👤 Sheng F Cai

The decidua plays a crucial role in providing structural and trophic support to the developing conceptus before placentation. Following embryo attachment, embryonic components intimately interact with the decidual tissue. While evidence indicates the participation of embryo-derived factors in crosstalk with the uterus, the extent of their impact on post-implantation decidual development requires further investigation. Here, we utilize transgenic mouse models to selectively eliminate primary trophoblast giant cells (pTGCs), the embryonic cells that interface with maternal tissue at the forefront. pTGC ablation impairs decidualization and compromises decidual interferon response and lipid metabolism. Mechanistically, pTGCs release factors such as interferon kappa (IFNK) to strengthen the decidual interferon response and lipoprotein lipase (LPL) to enhance lipid accumulation within the decidua, thereby promoting decidualization. This study presents genetic and metabolomic evidence reinforcing the proactive role of pTGC-derived factors in mobilizing maternal resources to strengthen decidualization, facilitating the normal progression of early pregnancy. Show less

MNDA (myeloid nuclear differentiation antigen) has been considered as a potential diagnostic marker for marginal zone lymphoma (MZL), but its utility in distinguishing MZL from other B-cell non-Hodgkin lymphomas (B-NHLs) and its clinicopathologic relevance in diffuse large B-cell lymphoma (DLBCL) are ambiguous. We comprehensively investigated MNDA expression in a large series of B-NHLs and evaluated its diagnostic value. MNDA expression in a cohort of 1293 cases of B-NHLs and 338  cases of reactive lymphoid hyperplasia (RLH) was determined using immunohistochemistry and compared among different types of B-NHL. The clinicopathologic relevance of MNDA in DLBCL was investigated. MNDA was highly expressed in MZLs (437/663, 65.9%), compared with the confined staining in marginal zone B-cells in RLH; whereas neoplastic cells with plasmacytic differentiation lost MNDA expression. MNDA expression was significantly higher in mantle cell lymphoma (MCL, 79.6%, p = 0.006), whereas lower in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL, 44.8%, p = 0.001) and lymphoplasmacytic lymphoma (LPL, 25%, p = 0.016), and dramatically lower in follicular lymphoma (FL, 5.2%, p < 0.001), compared with MZL. 29.6% (63/213) of DLBCLs were positive for MNDA. The cases in non-GCB group exhibited a higher rate of MNDA positivity (39.8%) compared to those in GCB group (16.3%) (p < 0.001), and MNDA staining was more frequently observed in DLBCLs with BCL2/MYC double-expression (50%) than those without BCL2/MYC double-expression (24.8%) (p = 0.001). Furthermore, there was a significant correlation between MNDA and CD5 expression in DLBCL (p = 0.036). MNDA was highly expressed in MZL with a potential utility in differential diagnosis between MZL and RLH as well as FL, whereas its value in distinguishing MZL from MCL, CLL/SLL is limited. In addition, MNDA expression in DLBCL was more frequently seen in the non-GCB group and the BCL2/MYC double-expression group, and demonstrated a correlation with CD5, which deserves further investigation. The clinical relevance of MNDA and its correlation with the prognosis of these lymphomas also warrant to be fully elucidated. Show less

The study aims to explore the relationship between lipoprotein lipase In total, 80 participants were involved in this study (54 patients with HLAP and 26 controls). All coding regions and intron-exon boundaries of the The rate of rare Detecting rare variants in 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. 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

Lipid metabolism plays an essential role in nervous system development. Cholesterol deficiency leads to a variety of neurodevelopmental disorders, such as autism spectrum disorder and fragile X syndrome. There have been a lot of efforts to search for biological markers associated with and causal to ADHD, among which lipid is one possible etiological factor that is quite widely studied. We aimed to evaluate the causal relationship between lipids traits, lipid-lowering drugs, and attention deficit hyperactivity disorder (ADHD) outcomes using Mendelian randomization (MR) studies. We used summary data from genome-wide association studies to explore the causal relationships between circulating lipid-related traits and ADHD. Then, quantitative trait loci for the expression of lipid-lowering drug target genes and genetic variants associated with lipid traits were extracted. Summary-data-based MR and inverse-variance-weighted MR (IVW-MR) were used to investigate the correlation between the expression of these drug-target genes and ADHD. After rigorous screening, 939 instrumental variables were finally included for univariable mendelian randomization analysis. However, there is no correlation between lipid profile and ADHD risk. Drug target analysis by IVW-MR method observed that Our results suggest that Show less

