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1.  Conformal Nanopatterning of Extracellular Matrix Proteins onto Topographically Complex Surfaces 
Nature methods  2014;12(2):134-136.
We report a method for conformal nanopatterning of extracellular matrix proteins onto engineered surfaces independent of underlying microtopography. This enables fibronectin, laminin, and other proteins to be applied to biomaterial surfaces in complex geometries inaccessible using traditional soft lithography techniques. Engineering combinatorial surfaces that integrate topographical and biochemical micropatterns enhances control of the biotic-abiotic interface, used here to understand cardiomyocyte response to competing physical and chemical cues in the microenvironment.
PMCID: PMC4435615  PMID: 25506720
2.  Pleiotropic genes for metabolic syndrome and inflammation 
Molecular genetics and metabolism  2014;112(4):317-338.
Metabolic syndrome (MetS) has become a health and financial burden worldwide. The MetS definition captures clustering of risk factors that predict higher risk for diabetes mellitus and cardiovascular disease. Our study hypothesis is that additional to genes influencing individual MetS risk factors, genetic variants exist that influence MetS and inflammatory markers forming a predisposing MetS genetic network. To test this hypothesis a staged approach was undertaken. (a) We analyzed 17 metabolic and inflammatory traits in more than 85,500 participants from 14 large epidemiological studies within the Cross Consortia Pleiotropy Group. Individuals classified with MetS (NCEP definition), versus those without, showed on average significantly different levels for most inflammatory markers studied. (b) Paired average correlations between 8 metabolic traits and 9 inflammatory markers from the same studies as above, estimated with two methods, and factor analyses on large simulated data, helped in identifying 8 combinations of traits for follow-up in meta-analyses, out of 130,305 possible combinations between metabolic traits and inflammatory markers studied. (c) We performed correlated meta-analyses for 8 metabolic traits and 6 inflammatory markers by using existing GWAS published genetic summary results, with about 2.5 million SNPs from twelve predominantly largest GWAS consortia. These analyses yielded 130 unique SNPs/genes with pleiotropic associations (a SNP/gene associating at least one metabolic trait and one inflammatory marker). Of them twenty-five variants (seven loci newly reported) are proposed as MetS candidates. They map to genes MACF1, KIAA0754, GCKR, GRB14, COBLL1, LOC646736-IRS1, SLC39A8, NELFE, SKIV2L, STK19, TFAP2B, BAZ1B, BCL7B, TBL2, MLXIPL, LPL, TRIB1, ATXN2, HECTD4, PTPN11, ZNF664, PDXDC1, FTO, MC4R and TOMM40. Based on large data evidence, we conclude that inflammation is a feature of MetS and several gene variants show pleiotropic genetic associations across phenotypes and might explain a part of MetS correlated genetic architecture. These findings warrant further functional investigation.
PMCID: PMC4122618  PMID: 24981077
3.  Spatiotemporal Clustering Analysis and Risk Assessments of Human Cutaneous Anthrax in China, 2005–2012 
PLoS ONE  2015;10(7):e0133736.
To investigate the epidemic characteristics of human cutaneous anthrax (CA) in China, detect the spatiotemporal clusters at the county level for preemptive public health interventions, and evaluate the differences in the epidemiological characteristics within and outside clusters.
CA cases reported during 2005–2012 from the national surveillance system were evaluated at the county level using space-time scan statistic. Comparative analysis of the epidemic characteristics within and outside identified clusters was performed using using the χ2 test or Kruskal-Wallis test.
The group of 30–39 years had the highest incidence of CA, and the fatality rate increased with age, with persons ≥70 years showing a fatality rate of 4.04%. Seasonality analysis showed that most of CA cases occurred between May/June and September/October of each year. The primary spatiotemporal cluster contained 19 counties from June 2006 to May 2010, and it was mainly located straddling the borders of Sichuan, Gansu, and Qinghai provinces. In these high-risk areas, CA cases were predominantly found among younger, local, males, shepherds, who were living on agriculture and stockbreeding and characterized with high morbidity, low mortality and a shorter period from illness onset to diagnosis.
CA was geographically and persistently clustered in the Southwestern China during 2005–2012, with notable differences in the epidemic characteristics within and outside spatiotemporal clusters; this demonstrates the necessity for CA interventions such as enhanced surveillance, health education, mandatory and standard decontamination or disinfection procedures to be geographically targeted to the areas identified in this study.
PMCID: PMC4514625  PMID: 26208355
4.  NagC represses N-acetyl-glucosamine utilization genes in Vibrio fischeri within the light organ of Euprymna scolopes 
Bacteria often use transcription factors to regulate the expression of metabolic genes in accordance to available nutrients. NagC is a repressor conserved among γ-proteobacteria that regulates expression of enzymes involved in the metabolism of N-acetyl-glucosamine (GlcNAc). The polymeric form of GlcNAc, known as chitin, has been shown to play roles in chemotactic signaling and nutrition within the light organ symbiosis established between the marine bacterium Vibrio fischeri and the Hawaiian squid Euprymna scolopes. Here, we investigate the impact of NagC regulation on the physiology of V. fischeri. We find that NagC repression contributes to the fitness of V. fischeri in the absence of GlcNAc. In addition, the inability to de-repress expression of NagC-regulated genes reduces the fitness of V. fischeri in the presence of GlcNAc. We find that chemotaxis toward GlcNAc or chitobiose, a dimeric form of GlcNAc, is independent of NagC regulation. Finally, we show that NagC represses gene expression during the early stages of symbiosis. Our data suggest that the ability to regulate gene expression with NagC contributes to the overall fitness of V. fischeri in environments that vary in levels of GlcNAc. Furthermore, our finding that NagC represses gene expression within the squid light organ during an early stage of symbiosis supports the notion that the ability of the squid to provide a source of GlcNAc emerges later in host development.
