAP2A levels experienced abbreviated overall survival. Mechanistically, TFAP2A was identified as a transcriptional activator of SNAI1, a crucial regulator of epithelial-mesenchymal transition (EMT) and cellular proliferation, thereby augmenting the oncogenic properties of TFAP2A in TNBC. Moreover, miR-8072 was unveiled as a negative regulator of TFAP2A, exerting potent inhibitory effects on TNBC cell growth and migration. Importantly, the tumor-suppressive actions mediated by the miR-8072/TFAP2A axis were intricately associated with the attenuation of AKT/ERK signaling cascades and the blockade of EMT processes. Our findings unravel the role and underlying molecular mechanism of TFAP2A in driving tumorigenesis of TNBC. Targeting the TFAP2A/SNAI1 pathway and utilizing miR-8072 as a suppressor represent promising therapeutic strategies for treating TNBC. Show less
Dorper and Tan sheep are renowned for their rapid growth and exceptional meat quality, respectively. Previous research has provided evidence of the impact of gut microbiota on breed characteristics. T Show more
Dorper and Tan sheep are renowned for their rapid growth and exceptional meat quality, respectively. Previous research has provided evidence of the impact of gut microbiota on breed characteristics. The precise correlation between the gastrointestinal tract and peripheral organs in each breed is still unclear. Investigating the metabolic network of the intestinal organ has the potential to improve animal growth performance and enhance economic benefits through the regulation of intestinal metabolites. In this study, we identified the growth advantage of Dorper sheep and the high fat content of Tan sheep. A transcriptome study of the brain, liver, skeletal muscle, and intestinal tissues of both breeds revealed 3,750 differentially expressed genes (DEGs). The genes PPARGC1A, LPL, and PHGDH were found to be highly expressed in Doper, resulting in the up-regulation of pathways related to lipid oxidation, glycerophospholipid metabolism, and amino acid anabolism. Tan sheep highly express the BSEP, LDLR, and ACHE genes, which up-regulate the pathways involved in bile transport and cholesterol homeostasis. Hindgut content analysis identified 200 differentially accumulated metabolites (DAMs). Purines, pyrimidines, bile acids, and fatty acid substances were more abundant in Dorper sheep. Based on combined gene and metabolite analyses, we have identified glycine, serine, and threonine metabolism, tryptophan metabolism, bile secretion, cholesterol metabolism, and neuroactive ligand-receptor interaction as key factors contributing to the differences among the breeds. This study indicates that different breeds of sheep exhibit unique breed characteristics through various physiological regulatory methods. Dorper sheep upregulate metabolic signals related to glycine, serine, and threonine, resulting in an increase in purine and pyrimidine substances. This, in turn, promotes the synthesis of amino acids and facilitates body development, resulting in a faster rate of weight gain. Tan sheep accelerate bile transport, reduce bile accumulation in the intestine, and upregulate cholesterol homeostasis signals in skeletal muscles. This promotes the accumulation of peripheral and intramuscular fat, resulting in improved meat quality. This work adopts a joint analysis method of multi-tissue transcriptome and gut metabolome, providing a successful case for analyzing the mechanisms underlying the formation of various traits. Show less
Pregnancy complications such as spontaneous abortion, preeclampsia, and preterm birth persist, despite current interventions aimed at their prevention and treatment largely proving unsuccessful. Inter Show more