Inflammation and immune factors are the core of intervertebral disc degeneration (IDD), but the immune environment and epigenetic regulation process of IDD remain unclear. This study aims to identify immune-related diagnostic candidate genes for IDD, and search for potential pathogenesis and therapeutic targets for IDD. Gene expression datasets were obtained from the Gene Expression Omnibus (GEO). Differential expression immune genes (Imm-DEGs) were identified through weighted gene correlation network analysis (WGCNA) and linear models for microarray data analysis (Limma). LASSO algorithm was used to identify feature genes related to IDD, which were compared with core node genes in PPI network to obtain hub genes. Based on the coefficients of hub genes, a risk model was constructed, and the diagnostic value of hub genes was further evaluated through receiver operating characteristic (ROC) analysis. Xcell, an immunocyte analysis tool, was used to estimate the infiltration of immune cells. Finally, nucleus pulposus cells were co-cultured with macrophages to create an M1 macrophage immune inflammatory environment, and the changes of hub genes were verified. Combined with the results of WGCNA and Limma gene differential analysis, a total of 30 Imm-DEGs were identified. Imm-DEGs enriched in multiple pathways related to immunity and inflammation. LASSO algorithm identified 10 feature genes from Imm-DEGs that significantly affected IDD, and after comparison with core node genes in the PPI network of Imm-DEGs, 6 hub genes (NR1H3, SORT1, PTGDS, AGT, IRF1, TGFB2) were determined. Results of ROC curves and external dataset validation showed that the risk model constructed with the 6 hub genes had high diagnostic value for IDD. Immunocyte infiltration analysis showed the presence of various dysregulated immune cells in the degenerative nucleus pulposus tissue. In vitro experimental results showed that the gene expression of NR1H3, SORT1, PTGDS, IRF1, and TGFB2 in nucleus pulposus cells in the immune inflammatory environment was up-regulated, but the change of AGT was not significant. The hub genes NR1H3, SORT1, PTGDS, IRF1, and TGFB2 can be used as immunorelated biomarkers for IDD, and may be potential targets for immune regulation therapy for IDD. Show less

Allergic rhinitis (AR) resulted in impairing human health and quality of life seriously. There is currently no definitive remedy for AR. Recent studies have shown that autophagy may regulate airway inflammation. Our comprehension of autophagy and its molecular mechanism in the field of AR condition remains incomplete. Our research endeavors to bridge this knowledge deficit by investigating the correlation between AR and autophagy. The AR-related gene expression profile GSE50223 was screened and downloaded. The "limma" package of R software was utilized to identify differentially expressed genes associated with autophagy. GO, KEGG, and Gene set enrichment analyses were conducted. A PPI network of differentially expressed autophagy-related genes were established and further identified through the CytoHubba algorithm. A receiver operating characteristic curve analysis was employed to evaluate the diagnostic effectiveness of the hub genes and to examine the relationship between autophagy-related genes and AR. Finally, qRT-PCR was carried out to confirm the chosen autophagy-related genes using clinical samples. 21 autophagy-related genes in allergic rhinitis were identified. BECN1, PIK3C3, GABARAPL2, ULK2, and UVRAG were considered as significant differentially expressed autophagy-related genes. However, additional molecular biological experiments will be necessary to elucidate the underlying mechanism connecting autophagy and AR. Show less

