👤 Chunhua Fan

Acute aortic dissection (AAD) is a life-threatening cardiovascular disease. Recent studies have shown that DNA methylation may be associated with the pathological mechanism of AAD, but the panorama of DNA methylation needs to be explored. DNA methylation patterns were screened using Infinium Human Methylation 450 K BeadChip in the aortic tissues from 4 patients with Stanford-A AAD and 4 controls. Gene enrichment was analyzed by Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and gene ontology (GO). DNA methylation levels of candidate genes were determined by pyrosequencing in the replication cohort including 16 patients with AAD and 7 controls. Protein expression level of candidate gene was assessed by Western blot. A total of 589 differentially methylated positions including 315 hypomethylated and 274 hypermethylated positions were found in AAD group. KEGG analysis demonstrated that differentially methylated position-associated genes were enriched in MAPK signaling pathway, TNF signaling pathway and apoptosis pathway, et al. GO analysis demonstrated that differentially methylated position-associated genes were enriched in protein binding, angiogenesis and heart development et al. The differential DNA methylation in five key genes, including Fas, ANGPT2, DUSP6, FARP1 and CARD6, was authenticated in the independent replication cohort. The protein expression level of the Fas was increased by 1.78 times, indicating the possible role of DNA methylation in regulation of gene expression. DNA methylation was markedly changed in the aortic tissues of Stanford-A AAD and associated with gene dysregulation, involved in AAD progression. Show less

A better understanding of the biological and environmental variables that contribute to exceptional longevity has the potential to inform the treatment of geriatric diseases and help achieve healthy aging. Here, we compared the gut microbiome and blood metabolome of extremely long-lived individuals (94-105 years old) to that of their children (50-79 years old) in 116 Han Chinese families. We found extensive metagenomic and metabolomic remodeling in advanced age and observed a generational divergence in the correlations with socioeconomic factors. An analysis of quantitative trait loci revealed that genetic associations with metagenomic and metabolomic features were largely generation-specific, but we also found 131 plasma metabolic quantitative trait loci associations that were cross-generational with the genetic variants concentrated in six loci. These included associations between FADS1/2 and arachidonate, PTPA and succinylcarnitine and FLVCR1 and choline. Our characterization of the extensive metagenomic and metabolomic remodeling that occurs in people reaching extreme ages may offer new targets for aging-related interventions. Show less

The single nucleotide polymorphisms (SNPs) in the fatty acid desaturases and elongases might associate with the endogenous synthesis of polyunsaturated fatty acids (PUFAs). However, the related epidemiological evidence is still conflicting. So we aimed to clearly evaluate the interactions between maternal DHA-rich n-3 PUFAs supplementation and the known 26 SNPs on the profiles of PUFAs in the colostrum using a Chinese birth cohort. Totally, 1050 healthy mother-infant pairs were enrolled in this study at gestational 6-8 weeks when they established their pregnancy files at Fuxing Hospital affiliated to Capital Medical University in Beijing from January to December 2018. Meanwhile, their venous blood samples were obtained for DNA extraction to detect the genotypes of SNPs in the Fads1, Fads2, Fads3, Elovl2 and Elovl5 using the Matrix-Assisted Laser Desorption Ionization Time of Flight Mass Spectrometry. Then the colostrum samples were collected to determine the profiles of PUFAs by gas chromatography. Maternal DHA-rich n-3 PUFAs supplementation from the early and middle pregnancy could reduce the infant BMI at birth, and impact the profiles of PUFAs in the colostrum, as higher n-3 PUFAs (EPA, DHA, DHA/ALA and DHA/EPA), lower n-6 PUFAs (AA and AA/LA) and ∑-6/n-3ΣPUFAs. Moreover, there were significant correlations between multiple SNPs and the profiles of n-6 PUFAs (rs76996928 for LA, rs174550, rs174553 and rs174609 for AA, rs174550 and rs76996928 for AA/LA) and n-3 PUFAs in the colostrum (rs174448, rs174537, rs174550, rs174553, rs174598, rs3168072, rs174455 and rs174464 for ALA, rs174550, rs174553 and rs174598 for EPA, rs174455 and rs174464 for DHA, rs174448 and rs3168072 for DHA/EPA) using the multiple linear regressions by adjusting the maternal age, gestational week, mode of delivery, infant sex and BMI at birth, and all these above significant SNPs had the cumulative effects on the profiles of PUFAs. Furthermore, the pairwise comparisons also showed the meaningful interactions between maternal DHA-rich n-3 PUFAs supplementation and related genotypes of SNPs (rs76996928 for LA, rs174598 for EPA, rs174448 for DHA and DHA/EPA) on the contents of PUFAs in the colostrum. Results from this birth cohort study proved that the pregnant women with the following SNPs such as Fads3 rs174455 T, Fads3 rs174464 A and Fads1 rs174448 G alleles should pay more attention on their exogenous DHA supplementation from the early and middle pregnancy for the blocked endogenous synthesis. This study was approved by the Ethics Committee of Beijing Pediatric Research Institution, Beijing Children's Hospital affiliated to Capital Medical University (2016-08), which was also registered at the website of http://www.chictr.org.cn/showproj.aspx?proj=4673 (No: ChiCTR-OCH-14004900). Show less