Pregnancy complications such as spontaneous abortion, preeclampsia, and preterm birth persist, despite current interventions aimed at their prevention and treatment largely proving unsuccessful. Interleukin-27 (IL-27), composed of p28 and EBI3 subunits, binds to IL-27R, which consists of gp130 and IL-27Rα (also known as WSX-1 or TCCR), and plays a pivotal role in tumor development and inflammation regulation. At the maternal-fetal interface, IL-27 expression has been detected in trophoblasts, endometrial stromal cells, and decidual cells. Abnormal levels of IL-27/IL-27R have been linked to adverse pregnancy outcomes, including spontaneous miscarriage, preeclampsia, and preterm birth. This review aims to explore the expression of IL-27 at the maternal-fetal interface and its signaling pathway, uncovering the complex role of IL-27 in pregnancy complications. A comprehensive literature review was conducted using PubMed/Medline, Scopus, and Embase databases, analyzing studies on IL-27 expression and its signaling pathways at the maternal-fetal interface. The review focused on identifying the presence of IL-27 in various cell types and linking abnormal IL-27/IL-27R expression to pregnancy complications such as spontaneous miscarriage, preeclampsia, and preterm birth. IL-27 plays a complex role at the maternal-fetal interface, with abnormal expression linked to several pregnancy complications. These findings highlight the need for further research to elucidate IL-27's mechanisms and develop targeted interventions. Future studies should aim to develop targeted interventions and improve therapeutic strategies for managing pregnancy complications. Show less
The coronavirus disease 2019 (COVID-19) pandemic has caused extensive disruption of public health worldwide. There were reports of COVID-19 patients having multiple complications. This study investiga Show more
The coronavirus disease 2019 (COVID-19) pandemic has caused extensive disruption of public health worldwide. There were reports of COVID-19 patients having multiple complications. This study investigated COVID-19 from a genetic perspective. We conducted RNA sequencing (RNA-Seq) analysis of respiratory tract samples from 24 patients with COVID-19. Eight patients receiving mechanical ventilation or extracorporeal membrane oxygenation were regarded as severe cases; the remaining 16 patients were regarded as non-severe cases. After quality control, statistical analyses were performed by logistic regression and the Kolmogorov-Smirnov test to identify genes associated with disease severity. Six genes were associated with COVID-19 severity in both statistical tests, namely RNA sequencing analysis showed that severe acute respiratory syndrome coronavirus 2 infection is associated with the overexpression of genes involved in nervous system disorders. Show less
Retinal neovascularization poses heightened risks of vision loss and blindness. Despite its clinical significance, the molecular mechanisms underlying the pathogenesis of retinal neovascularization re Show more
Retinal neovascularization poses heightened risks of vision loss and blindness. Despite its clinical significance, the molecular mechanisms underlying the pathogenesis of retinal neovascularization remain elusive. This study utilized single-cell multiomics profiling in an oxygen-induced retinopathy (OIR) model to comprehensively investigate the intricate molecular landscape of retinal neovascularization. Mice were exposed to hyperoxia to induce the OIR model, and retinas were isolated for nucleus isolation. The cellular landscape of the single-nucleus suspensions was extensively characterized through single-cell multiomics sequencing. Single-cell data were integrated with genome-wide association study (GWAS) data to identify correlations between ocular cell types and diabetic retinopathy. Cell communication analysis among cells was conducted to unravel crucial ligand-receptor signals. Trajectory analysis and dynamic characterization of Müller cells were performed, followed by integration with human retinal data for pathway analysis. The multiomics dataset revealed six major ocular cell classes, with Müller cells/astrocytes showing significant associations with proliferative diabetic retinopathy (PDR). Cell communication analysis highlighted pathways that are associated with vascular proliferation and neurodevelopment, such as Vegfa-Vegfr2, Igf1-Igf1r, Nrxn3-Nlgn1, and Efna5-Epha4. Trajectory analysis identified a subset of Müller cells expressing genes linked to photoreceptor degeneration. Multiomics data integration further unveiled positively regulated genes in OIR Müller cells/astrocytes associated with axon development and neurotransmitter transmission. This study significantly advances our understanding of the intricate cellular and molecular mechanisms underlying retinal neovascularization, emphasizing the pivotal role of Müller cells. The identified pathways provide valuable insights into potential therapeutic targets for PDR, offering promising directions for further research and clinical interventions. Show less