The assessment of animal genetic structure had significant importance for the preservation and breeding of animal germplasm resources. Selection signals are genotype markers generated during the process of biological evolution, and the detection of selection signals could reveal the direction of species evolution. The aim of this study was to generate a whole-genome resequencing data from Jinding duck, Shanma duck, Youxian Partridge duck, and Taiwan Brown tsaiya duck to reveal their population structure and selection signals. The population structure analysis revealed significant genetic differences among the 4 indigenous laying ducks, indicating their independent lineage. Specifically, Shanma duck and Youxian partridge duck were closely and likely originated from a common ancestor. In addition, selection sweep analysis was performed using the population genetic differentiation coefficient (Fst) and nucleotide diversity ratio (π ratio). The top 5% was used as the threshold for the Fst and π ratio, and the 2 thresholds were combined to identify selected genomic regions. In the selected regions of the 3 comparison groups, 136, 143, and 268 candidate genes were detected. Further screening of all candidate genes revealed that 35 candidate genes appeared simultaneously in 3 comparative groups, with 16 genes annotated. The 16 genes were analyzed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. The results revealed 5 functional genes (AQP3, PIK3C3, NOL6, RPP25, and DCTN3) that may be related to important economic traits in laying ducks and involved mainly invasopressin-regulated water reabsorption, ribosome biogenesis, and the PI3K signaling pathway. The results provide insights into the protection and exploitation of genetic resources of Chinese indigenous laying ducks. Show less

The excessive activation of immune responses will trigger autoimmune diseases or inflammatory injury. The endosomal sorting complexes required for transport (ESCRT) system can capture and mediate ubiquitinated protein degradation, which timely terminates signaling pathway hyperactivation. However, whether the ESCRT system participates in regulating RIGI-like receptor (RLR)-mediated antiviral responses remains unknown. In this study, we show that LTN1/listerin, a major component of RQC, can recruit E3 ubiquitin ligase TRIM27 to trigger K63-linked polyubiquitination of RIGI and IFIH1/MDA5. This K63-linked polyubiquitination facilitates the sorting and degradation of RIGI and IFIH1 proteins through the ESCRT-dependent pathway. Concordantly, LTN1 deficiency enhances the innate antiviral response to infection with RNA viruses. Thus, our work uncovers a new mechanism for RIGI and IFIH1 degradation and identifies the role of LTN1 in negatively regulating RLR-mediated antiviral innate immunity, which may provide new targets for the intervention of viral infection. Show less

PP2A B55α, encoded by PPP2R2A, acts as a regulatory subunit of the serine/threonine phosphatase PP2A. Despite a frequent loss of heterozygosity of PPP2R2A in cases of non-small cell lung cancer (NSCLC), research on PP2A B55α's functions remains limited and controversial. To investigate the biological roles of PP2A B55α, we conducted bulk RNA-sequencing to assess the impact of PPP2R2A knockdown using two shRNAs in a NSCLC cell line. Gene set enrichment analysis (GSEA) of the RNA-sequencing data revealed significant enrichment of the epithelial-mesenchymal transition (EMT) pathway, with SNAI2 (the gene encoding Slug) emerging as one of the top candidates. Our findings demonstrate that PP2A B55α suppresses EMT, as PPP2R2A deficiency through knockdown or homozygous or hemizygous depletion promotes EMT and metastatic behavior in NSCLC cells, as evidenced by changes in EMT biomarkers, invasion and migration abilities, as well as metastasis in a tail vein assay. Mechanistically, PP2A B55α inhibits EMT by downregulating SNAI2 expression via the GSK3β-β-catenin pathway. Importantly, PPP2R2A deficiency also slows cell proliferation by disrupting DNA replication, particularly in PPP2R2A Show less

β-elemene has been observed to exert inhibitory effects on a multitude of tumors, primarily through multiple pathways such as the inhibition of cancer cell proliferation and the induction of apoptosis. The present study is designed to elucidate the role and underlying mechanisms of β-elemene in the therapeutic intervention of non-small cell lung cancer (NSCLC). Both Show less