In recent years, abnormal endoplasmic reticulum stress (ERS) response, as an important regulator of immunity, may play a vital role in the occurrence, development, and treatment of glioma. Weighted correlation network analysis (WGCNA) based on six glioma datasets was used to screen eight prognostic-related differentially expressed ERS-related genes (PR-DE-ERSGs) and to construct a prognostic model. BMP2 and HEY2 were identified as protective factors (HR < 1), and NUP107, DRAM1, F2R, PXDN, RNF19A, and SCG5 were identified as risk factors for glioma (HR > 1). QRT-PCR further supported significantly higher DRAM1 and lower SCG5 relative mRNA expression in gliomas. Our model has demonstrated excellent performance in predicting the prognosis of glioma patients from numerous datasets. In addition, the model shows good stability in multiple tests. Our model also shows broad clinical promise in predicting drug treatment effects. More immune cells/processes in the high-risk population with poor prognosis illustrate the importance of the tumor immunosuppressive environment in glioma. The potential role of the HEY2-based competitive endogenous RNA (ceRNA) regulatory network in glioma was validated and revealed the possible important role of glycolysis in glioma ERS. IDH1 and TP53 mutations with better prognosis were strongly associated with the risk score and PR-DE-ERSGs expression in the model. mDNAsi was also closely related to the risk score and clinical characteristics. Show less

To investigate the correlation between interleukin-27 and CXCL10 and other cytokines in pulmonary tuberculosis and to further explore the related miRNAs through bioinformatics. Collect the lesion tissue and peripheral blood of pulmonary tuberculosis patients and the peripheral blood of healthy controls. Immunohistochemical staining and qRT-PCR were used to observe the expression of interleukin-27, CXCL9, CXCL10, and CXCL11. Then, predict the key miRNA, qRT-PCR was used to verify the expression of miRNA in the peripheral blood and evaluated the correlation between them. Both immunohistochemical staining and qRT-PCR indicated that the expressions of IL-27, CXCL9, CXCL10, and CXCL11 were significantly increased in tuberculosis patients, and IL-27 was significantly correlated with CXCL10 ( Our data shows that interleukin-27 and CXCL10 are significantly related in pulmonary tuberculosis, and has-let-7b-5p and has-miR-30a-3p are also related to interleukin-27 and CXCL10. It laid the foundation for subsequently exploiting the potential biomarkers in tuberculosis disease. Show less

Remyelination is a refractory feature of demyelinating diseases such as multiple sclerosis (MS). Studies have shown that promoting oligodendrocyte precursor cell (OPC) differentiation, which cannot be achieved by currently available therapeutic agents, is the key to enhancing remyelination. Bu Shen Yi Sui capsule (BSYSC) is a traditional Chinese herbal medicine over many years of clinical practice. We have found that BSYSC can effectively treat MS. In this study, the effects of BSYSC in promoting OPCs differentiation and remyelination were assessed using an experimental autoimmune encephalomyelitis (EAE) model in vivo and cultured OPCs in vitro. The results showed that BSYSC reduced clinical function scores and increased neuroprotection. The expression of platelet-derived growth factor receptor Show less