Age at first egg (AFE) has consistently garnered interest as a crucial reproductive indicator within poultry production. Previous studies have elucidated the involvement of the hypothalamic-pituitary- Show more
Age at first egg (AFE) has consistently garnered interest as a crucial reproductive indicator within poultry production. Previous studies have elucidated the involvement of the hypothalamic-pituitary-ovarian (HPO) and hypothalamic-pituitary-thyroid (HPT) axes in regulating poultry sexual maturity. Concurrently, there was evidence suggesting a potential co-regulatory relationship between these 2 axes. However, as of now, no comprehensive exploration of the key pathways and genes responsible for the crosstalk between the HPO and HPT axes in the regulation of AFE has been reported. In this study, we conducted a comparative analysis of morphological differences and performed transcriptomic analysis on the hypothalamus, pituitary, thyroid, and ovarian stroma between normal laying group (NG) and abnormal laying group (AG). Morphological results showed that the thyroid index difference (D-) value (thyroid index D-value=right thyroid index-left thyroid index) was significantly (P < 0.05) lower in the NG than in the AG, while the ovarian index was significantly (P < 0.01) higher in the NG than in the AG. Furthermore, between NG and AG, we identified 99, 415, 167, and 1182 differentially expressed genes (DEGs) in the hypothalamus, pituitary, thyroid, and ovarian stroma, respectively. Gene ontology (GO) analysis highlighted that DEGs from 4 tissues were predominantly enriched in the "biological processes" category. Additionally, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed that 16, 14, 3, and 26 KEGG pathways were significantly enriched (P < 0.05) in the hypothalamus, pituitary, thyroid, and ovarian stroma. The MAPK signaling pathway emerged as the sole enriched pathway across all 4 tissues. Employing an integrated analysis of the protein-protein interaction (PPI) network and correlation analysis, we found GREB1 emerged as a pivotal component within the HPO axis to regulate estrogen-related signaling in the HPT axis, meanwhile, the HPT axis influenced ovarian development by regulating thyroid hormone-related signaling mainly through OPN5. Then, 10 potential candidate genes were identified, namely IGF1, JUN, ERBB4, KDR, PGF, FGFR1, GREB1, OPN5, DIO3, and THRB. These findings establish a foundation for elucidating the physiological and genetic mechanisms by which the HPO and HPT axes co-regulate goose AFE. Show less
CircRNA, a non-coding RNA, is an ideal biomarker and a suitable potential therapeutic target for various disease due to its high stability, species conservation and cell/tissue specificity. Our previo Show more
CircRNA, a non-coding RNA, is an ideal biomarker and a suitable potential therapeutic target for various disease due to its high stability, species conservation and cell/tissue specificity. Our previous study has found a circular RNA WWP2 (circWWP2) was significantly decreased in chicken macrophages during bacterial infection. However, the function of circWWP2 in chicken macrophages remains unclear. In this study, it was demonstrated that circWWP2 was a stable circular RNA created by back-splicing of exons 2 to 4 of WWP2 via PCR amplification, Sanger sequencing, RNase R exonuclease digestion, and RT-qPCR. Moreover, bioinformatics analysis showed circWWP2 could interact with 13 miRNAs and target 3,264 genes, which were significantly enriched in lysosomes, IgA-producing intestinal immune networks for IgA production, and Notch signaling pathway. Furthermore, CCK8 and RT-qPCR indicated that overexpression of circWWP2 could promote lipopolysaccharide (LPS)-induced cellular injury by decreasing cell viability and increasing the expression levels of pro-inflammatory cytokines and pro-apoptosis genes, and NO production. CircWWP2 may exert a potential target for the treatment of bacterial infection. Further experiments are necessary to validate the specific mechanism that circWWP2 regulates LPS induced cellular immune responses. Show less
Structural variations (SVs) have significant impacts on complex phenotypes by rearranging large amounts of DNA sequence. We present a comprehensive SV catalog based on the whole-genome sequence of 106 Show more