Glucose-dependent insulinotropic polypeptide receptor (GIPR) is a potential drug target for metabolic disorders. It works with glucagon-like peptide-1 receptor and glucagon receptor in humans to maintain glucose homeostasis. Unlike the other two receptors, GIPR has at least 13 reported splice variants (SVs), more than half of which have sequence variations at either C or N terminus. To explore their roles in endogenous peptide-mediated GIPR signaling, we determined the cryoelectron microscopy (cryo-EM) structures of the two N terminus-altered SVs (referred as GIPR-202 and GIPR-209 in the Ensembl database, SV1 and SV2 here, respectively) and investigated the outcome of coexpressing each of them in question with GIPR in HEK293T cells with respect to ligand binding, receptor expression, cAMP (adenosine 3,5-cyclic monophosphate) accumulation, β-arrestin recruitment, and cell surface localization. It was found that while both N terminus-altered SVs of GIPR neither bound to the hormone nor elicited signal transduction per se, they suppressed ligand binding and cAMP accumulation of GIPR. Meanwhile, SV1 reduced GIPR-mediated β-arrestin 2 responses. The cryo-EM structures of SV1 and SV2 showed that they reorganized the extracellular halves of transmembrane helices 1, 6, and 7 and extracellular loops 2 and 3 to adopt a ligand-binding pocket-occupied conformation, thereby losing binding ability to the peptide. The results suggest a form of signal bias that is constitutive and ligand-independent, thus expanding our knowledge of biased signaling beyond pharmacological manipulation (i.e., ligand specific) as well as constitutive and ligand-independent (e.g., SV1 of the growth hormone-releasing hormone receptor). Show less

The melanocortin pathway is well established to be critical for body-weight regulation in both rodents and humans. Despite extensive studies focusing on this pathway, the downstream brain sites that mediate its action are not clear. Here, we found that, among the known paraventricular hypothalamic (PVH) neuron groups, those expressing melanocortin receptors 4 (PVH Show less

The melanocortin action is well perceived for its ability to regulate body weight bidirectionally with its gain of function reducing body weight and loss of function promoting obesity. However, this notion cannot explain the difficulty in identifying effective therapeutics toward treating general obesity via activation of the melanocortin action. Here, we provide evidence that altered melanocortin action is only able to cause one-directional obesity development. We demonstrate that chronic inhibition of arcuate neurons expressing proopiomelanocortin (POMC) or paraventricular hypothalamic neurons expressing melanocortin receptor 4 (MC4R) causes massive obesity. However, chronic activation of these neuronal populations failed to reduce body weight. Furthermore, gain of function of the melanocortin action through overexpression of MC4R, POMC or its derived peptides had little effect on obesity prevention or reversal. These results reveal a bias of the melanocortin action towards protection of weight loss and provide a neural basis behind the well-known, but mechanistically ill-defined, predisposition to obesity development. Show less

Locally advanced and metastatic pancreatic cancer (PC) frequently grows in adipose tissue and has a poor prognosis. Although adipose tissue is largely composed of adipocytes, the mechanisms by which adipocytes impact PC are poorly understood. Using an Show less

Diabetic retinopathy (DR) is a common complication in patients with diabetes, and proliferative DR (PDR) has become an important cause of blindness; however, the mechanisms involved have not been fully elucidated. miRNAs and long noncoding RNAs can play an important role in DR, and they can accurately regulate the expression of target genes through a new regulatory model: competing endogenous RNAs. We isolated total RNA of extracellular vesicles (EVs) in the serum of healthy individuals and individuals with diabetes without DR, non-PDR, or PDR, and performed deep sequencing. We found aberrantly low expression of PPT2-EGFL8 and significantly increased level of miR-423-5p. PPT2-EGFL8 adsorbs miR-423-5p as a molecular sponge and inhibits hypoxia-induced human retinal microvascular endothelial cells proliferation. In an oxygen-induced retinopathy (OIR) model and a streptozotocin-induced diabetes model, Egfl8-overexpression treatment reduces diabetes-related reactive gliosis, inflammation, and acellular capillaries and attenuates the development of pathological neovascularization. In addition, PPT2-EGFL8 targeting miR-423-5p plays an important role in hypoxia-induced peroxisome proliferator-activated receptor-β/δ (PPARD)/angiopoietin-like 4 (ANGPTL4) signaling activation, especially the expression of the C-terminal ANGPTL4 fragment. Finally, ANGPTL4 significantly induces retinal vessel breakage in the inner limiting membrane and facilitates retinal vessel sprouting into the vitreous in the OIR mice. Thus, either new biomarkers or new therapeutic targets may be identified with translation of these findings. Show less