Resistance to gefitinib remains a major obstacle for the successful treatment of non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations. In this paper, we studied the precise actions of circular RNA (circRNA) microtubule actin crosslinking factor 1 (circ_MACF1) in gefitinib resistance. We established gefitinib-resistant NSCLC cells (PC9/GR and A549/GR). The levels of circ_MACF1, microRNA (miR)-942-5p, and transforming growth factor beta receptor 2 (TGFBR2) were gauged by quantitative real-time PCR (qRT-PCR) or western blot. Subcellular fractionation and Ribonuclease R (RNase R) assays were done to characterize circ_MACF1. Cell survival, proliferation, colony formation, apoptosis, migration, and invasion were detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), 5-Ethynyl-2'-Deoxyuridine (EdU), colony formation, flow cytometry, and transwell assays, respectively. Dual-luciferase reporter assays were used to verify the direct relationship between miR-942-5p and circ_MACF1 or TGFBR2. The xenograft assays were used to assess the role of circ_MACF1 in vivo. Circ_MACF1 was down-regulated in A549/GR and PC9/GR cells. Overexpression of circ_MACF1 repressed proliferation, migration, invasion, and promoted apoptosis and gefitinib sensitivity of A549/GR and PC9/GR cells in vitro, as well as inhibited tumor growth under gefitinib in vivo. Circ_MACF1 directly targeted miR-942-5p, and miR-942-5p mediated the regulatory effects of circ_MACF1. TGFBR2 was identified as a direct and functional target of miR-942-5p. Circ_MACF1 modulated TGFBR2 expression through miR-942-5p. Our findings demonstrated that circ_MACF1 regulated cell functional behaviors and gefitinib sensitivity of A549/GR and PC9/GR cells at least partially by targeting miR-942-5p to induce TGFBR2 expression. Show less

The nuclear receptors liver X receptor (LXR) α and β play crucial roles in hepatic metabolism. Many genes induced in response to pharmacologic LXR agonism have been defined; however, the transcriptional consequences of loss of LXR binding to its genomic targets are less well characterized. Here, we addressed how deletion of both LXRα and LXRβ from mouse liver (LXR double knockout [DKO]) affects the transcriptional regulatory landscape by integrating changes in LXR binding, chromatin accessibility, and gene expression. Many genes involved in fatty acid metabolism showed reduced expression and chromatin accessibility at their intergenic and intronic regions in LXRDKO livers. Genes that were up-regulated with LXR deletion had increased chromatin accessibility at their promoter regions and were enriched for functions not linked to lipid metabolism. Loss of LXR binding in liver reduced the activity of a broad set of hepatic transcription factors, inferred through changes in motif accessibility. By contrast, accessibility at promoter nuclear factor Y (NF-Y) motifs was increased in the absence of LXR. Unexpectedly, we also defined a small set of LXR targets for direct ligand-dependent repression. These genes have LXR-binding sites but showed increased expression in LXRDKO liver and reduced expression in response to the LXR agonist. In summary, the binding of LXRs to the hepatic genome has broad effects on the transcriptional landscape that extend beyond its canonical function as an activator of lipid metabolic genes. Show less

To investigate the differential expression gene modules and hub genes associated with Alzheimer's disease (AD) by weighted gene co-expression network analysis (WGCNA) and annotate the biological functions of these modules. We downloaded transcriptome sequencing data from the GEO database, and according to the correlation of the genes, a gene co-expression network was constructed with the parameter setting of β=8 and a correlation coefficient threshold of 0.85. Pearson correlation test was used to calculate the correlation between the module genes and clinical traits to screen the gene modules significantly associated with AD and identify the hub genes according to the connectivity within modules. GO functional enrichment analysis and KEGG pathway analysis were used to annotate the functions of the modules. A cell model of AD was established in SH-SY5Y cells by Aβ1-42 treatment, and the mRNA expression levels of the hub genes were compared between the Aβ1-42-treated cells and the control cells. Ten gene co-expression modules were constructed based on the correlations of gene expression, in which the brown ( The brown and turquoise modules are closely correlated with AD. The hub genes including MTSS1L, GMPR2, ACP2, ACTG1 and LANCL2 selected from the modules may participate in AD pathogenesis by regulating DNA damage and repair. Show less