Structural variations (SVs) have significant impacts on complex phenotypes by rearranging large amounts of DNA sequence. We present a comprehensive SV catalog based on the whole-genome sequence of 1060 pigs (Sus scrofa) representing 101 breeds, covering 9.6% of the pig genome. This catalog includes 42,487 deletions, 37,913 mobile element insertions, 3308 duplications, 1664 inversions, and 45,184 break ends. Estimates of breed ancestry and hybridization using genotyped SVs align well with those from single nucleotide polymorphisms. Geographically stratified deletions are observed, along with known duplications of the KIT gene, responsible for white coat color in European pigs. Additionally, we identify a recent SINE element insertion in MYO5A transcripts of European pigs, potentially influencing alternative splicing patterns and coat color alterations. Furthermore, a Yorkshire-specific copy number gain within ABCG2 is found, impacting chromatin interactions and gene expression across multiple tissues over a stretch of genomic region of ~200 kb. Preliminary investigations into SV's impact on gene expression and traits using the Pig Genotype-Tissue Expression (PigGTEx) data reveal SV associations with regulatory variants and gene-trait pairs. For instance, a 51-bp deletion is linked to the lead eQTL of the lipid metabolism regulating gene FADS3, whose expression in embryo may affect loin muscle area, as revealed by our transcriptome-wide association studies. This SV catalog serves as a valuable resource for studying diversity, evolutionary history, and functional shaping of the pig genome by processes like domestication, trait-based breeding, and adaptive evolution. Show less
Cardiovascular disease (CVD) is the leading cause of death worldwide, and statin therapy is the cornerstone of atherosclerotic cardiovascular disease. However, clinical practice is unsatisfactory, and Show more
Cardiovascular disease (CVD) is the leading cause of death worldwide, and statin therapy is the cornerstone of atherosclerotic cardiovascular disease. However, clinical practice is unsatisfactory, and there is significant interest in the risk of residual cardiovascular events. Traditional study methods make it difficult to exclude the crosstalk of confounding factors, and we investigated the impact of the ApoB/ApoA1 ratio on CVD using two-sample Mendelian randomization (MR) and multivariate Mendelian randomization (MVMR) methods. Two-sample MR and MVMR analyses were performed using pooled statistics from genome-wide association studies (GWAS) of ApoB/ApoA1 ratio (BAR), lipoprotein (a) (Lp(a)), and triglyceride (TG) in Europeans to assess the causal relationship between BAR, Lp(a), and TG with coronary artery disease (CAD). The genetic prediction of BAR was significantly correlated with CAD (Inverse variance weighted (IVW) beta = 0.255; OR = 1.291; 95 % CI = 1.061-1.571; P = 0.011) in a two-sample MR analysis. MVMR studies showed that BAR (beta = 0.373; OR = 1.452; 95 % CI = 1.305-1.615; P = 7.217e-12), Lp (a) (beta = 0.238; OR = 1.269; 95 % CI = 1.216-1.323; P = 2.990e-28), and TG (beta = 0.155; OR = 1.168; 95 % CI = 1.074-1.270; P = 2.829e-04) were significantly associated with CAD. After further colinearity analyses of LASSO regressions, the results of multivariate analyses were similar for IVW, MR-Egger, MR-Lasso, and median methods. BAR is causally related to coronary artery disease. BAR is an independent predictor of CAD risk, independent of routine lipid measurements and other risk factors. TG and Lp(a) may be causally related to CAD, subject to verification in clinical practice. 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
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
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
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
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
Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia worldwide. Dysregulation of various metabolism pathways may mediate the development of AD pat Show more
Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia worldwide. Dysregulation of various metabolism pathways may mediate the development of AD pathology and cognitive dysfunction. Variants of triggering receptor expressed on myeloid cells-2 (TREM2) are known to increase the risk of developing AD. TREM2 plays a role in AD development by maintaining cellular energy and biosynthesis, but the precise mechanism through which it accomplishes this is unknown. Metabolomic analysis of hippocampal tissue from APP/PS1 and APP/PS1-TREM2 knockout (KO) mice found that TREM2 KO was associated with abnormalities in several metabolism pathways, and the effect was particularly pronounced in lipid metabolism and glucose metabolism pathways. Consistently, transcriptomic analysis of these mice determined that most differentially expressed genes were involved in energy metabolism pathways. We screened seven differentially expressed genes in APP/PS1-TREM2 KO mice that may influence AD development by altering energy metabolism. Integrative analysis of the metabolomic and transcriptomic profiles showed that TREM2 may regulate lipid metabolism and sphingolipid metabolism by affecting lipoprotein lipase (LPL) expression, thereby influencing AD progression. Our results prompt further studies of the interactions among TREM2, LPL, glucolipid metabolism, and sphingolipid metabolism in AD to identify new diagnostic and treatment strategies. Show less
In this study, we aimed to investigate the relationship between the intraocular levels of inflammatory factors and myopia-related retinal vascular and neuronal degeneration. One hundred and forty-seve Show more
In this study, we aimed to investigate the relationship between the intraocular levels of inflammatory factors and myopia-related retinal vascular and neuronal degeneration. One hundred and forty-seven patients with Implantable Collamer Lens (ICL) implantation were enrolled and all participants received comprehensive ophthalmic examination. About 100~150 ul of aqueous humor was collected immediately before ICL surgery. The levels of inflammatory factors including Aggrecan, April, BAFF, CCL5, CD163, Chi3l1, gp130, IL-6Rα, IL-8, IL-10, IL-11, IL-12, IL-19, IL-27, IL-28A, IL-34, IFN-β, IFN-γ, MMP-1, MMP-2, MMP-3 and PTX3 in the aqueous humor were measured using the Luminex Multiplexing system. Results showed that aqueous humor levels of pro-inflammatory factors Chi3l1, IL-6Rα, IL-8, IL-12, IL-27, inflammation-related cytokines April, BAFF and IL-34 progressively increased from the progression of myopic retinopathy. Conversely, the aqueous levels of IL-11 and Aggrecan gradually decreased from the progression of myopic retinopathy. Correlation analysis showed that the intraocular levels of Chi3l1, IL-6Rα, IL-8, IL-27 and BAFF were negatively correlated with retinal vascular density. The intraocular level of IL-6Rα was negatively correlated with retinal neuronal thickness. Protein-Protein Interaction (PPI) analysis revealed that Chi3l1 and Aggrecan were the upstream cytokines that affect IL-10 and IL-8 in the pathological myopic eyes. KEGG pathway analysis showed that cytokine-cytokine receptor interaction, JAK-STAT signaling pathway, rheumatoid arthritis, and chagas disease were influenced by these altered inflammatory factors (adjusted p-value<0.001). The production of inflammatory factors in the eyes of individuals with high myopia and pathological myopia was altered, and the elevated levels of intraocular pro-inflammatory factors such as Chi3l1, IL-6Rα, and IL-8 were closely associated with myopia-related retinal microvascular and neurodegeneration. Show less
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
The most common cause of death in patients with peripheral artery disease (PAD) are major adverse cardiovascular events (MACEs), including myocardial infarction (MI) and stroke. However, data on bioma Show more
The most common cause of death in patients with peripheral artery disease (PAD) are major adverse cardiovascular events (MACEs), including myocardial infarction (MI) and stroke. However, data on biomarkers that could be used to help predict MACEs in patients with PAD to guide clinical decision making is limited. Angiogenesis-related proteins have been demonstrated to play an important role in systemic atherosclerosis and may act as prognostic biomarkers for MACEs in patients with PAD. In this study, we evaluated a large panel of angiogenesis-related proteins and identified specific biomarkers associated with MACEs in patients with PAD. We conducted a prognostic study using a prospectively recruited cohort of 406 patients (254 with PAD and 152 without PAD). Plasma concentrations of 22 circulating angiogenesis-related proteins