Myocardial infarction (MI) is a major cause of death and disability worldwide, but current treatments are limited by their invasiveness, side effects, and lack of efficacy. Novel drug targets for MI prevention are urgently needed. In this study, we used Mendelian randomization to identify potential therapeutic targets for MI using plasma protein quantitative trait loci as exposure variables and MI as the outcome variable. We further validated our findings using reverse causation analysis, Bayesian co-localization analysis, and external datasets. We also constructed a protein-protein interaction network to explore the relationships between the identified proteins and known MI targets. Our analysis revealed 2 proteins, LPA and APOA5, as potential drug targets for MI, with causal effects on MI risk confirmed by multiple lines of evidence. LPA and APOA5 are involved in lipid metabolism and interact with target proteins of current MI medications. We also found 4 other proteins, IL1RN, FN1, NT5C, and SEMA3C, that may have potential as drug targets but require further confirmation. Our study demonstrates the utility of Mendelian randomization and protein quantitative trait loci in discovering novel drug targets for complex diseases such as MI. It provides insights into the underlying mechanisms of MI pathology and treatment. Show less

As one of the prevalent tumors worldwide, gastric cancer (GC) has obtained sufficient attention in its clinical management and prognostic stratification. Senescence-related genes are involved in the tumorigenesis and progression of GC. A machine learning algorithm-based prognostic signature was developed from six senescence-related genes including Show less

Exploring the potential lead compounds for Alzheimer's disease (AD) remains one of the challenging tasks. Here, we report that the plant extract conophylline (CNP) impeded amyloidogenesis by preferentially inhibiting BACE1 translation via the 5' untranslated region (5'UTR) and rescued cognitive decline in an animal model of APP/PS1 mice. ADP-ribosylation factor-like protein 6-interacting protein 1 (ARL6IP1) was then found to mediate the effect of CNP on BACE1 translation, amyloidogenesis, glial activation, and cognitive function. Through analysis of the 5'UTR-targetd RNA-binding proteins by RNA pulldown combined with LC-MS/MS, we found that FMR1 autosomal homolog 1 (FXR1) interacted with ARL6IP1 and mediated CNP-induced reduction of BACE1 by regulating the 5'UTR activity. Without altering the protein levels of ARL6IP1 and FXR1, CNP treatment promoted ARL6IP1 interaction with FXR1 and inhibited FXR1 binding to the 5'UTR both in vitro and in vivo. Collectively, CNP exhibited a therapeutic potential for AD via ARL6IP1. Through pharmacological manipulation, we uncovered a dynamic interaction between FXR1 and the 5'UTR in translational control of BACE1, adding to the understanding of the pathophysiology of AD. Show less

Dementia is the main clinical feature of Alzheimer's disease (AD). Orexin has recently been linked to AD pathogenesis, and exogenous orexin-A (OXA) aggravates spatial memory impairment in APP/PS1 mice. However, the effects of OXA on other types of cognitive deficits, especially in 3xTg-AD mice exhibiting both plaque and tangle pathologies, have not been reported. Furthermore, the potential electrophysiological mechanism by which OXA affects cognitive deficits and the molecular mechanism by which OXA increases amyloid β (Aβ) levels are unknown. In the present study, the effects of OXA on cognitive functions, synaptic plasticity, Aβ levels, tau hyperphosphorylation, BACE1 and NEP expression, and circadian locomotor rhythm were evaluated. The results showed that OXA aggravated memory impairments and circadian rhythm disturbance, exacerbated hippocampal LTP depression, and increased Aβ and tau pathologies in 3xTg-AD mice by affecting BACE1 and NEP expression. These results indicated that OXA aggravates cognitive deficits and hippocampal synaptic plasticity impairment in 3xTg-AD mice by increasing Aβ production and decreasing Aβ clearance through disruption of the circadian rhythm and sleep-wake cycle. Show less