The apextrin C-terminal (ApeC) domain is a class of newly discovered protein domains with an origin dating back to prokaryotes. ApeC-containing proteins (ACPs) have been found in various marine and aquatic invertebrates, but their functions and the underlying mechanisms are largely unknown. Early studies suggested that amphioxus ACP1 and ACP2 bind to bacterial cell walls and have a role in immunity. Here we identified another two amphioxus ACPs (ACP3 and ACP5), which belong to the same phylogenetic clade with ACP1/2, but show distinct expression patterns and sequence divergence (40-50% sequence identities). Both ACP3 and ACP5 were mainly expressed in the intestine and hepatic cecum, and could be up-regulated after bacterial challenge. Both prokaryotic-expressed recombinant ACP3 and ACP5 could bind with several species of bacteria and yeasts, showing agglutinating activity but no microbicidal activity. ELISA assays suggested that their ApeC domains could interact with peptidoglycan (PGN), but not with lipoteichoic acid (LTA), lipopolysaccharides (LPS) and zymosan A. Furthermore, they can only bind to Lys-type PGN from Show less

Anti-inflammatory therapies have the potential to become an effective treatment for obesity-related diseases. However, the huge gap of immune system between human and rodent leads to limitations of drug discovery. This work aims at constructing a transgenic pig model with higher risk of metabolic diseases and outlining the immune responses at the early stage of metaflammation by transcriptomic strategy. We used CRISPR/Cas9 techniques to targeted knock-in three humanized disease risk genes, Show less

Melanocortin-3 receptor (MC3R) is a regulator of energy homeostasis, and interaction of MC3R and melanocortin-2 receptor accessory protein 2 (MRAP2) plays a critical role in MC3R signaling of mammals. However, the physiological roles of MC3R in teleosts are not well understood. In this study, qRT-PCR was used to measure gene expression. Radioligand binding assay was used to study the binding properties of topmouth culter MC3R (caMC3R). Intracellular cAMP generation was determined by RIA, and caMC3R expression was quantified with flow cytometry. We showed that culter mc3r had higher expression in the CNS. All agonists could bind and stimulate caMC3R to increase dose dependently intracellular cAMP accumulation. Compared to human MC3R, culter MC3R showed higher constitutive activity, higher efficacies, and Rmax to alpha-melanocyte-stimulating hormone (α-MSH), des-α-MSH, and adrenocorticotrophic hormone. Both caMRAP2a and caMRAP2b markedly decreased caMC3R basal cAMP production. However, only caMRAP2a significantly decreased cell surface expression, Bmax, and Rmax of caMC3R. Expression analysis suggested that MRAP2a and MRAP2b might be more important in regulating MC3R/MC4R signaling during larval period, and reduced mc3r, mc4r, and pomc expression might be primarily involved in modulation of MC3R/MC4R in adults. These data indicated that the cloned caMC3R was a functional receptor. MRAP2a and MRAP2b had different effects on expression and signaling of caMC3R. In addition, expression analysis suggested that MRAP2s, receptors, and hormones might play different roles in regulating culter development and growth. Show less

To explore susceptibility genes and pathways for non-syndromic cleft lip with or without cleft palate (NSCL/P). Two genome-wide association studies (GWAS) datasets, including 858 NSCL/P cases and 1,248 controls, were integrated with expression quantitative trait loci (eQTL) dataset identified by Genotype-Tissue Expression (GTEx) project in whole-blood samples. The expression of the candidate genes in mouse orofacial development was inquired from FaceBase. Protein-protein interaction (PPI) network was visualized to identify protein functions. Go and KEGG pathway analyses were performed to explore the underlying risk pathways. A total of 233 eQTL single-nucleotide polymorphisms (SNPs) in 432 candidate genes were identified to be associated with the risk of NSCL/P. One hundred and eighty-three susceptible genes were expressed in mouse orofacial development according to FaceBase. PPI network analysis highlighted that these genes involved in ubiquitin-mediated proteolysis (KCTD7, ASB1, UBOX5, ANAPC4) and DNA synthesis (XRCC3, RFC3, KAT5, RHNO1) were associated with the risk of NSCL/P. GO and KEGG pathway analyses revealed that the fatty acid metabolism pathway (ACADL, HSD17B12, ACSL5, PPT1, MCAT) played an important role in the development of NSCL/P. Our results identified novel susceptibility genes and pathways associated with the development of NSCL/P. Show less