were measured at baseline, and the cohort was followed for 2 years. The primary outcome was 2-year MACEs (composite of MI, stroke, or death). Plasma protein concentrations were compared between PAD patients with and without 2-year MACEs using Mann-Whitney U tests. Differentially expressed proteins were further investigated in terms of their prognostic potential. Specifically, Cox proportional hazards analysis was performed to determine the independent association between differentially expressed proteins and 2-year MACEs, controlling for all baseline demographic and clinical characteristics, including existing coronary artery disease and cerebrovascular disease. Kaplan-Meier analysis was conducted to assess 2-year freedom from MACEs in patients with low vs. high levels of the differentially expressed proteins based on median plasma concentrations. The mean age of the cohort was 68.8 (SD 11.1), and 134 (33%) patients were female. Two-year MACEs occurred in 63 (16%) individuals. The following proteins were significantly elevated in PAD patients with 2-year MACEs compared to those without 2-year MACEs: endostatin (69.15 [SD 58.15] vs. 51.34 [SD 29.07] pg/mL, Among a panel of 22 angiogenesis-related proteins, endostatin, ANGPTL4, and ANGPTL3 were identified to be independently and specifically associated with 2-year MACEs in patients with PAD. Measurement of plasma concentrations of these proteins can support MACE risk stratification in patients with PAD, thereby informing clinical decisions on multidisciplinary referrals to cardiologists, neurologists, and vascular medicine specialists and guiding aggressiveness of medical treatment, thereby improving cardiovascular outcomes in patients with PAD. 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
To investigate the correlation of apolipoprotein B/A1 (Apo B/A1) ratio with hemodynamics and degree of hearing impairment in elderly patients with sudden sensorineural hearing loss (SSNHL). A total of Show more
To investigate the correlation of apolipoprotein B/A1 (Apo B/A1) ratio with hemodynamics and degree of hearing impairment in elderly patients with sudden sensorineural hearing loss (SSNHL). A total of 82 elderly patients with SSNHL diagnosed and treated in our hospital from July 2019 to September 2022 were retrospectively selected as the research group. The patients were divided into the mild group (22 cases), the moderate group (45 cases), and the severe group (15 cases) according to the degree of hearing impairment. 82 elderly people who underwent physical examination in our hospital during the same period were selected as the control group. The ApoB/A1 ratio and hemodynamic [whole blood low-shear viscosity (LSV), whole blood high-shear viscosity (HSV) and plasma viscosity (PV)] were measured in the two groups. The correlation of ApoB/A1 ratio with hemodynamics and degree of hearing impairment was analyzed. The predictive value of ApoB/A1 ratio and hemodynamics for the severity of SSNHL in elderly patients was analyzed. Compared with the control group, the ApoB/A1 ratio, and the levels of LSV, HSV and PV were higher in the research group ( The contents of ApoB/A1, HSV, LSV and PV were significantly increased in elderly patients with SSNHL, and their levels are significantly related to the degree of hearing impairment. The combined detection has high value in evaluating the severity of the disease. Show less
Tumour metabolic reprogramming is pivotal for tumour survival and proliferation. Investigating potential molecular mechanisms within the heterogeneous and clinically aggressive triple-negative breast Show more
Tumour metabolic reprogramming is pivotal for tumour survival and proliferation. Investigating potential molecular mechanisms within the heterogeneous and clinically aggressive triple-negative breast cancer (TNBC) subtype is essential to identifying novel therapeutic targets. Accordingly, we investigated the role of branched-chain α-keto acid dehydrogenase kinase (BCKDK) in promoting tumorigenesis in TNBC. We analysed The Cancer Genome Atlas dataset and immunohistochemically stained surgical specimens to investigate BCKDK expression and its prognostic implications in TNBC. The effects of BCKDK on tumorigenesis were assessed using cell viability, colony formation, apoptosis, and cell cycle assays, and subsequently validated in vivo. Metabolomic screening was