Ischemia stroke is thought to be one of the vascular risks associated with neurodegenerative diseases, such as Alzheimer's disease (AD). Hydroxysafflor yellow A (HSYA) has been reported to protect against stroke and AD, while the underlying mechanism remains unclear. In this study, SH-SY5Y cell model treated with oxygen-glucose deprivation/reperfusion (OGD/R) was used to explore the potential mechanism of HSYA. Results from cell counting kit-8 (CCK-8) showed that 10 μM HSYA restored the cell viability after OGD 2 hours/R 24 hours. HSYA reduced the levels of malondialdehyde and reactive oxygen species, while improved the levels of superoxide dismutase and glutathione peroxidase. Furthermore, apoptosis was inhibited, and the expression of brain-derived neurotrophic factor was improved after HSYA treatment. In addition, the expression levels of amyloid-β peptides (Aβ) and BACE1 were decreased by HSYA, as well as the expression levels of binding immunoglobulin heavy chain protein, PKR-like endoplasmic reticulum (ER) kinase pathway, and activating transcription factor 6 pathway, whereas the expression level of protein disulfide isomerase was increased. Based on these results, HSYA might reduce Aβ toxicity after OGD/R by interfering with apoptosis, oxidation, and neurotrophic factors, as well as relieving ER stress. Show less

Necroptosis plays an essential role in oncogenesis and tumor progression in hepatocellular carcinoma (HCC). This study aimed to investigate the role of necroptosis in the development and progression of HCC. Specifically, we constructed a prognostic prediction model using necroptosis-associated genes (NAGs) to predict patient outcomes. Using data from The Cancer Genome Atlas (TCGA) database, we analyzed gene expression and clinical data. We identified a 5-gene model associated with NAGs and explored genetic features and immune cell infiltration using the CIBERSORT algorithm. In addition, we conducted single-cell RNA sequencing to investigate the potential role of necroptosis in HCC. We constructed a 5-gene prognostic model based on NAGs that demonstrated excellent predictive accuracy in both training and validation sets. Using multifactorial cox regression analysis, we confirmed the risk score derived from the model as an independent predictor of prognosis, surpassing other clinical characteristics. Patients with high risk scores had significantly worse prognosis than those with low risk scores. To enhance the clinical utility of the necroptosis score, we constructed an accurate nomogram. Additionally, we compared metabolic pathway and immune microenvironment differences between HCC tumors with high and low risk scores. Our single-cell RNA sequencing analyses revealed that necroptosis in HCC was primarily associated with a specific subset of macrophages. Our study revealed the presence of two distinct necroptosis subtypes in HCC and developed a robust prognostic model with exceptional predictive accuracy. We observed significantly higher infiltration of M0 macrophages in the high-risk group. We propose that rescuing cytochrome c metabolism in HCC could serve as a potential therapeutic strategy. Furthermore, at a single-cell resolution, our analysis identified myeloid cells as the primary cells exhibiting necroptosis. Specifically, macrophages expressing CD5L, CETP, and MARCO, which may belong to a subset of tissue-resident macrophages, were found to be highly susceptible to necroptosis. These findings suggest the involvement of this specific macrophage subset in potential antitumor therapies. Our study provides novel insights into predicting patient prognosis and developing personalized therapeutic approaches for HCC. Show less

Metabolic pathways are related to physiological functions and disease states and are influenced by genetic variation and environmental factors. Hispanics/Latino individuals have ancestry-derived genomic regions (local ancestry) from their recent admixture that have been less characterized for associations with metabolite abundance and disease risk. We performed admixture mapping of 640 circulating metabolites in 3887 Hispanic/Latino individuals from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). Metabolites were quantified in fasting serum through non-targeted mass spectrometry (MS) analysis using ultra-performance liquid chromatography-MS/MS. Replication was performed in 1856 nonoverlapping HCHS/SOL participants with metabolomic data. By leveraging local ancestry, this study identified significant ancestry-enriched associations for 78 circulating metabolites at 484 independent regions, including 116 novel metabolite-genomic region associations that replicated in an independent sample. Among the main findings, we identified Native American enriched genomic regions at chromosomes 11 and 15, mapping to FADS1/FADS2 and LIPC, respectively, associated with reduced long-chain polyunsaturated fatty acid metabolites implicated in metabolic and inflammatory pathways. An African-derived genomic region at chromosome 2 was associated with N-acetylated amino acid metabolites. This region, mapped to ALMS1, is associated with chronic kidney disease, a disease that disproportionately burdens individuals of African descent. Our findings provide important insights into differences in metabolite quantities related to ancestry in admixed populations including metabolites related to regulation of lipid polyunsaturated fatty acids and N-acetylated amino acids, which may have implications for common diseases in populations. Show less