We investigated the role of ANGPTL3 and ANGPTL4 in atherosclerosis development and determined whether plasma concentrations of ANGPTL3 and ANGPTL4 are related to the degree of coronary stenosis. A total of 305 consecutive patients with angina who underwent diagnostic coronary angiography were enrolled in the study between August 2017 and August 2018. The levels of ANGPTL3 and ANGPTL4 were measured by using competitive ELISA kits. According to the degree of coronary artery stenosis, patients were classified into four types: coronary artery stenosis of < 10%, 10-50%, 50-75, and > 75%. The plasma ANGPTL3 level was higher (51.71 ± 52.67 vs. 24.65 ± 10.32 ng/mL, P < 0.001) and that of ANGPTL4 was lower (454.66 ± 269.05 vs. 875.49 ± 961.15 ng/mL, P < 0.001) in the coronary artery stenosis ≥ 10% group than in the < 10% group. ANGPTL3 and ANGPTL4 levels were significantly associated with the severity of coronary vascular stenosis. ROC curve analyses indicated that ANGPTL3 concentrations above 30.5 ng/mL can predict atherosclerosis with a sensitivity of 71.2% and specificity of 75.3%, and that ANGPTL4 levels below 497.5 ng/mL can predict atherosclerosis with a sensitivity of 63.9% and specificity of 74.5%. ANGPTL3 and ANGPTL4 were determined to be independent risk factors for coronary atherosclerosis with odds ratios (ORs) of 0.189 (95% CI 0.097-0.368, P < 0.001) and 3.625 (95% CI 1.873-7.016, P < 0.001), respectively. Increased ANGPTL3 or decreased ANGPTL4 shows an association with coronary atherosclerosis and, may become a predictor of coronary atherosclerosis in the future. Show less

Cancer-associated fibroblasts (CAFs) with different gene profiles from normal fibroblasts (NFs) have been implicated in tumor progression. Angiopoietin-like protein 4 (ANGPTL4) has been shown to regulate tumor angiogenesis and metastasis, and predict poor prognosis. However, the ANGPTL4 expression in CAFs, especially in gallbladder CAFs (GCAFs) and its relationship with patient prognosis is unclear. Affymetrix gene profile chip analysis in vitro was performed to detect the different gene expression profiles between GCAFs and NFs. RT-qPCR, immunohistochemistry, and western blotting were performed to investigate the different expression levels of ANGPTL4 in GCAFs/NFs in vitro and in an in vivo nude mouse model of xenograft tumors. Finally, the ANGPTL4 expression was investigated in the stroma of different lesion tissues of the human gallbladder by immunohistochemistry, especially the expression in GCAFs in vivo by co-immunofluorescence, and their prognostic significance in patients with gallbladder cancer (GBC) was assessed. ANGPTL4 was upregulated in both GCAFs in vitro and in the xenograft stroma of nude mice in vivo, and its expression was also significantly upregulated in human GBC stroma co-localized with the interstitial markers fibroblast secreted protein-1 and α-smooth muscle actin. In addition, the elevated ANGPTL4 expression in GCAFs was correlated with tumor differentiation, liver metastasis, venous invasion and Nevin staging, and GBC patients with an elevated ANGPTL4 expression in GACFs were found to have a lower survival rate. Increased ANGPTL4 expression in GCAFs correlates with poor patient prognosis, which indicates a potential therapeutic target for human GBCs. Show less