performed via isotope tracer studies. The downstream target was confirmed using mass spectrometry and a co-immunoprecipitation experiment coupled with immunofluorescence analysis. Upstream transcription factors were also examined using chromatin immunoprecipitation and luciferase assays. BCKDK was upregulated in TNBC tumour tissues and associated with poor prognosis. BCKDK depletion led to reduced cell proliferation both in vitro and vivo. MYC-associated zinc finger protein (MAZ) was confirmed as the major transcription factor directly regulating BCKDK expression in TNBC. Mechanistically, BCKDK interacted with glucose-6-phosphate dehydrogenase (G6PD), leading to increased flux in the pentose phosphate pathway for macromolecule synthesis and detoxification of reactive oxygen species. Forced expression of G6PD rescued the growth defect in BCKDK-deficient cells. Notably, the small-molecule inhibitor of BCKDK, 3,6-dichlorobenzo(b)thiophene-2-carboxylic acid, exhibited anti-tumour effects in a patient-derived tumour xenograft model. Our findings hold significant promise for developing targeted therapies aimed at disrupting the MAZ/BCKDK/G6PD signalling pathway, offering potential advancements in treating TNBC through metabolic reprogramming. Show less
Glioblastoma, IDH-Wild type (GBM, CNS WHO Grade 4) is a highly heterogeneous and aggressive primary malignant brain tumor with high morbidity, high mortality, and poor patient prognosis. The global bu Show more
Glioblastoma, IDH-Wild type (GBM, CNS WHO Grade 4) is a highly heterogeneous and aggressive primary malignant brain tumor with high morbidity, high mortality, and poor patient prognosis. The global burden of GBM is increasing notably due to limited treatment options, drug delivery problems, and the lack of characteristic molecular targets. OTU deubiquitinase 4 (OTUD4) is a potential predictive factor for several cancers such as breast cancer, liver cancer, and lung cancer. However, its function in GBM remains unknown. In this study, we found that high expression of OTUD4 is positively associated with poor prognosis in GBM patients. Moreover, we provided in vitro and in vivo evidence that OTUD4 promotes the proliferation and invasion of GBM cells. Mechanism studies showed that, on the one hand, OTUD4 directly interacts with cyclin-dependent kinase 1 (CDK1) and stabilizes CDK1 by removing its K11, K29, and K33-linked polyubiquitination. On the other hand, OTUD4 binds to fibroblast growth factor receptor 1 (FGFR1) and reduces FGFR1's K6 and K27-linked polyubiquitination, thereby indirectly stabilizing CDK1, ultimately influencing the activation of the downstream MAPK signaling pathway. Collectively, our results revealed that OTUD4 promotes GBM progression via OTUD4-CDK1-MAPK axis, and may be a prospective therapeutic target for GBM treatment. Show less
Familial hypercholesterolemia (FH) is a genetically inherited disorder caused by monogenic mutations or polygenic deleterious variants. Patients with FH innate with significantly elevated risks for co Show more
Familial hypercholesterolemia (FH) is a genetically inherited disorder caused by monogenic mutations or polygenic deleterious variants. Patients with FH innate with significantly elevated risks for coronary heart disease (CHD). FH prevalence based on genetic testing in Chinese CHD patients is missing. Whether classical index of coronary atherosclerosis severity can be used as indicators of FH needs to be explored. To investigate the FH prevalence in Chinese CHD patients and the association of SYNTAX I score with FH genotype. The monogenic and polygenic FH related genes were genotyped in 400 consecutively enrolled CHD patients. The clinical characteristics and SYNTAX I scores were analyzed in a retrospective nested case-control study. The prevalence of genetically confirmed FH in our CHD cohort was 8.75%. The cLDL-C level, SYNTAX I scores and incidences of triple vessel lesions in FH patients were significantly higher, while cLDL-C and SYNTAX I scores were independent risk factors for FH. Furthermore, cLDL-C levels of polygenic FH were significantly lower than monogenic FH, while their severity of coronary atherosclerosis was comparable. Our study revealed that the SYNTAX I score was an independent risk factor for FH. Besides, polygenic origin of FH should be taken into consideration for CHD patients suspected of FH. Show less