Lung adenocarcinoma is the most common type of lung cancer. Known risk variants explain only a small fraction of lung adenocarcinoma heritability. Here, we conducted a two-stage genome-wide association study of lung adenocarcinoma of East Asian ancestry (21,658 cases and 150,676 controls; 54.5% never-smokers) and identified 12 novel susceptibility variants, bringing the total number to 28 at 25 independent loci. Transcriptome-wide association analyses together with colocalization studies using a Taiwanese lung expression quantitative trait loci dataset (n = 115) identified novel candidate genes, including FADS1 at 11q12 and ELF5 at 11p13. In a multi-ancestry meta-analysis of East Asian and European studies, four loci were identified at 2p11, 4q32, 16q23, and 18q12. At the same time, most of our findings in East Asian populations showed no evidence of association in European populations. In our studies drawn from East Asian populations, a polygenic risk score based on the 25 loci had a stronger association in never-smokers vs. individuals with a history of smoking (P Show less

Prostate cancer is the most common malignant tumor of male urogenital system that occurs in prostate epithelium. However, relationship between CAV1 and KRT5 and prostate cancer remains unclear. The prostate cancer datasets GSE114740 and GSE200879 were downloaded from Gene Expression Omnibus generated by GPL11154 and GPL32170. De-batch processing was performed, differentially expressed genes (DEGs) were screened, and weighted gene co-expression network analysis. The construction and analysis of protein-protein interaction network, functional enrichment analysis, gene set enrichment analysis. Gene expression heat map was drawn and immune infiltration analysis was performed. Comparative toxicogenomics database analysis were performed to find the disease most related to core gene. In addition, the cell experiment was performed to verify the role of CAV1 and KRT5 by western blot. Divided into 4 groups: control, prostate cancer, prostate cancer-over expression, and prostate cancer- knock out. TargetScan screened miRNAs that regulated central DEGs; 770 DEGs were identified. According to Gene Ontology analysis, they were mainly concentrated in actin binding and G protein coupled receptor binding. In Kyoto Encyclopedia of Gene and Genome analysis, they were mainly concentrated in PI3K-Akt signal pathway, MAPK signal pathway, and ErbB signal pathway. The intersection of enrichment terms of differentially expressed genes and GOKEGG enrichment terms was mainly concentrated in ErbB signaling pathway and MAPK signaling pathway. Three important modules were generated. The protein-protein interaction network obtained 8 core genes (CAV1, BDNF, TGFB3, FGFR1, PRKCA, DLG4, SNAI2, KRT5). Heat map of gene expression showed that core genes (CAV1, TGFB3, FGFR1, SNAI2, KRT5) are highly expressed in prostate cancer tissues and low in normal tissues. Comparative toxicogenomics database analysis showed that core genes (CAV1, TGFB3, FGFR1, SNAI2, KRT5) were associated with prostate tumor, cancer, tumor metastasis, necrosis, and inflammation. CAV1 and KRT5 are up-regulated in prostate cancer. CAV1 and KRT5 are highly expressed in prostate cancer. The higher expression of CAV1 and KRT5, the worse prognosis. Show less

The mechanism by which aerobic exercise promotes cardiac function after myocardial infarction (MI) is still not fully understand. In this study, we investigated the role of fibroblast growth factor 21 (FGF21) in exercise protecting the cardiac function of MI mice. In vivo, MI was induced by left anterior descending coronary artery ligation in wild-type and Show less