The purpose of this study was to investigate the impact of single nucleotide polymorphisms (SNPs) in the ANGPTL4 gene and the SNP-SNP interactions on atherosclerotic ischemic stroke (IS) risk. A case-control study was conducted. A total of 360 patients with atherosclerotic IS and 342 controls between December 2018 and December 2019 from Longyan First Hospital affiliated to Fujian Medical University were included. A logistic regression model was used to examine the association between SNPs and atherosclerotic IS risk. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. Generalized multifactor dimensionality reduction was employed to analyze the SNP-SNP interaction. Logistic regression analysis showed that atherosclerotic IS risk was significantly lower in carriers with the rs11672433-T allele than those with the CC genotype (CT+ TT vs. CC); adjusted OR, 0.005; 95% CI, 0.02-0.11. We found a significant 2-locus model (P = 0.0010) involving rs11672433 and rs4076317; the cross-validation consistency of this model was 10 of 10, and the testing accuracy was 57.96%. Participants with the CT or TT of rs11672433 and CC of rs4076317 genotype have the lowest atherosclerotic IS risk, compared to subjects with CC of rs11672433 and the CC of rs4076317 genotype, OR (95%CI) was 0.06(0.02-0.22), after covariates adjustment for gender, age, smoking and alcohol status, hypertension, Diabetes mellitus, TG, TC, HDL-C, LDL-C, Uric acid. We found that rs11672433 was associated with decreased atherosclerotic IS risk; we also found that gene-gene interaction between rs11672433 and rs4076317 was associated with decreased atherosclerotic IS risk. Show less

Joint capsule fibrosis caused by excessive inflammation leading to post-traumatic joint contracture (PTJC). Fibroblasts trigger inflammation under the challenge of various proinflammatory cytokines. Macrophage migration inhibitory factor (MIF) is a prominent proinflammatory cytokine involved in inflammation- and fibrosis-associated pathophysiology, we investigated the role of MIF in PTJC. Using rat PTJC model and fibroblast inflammation model, we detected MIF expression in posterior joint capsule. Primary joint capsule fibroblasts (JFs) were used to investigate the effects of MIF on cell proliferation, migration and proinflammatory cytokines production. The mechanism of JF-mediated events was evaluated by qRT-PCR, western blot and immunoprecipitation. We screened the mRNA expression profile to identify gene candidates that mediate the effect of MIF on JFs. MIF increased in posterior joint capsule following PTJC and co-localized with fibroblasts. Injection of MIF inhibitor significantly suppressed joint capsule inflammation and fibrosis. MIF/CD74 axis elicited JF inflammation and may provide new therapeutic targets for joint capsule fibrosis in PTJC. Show less

Apolipoprotein A4 (ApoA4) regulates lipid and glucose metabolism and exerts anti-inflammatory effects in atherogenesis and colitis. The present study explored the presumed protective role of ApoA4 in carbon tetrachloride (CCl4)-induced acute liver injury (ALI) in mice. The ALI model in wild type (WT), ApoA4 knock-out (ApoA4-KO) and ApoA4 transgenic (ApoA4-TG) mice was induced by a single intraperitoneal administration of CCl4. Liver and blood were harvested from mice to assess liver functions, immunohistological changes, immune cell populations and cytokine profiles. ApoA4 deficiency aggravated, and ApoA4 overexpression alleviated CCl4-inflicted liver damage by controlling levels of anti-oxidant enzymes. ApoA4 deletion increased the recruitment of monocytes/macrophages into the injured liver and upregulated the plasma levels of IL-6, TNF-α and MCP-1, but lower IL-10 and IFN-γ. ApoA4 over-expression rescued this effect and resulted in lower percentages of monocytes/macrophages and dendritic cells, the ratio of blood pro-inflammatory to anti-inflammatory monocytes and reduced plasma concentrations of IL-6, but enhanced IL-10 and IFN-γ. We propose ApoA4 as a potential new therapeutic target for the management of liver damage. Show less

Elevated triglycerides (TG) are associated with, and may be causal for, cardiovascular disease (CVD), and co-morbidities such as type II diabetes and metabolic syndrome. Pathogenic variants in APOA5 and APOC3 as well as risk SNVs in other genes [APOE (rs429358, rs7412), APOA1/C3/A4/A5 gene cluster (rs964184), INSR (rs7248104), CETP (rs7205804), GCKR (rs1260326)] have been shown to affect TG levels. Knowledge of genetic causes for elevated TG may lead to early intervention and targeted treatment for CVD. We previously identified linkage and association of a rare, highly conserved missense variant in SLC25A40, rs762174003, with hypertriglyceridemia (HTG) in a single large family, and replicated this association with rare, highly conserved missense variants in a European American and African American sample. Here, we analyzed a longitudinal mixed-ancestry cohort (European, African and Asian ancestry, N = 8966) from the Electronic Medical Record and Genomics (eMERGE) Network. We tested associations between median TG and the genes of interest, using linear regression, adjusting for sex, median age, median BMI, and the first two principal components of ancestry. We replicated the association between TG and APOC3, APOA5, and risk variation at APOE, APOA1/C3/A4/A5 gene cluster, and GCKR. We failed to replicate the association between rare, highly conserved variation at SLC25A40 and TG, as well as for risk variation at INSR and CETP. Analysis using data from electronic health records presents challenges that need to be overcome. Although large amounts of genotype data is becoming increasingly accessible, usable phenotype data can be challenging to obtain. We were able to replicate known, strong associations, but were unable to replicate moderate associations due to the limited sample size and missing drug information. Show less

Circular RNA (circRNA), a subclass of non-coding RNA, plays a critical role in cancer tumorigenesis and metastasis. It has been suggested that circRNA acts as a microRNA sponge or a scaffold to interact with protein complexes; however, its full range of functions remains elusive. Recently, some circRNAs have been found to have coding potential. To investigate the role of circRNAs in gastric cancer (GC), parallel sequencing was performed using five paired GC samples. Differentially expressed circAXIN1 was proposed to encode a novel protein. FLAG-tagged circRNA overexpression plasmid construction, immunoblotting, mass spectrometry, and luciferase reporter analyses were applied to confirm the coding potential of circAXIN1. Gain- and loss-of-function studies were conducted to study the oncogenic role of circAXIN1 and AXIN1-295aa on the proliferation, migration, invasion, and metastasis of GC cells in vitro and in vivo. The competitive interaction between AXIN1-295aa and adenomatous polyposis coli (APC) was investigated by immunoprecipitation analyses. Wnt signaling activity was observed using a Top/Fopflash assay, real-time quantitative RT-PCR, immunoblotting, immunofluorescence staining, and chromatin immunoprecipitation. CircAXIN1 is highly expressed in GC tissues compared with its expression in paired adjacent normal gastric tissues. CircAXIN1 encodes a 295 amino acid (aa) novel protein, which was named AXIN1-295aa. CircAXIN1 overexpression enhances the cell proliferation, migration, and invasion of GC cells, while the knockdown of circAXIN1 inhibits the malignant behaviors of GC cells in vitro and in vivo. Mechanistically, AXIN1-295aa competitively interacts with APC, leading to dysfunction of the "destruction complex" of the Wnt pathway. Released β-catenin translocates to the nucleus and binds to the TCF consensus site on the promoter, inducing downstream gene expression. CircAXIN1 encodes a novel protein, AXIN1-295aa. AXIN1-295aa functions as an oncogenic protein, activating the Wnt signaling pathway to promote GC tumorigenesis and progression, suggesting a potential therapeutic target for GC. Show less

To compare phenotypic and genetic variations in polypoidal choroidal vasculopathy (PCV) between Caucasian and Asian patients. We analysed phenotypic and genotypic data from two sites, Association for Innovation and Biomedical Research on Light and Image, Portugal and Singapore National Eye Centre, Singapore. Baseline fundus photography, spectral domain-optical coherence tomography, indocyanine green and fluorescein angiography scans were analysed by respective reading centres using a standardised grading protocol. Single nucleotide polymorphisms across 8 PCV loci were compared between cases and controls selected from each population. One hundred and forty treatment-naïve PCV participants (35 Portuguese and 105 Singaporean) were included. The Portuguese cohort were older (72.33±8.44 vs 68.71±9.40 years, p=0.043) and were comprised of a lower proportion of males (43% vs 71%, p=0.005) compared with the Singaporean cohort. Differences in imaging features include higher prevalence of soft drusen (66% vs 30%, p=0.004), lower prevalence of subretinal haemorrhage (14% vs 67%, p<0.001), smaller polypoidal lesion (PL) area (0.09±0.09 vs 0.76±0.93 mm Among Asian and Caucasian patients with PCV, there are significant differences in the expression of phenotype. We also identified different polymorphisms associated with PCV in the two populations. Show less

Evidence suggests that Tripartite Motif Containing 11 (TRIM11) has pro-tumor activity in human non-small cell lung cancer (NSCLC). However, the roles and underlying mechanisms of TRIM11 in NSCLC have not yet been fully elucidated. In this work, human lung cancer cell lines (A549, H446, and H1975) were transfected with siRNA or lentiviruses to knockdown or overexpress TRIM11 and dual-specificity phosphatase 6 (DUSP6). The cell tumor response was assessed by determining the rate of proliferation, apoptosis, the uptake of 2-[N-(7-nitrobenz-2-oxa-1, 3-diaxol-4-yl) amino]-2-deoxyglucose (2-NBDG), and the secretion of lactic acid (LD). Dominant-negative (dn)-MEK1 was used to block the ERK1/2 pathway. The mechanism was investigated by assessing the protein levels of pyruvate kinase isozymes M2 (PKM2) and DUSP6, as well as the activation of ERK1/2 pathway. Our data confirmed the anti-cancer effect of siTRIM11 in human lung cancer by demonstrating inhibition of cancer cell proliferation, induction of apoptosis, prevention of 2-NBDG uptake, suppression of LD production, and prevention of lung cancer cell (A549) tumorigenicity in nude mice. The underlying mechanism involved the up-regulation of DUSP6 and the inhibition of ERK1/2 activity. Overexpression of TRIM11 induced tumorigenesis of NSCLC Show less

For successful outcomes in bone grafting, it is important to have a clear and detailed understanding of the fundamentals and basics in regenerative science. This article summarize the grafting materials and growth factors that are now in use to provide an improved understanding of the properties of each material and indications for subsequent use. The article gives an overview of the fundamentals of bone healing, including the physiology of regeneration. It is hoped that clinicians can make improved decisions that are based in literature when considering treatment options for restoring patients' functional dentition. Show less

Multiple osteochondromas (MO) is an autosomal dominant hereditary disorder, which typically manifests as skeletal dysplasia, mainly involving long bones and knees, ankles, elbows, wrists, shoulders, and pelvis. Previous studies have demonstrated that mutations in exostosin glycosyl transferase-1 ( Show less

Postprandial lipemia (PPL) is an important risk factor for cardiovascular disease. Inter-individual variation in the dietary response to a meal is known to be influenced by genetic factors, yet genes that dictate variation in postprandial lipids are not completely characterized. Genetic studies of the plasma lipidome can help to better understand postprandial metabolism by isolating lipid molecular species which are more closely related to the genome. We measured the plasma lipidome at fasting and 6 h after a standardized high-fat meal in 668 participants from the Genetics of Lipid-Lowering Drugs and Diet Network study (GOLDN) using ultra-performance liquid chromatography coupled to (quadrupole) time-of-flight mass spectrometry. A total of 413 unique lipids were identified. Heritable and responsive lipid species were examined for association with single-nucleotide polymorphisms (SNPs) genotyped on the Affymetrix 6.0 array. The most statistically significant SNP findings were replicated in the Amish Heredity and Phenotype Intervention (HAPI) Heart Study. We further followed up findings from GOLDN with a regional analysis of cytosine-phosphate-guanine (CpGs) sites measured on the Illumina HumanMethylation450 array. A total of 132 lipids were both responsive to the meal challenge and heritable in the GOLDN study. After correction for multiple testing of 132 lipids (α = 5 × 10 Show less

The fatty acid desaturase 1 (FADS1), also known as delta-5 desaturase (D5D), is one of the rate-limiting enzymes involved in the desaturation and elongation cascade of polyunsaturated fatty acids (PUFAs) to generate long-chain PUFAs (LC-PUFAs). Reduced function of D5D and decreased hepatic Show less

Cardiovascular diseases (CVDs) are seriously threatening to human life and health. Polyunsaturated fatty acids (PUFAs) are known for their role in preventing CVDs. It is beneficial to population health to promote the content of PUFAs in bovine milk. In recent years, limited research based on molecular mechanisms has focused on this field. The biological roles of numerous microRNAs (miRNAs) remain unknown. In this study, a promising and negatively correlated pair of the miRNA (miRNA-193a-5p) and a fatty acid desaturase 1 ( Show less