PMCID: PMC4505101
Vibrio; symbiosis; NagC; N-acetyl-glucosamine; Euprymna scolopes
5.  The g.-165 T>C Rather than Methylation Is Associated with Semen Motility in Chinese Holstein Bulls by Regulating the Transcriptional Activity of the HIBADH Gene 
PLoS ONE  2015;10(7):e0127670.
The 3-hydroxyisobutyrate dehydrogenase (HIBADH) is regarded as a human sperm-motility marker. However, the molecular mechanisms involved in the regulation of expression of the HIBADH gene in bulls remain largely unknown. HIBADH was detected in the testis, epididymis, and sperm via reverse transcription polymerase chain reaction and Western blot analysis. It is also expressed in the seminiferous epithelium, spermatids, and the entire epididymis, as detected by immunohistochemistry. Furthermore, HIBADH was expressed in the neck-piece and mid-piece of bull spermatids, as shown in the immunofluorescence assay. Using serially truncated bovine HIBADH promoters and luciferase constructs, we discovered an 878 bp (-703 bp to +175 bp) fragment that constitutes the core promoter region. One SNP g.-165 T>C of HIBADH was identified and genotyped in 307 Chinese Holstein bulls. Correlation analysis revealed that bulls with the TT genotype had higher initial sperm motility than those with the CC genotype (P < 0.05). Furthermore, the T- or C-containing loci (designated as pGL3-T and pGL3-C) were transiently transfected into MLTC-1 to test the effect of SNP on HIBADH expression. The luciferase reporter assay showed that the pGL3-T genotype exhibited 58% higher transcriptional activity than the pGL3-C genotype (P < 0.05). The bisulfite sequencing analysis revealed that the methylation pattern of the core promoter presented hypomethylation in the ejaculated semen in high-motility and low-motility bulls. The results demonstrated for the first time that the g.-165 T>C rather than methylation in the 5'-flanking region could affect the bovine sperm motility through the regulation of HIBADH gene transcriptional activity.
PMCID: PMC4489673  PMID: 26133183
6.  MiR-506 Suppresses Proliferation and Induces Senescence by Directly Targeting the CDK4/6-FOXM1 Axis in Ovarian Cancer 
The Journal of pathology  2014;233(3):308-318.
Ovarian carcinoma is the most lethal gynecological malignancy. Better understanding of the molecular pathogenesis of this disease and effective targeted therapies are needed to improve patient outcomes. MicroRNAs play important roles in cancer progression and have the potential for use as either therapeutic agents or targets. Studies in other cancers have suggested that miR-506 has antitumor activity, but its function has yet to be elucidated. We found that deregulation of miR-506 in ovarian carcinoma promotes an aggressive phenotype. Ectopic overexpression of miR-506 in ovarian cancer cells was sufficient to inhibit proliferation and to promote senescence. We also demonstrated that CDK4 and CDK6 are direct targets of miR-506, and that miR-506 can inhibit CDK4/6-FOXM1 signaling, which is activated in the majority of serous ovarian carcinomas. This newly recognized miR-506/CDK4/6-FOXM1 axis provides further insight into the pathogenesis of ovarian carcinoma and identifies a potential novel therapeutic agent.
PMCID: PMC4144705  PMID: 24604117
miR-506; ovarian carcinoma; proliferation; senescence; FOXM1
7.  Safety and Efficacy of Thermal Ablation for Small Renal Masses in Solitary Kidney: Evidence from Meta-Analysis of Comparative Studies 
PLoS ONE  2015;10(6):e0131290.
To evaluate comparative renal functional preservation, perioperative and oncologic outcomes, and complications of thermal ablation (TA) versus partial nephrectomy (PN) in management of Small renal masses (SRMs) in solitary kidney.
Methods and Findings
Medline, Embase, Web of Science and the Cochrane Library were systematically searched. A meta-analysis for comparative studies comparing TA with PN was performed. According to predefined inclusion criteria, seven datasets were identified from 8 observational studies including a total of 628 patients. Cumulated data showed the changes of creatinine (p=0.02) and estimated glomerular filtration rate (eGFR) (p<0.0001) in TA arm were significantly less than these in PN arm. Significantly less new-set chronic kidney disease (CKD) was observed in TA group (p=0.04). In terms of postoperative dialysis rate, the difference favoring TA was also noted, though there is no statistical significance (p=0.09). With regard to perioperative outcomes, our data demonstrated that patients who underwent TA had significantly shorter operation time (p=0.002), less blood loss (p<0.0001), shorter length of stay (p<0.00001), and less transfusion rate (p=0.01) than those underwent PN. In addition, patients underwent TA suffered less intra- and postoperative complications (p=0.007, p<0.00001; respectively). With regard to oncologic outcomes, disease-free survival (DFS) (p<0.00001) and cancer-specific survival (CSS) (p=0.01) in the PN arm were significantly better than these of the TA arm. But, TA yielded a comparable overall survival to PN (p=0.40). Sensitivity analyses led to very similar results with overall results, and confirmed its stability.
Our analysis indicates that PN have advantage in controlling cancer recurrence. However, TA is associated with significantly better renal functional preservation and perioperative outcomes, and less complications without increasing overall death. Our data suggest that indication for TA may be extended to select younger, healthier patients who desire a much less invasive therapeutic option.
PMCID: PMC4484808  PMID: 26121336
8.  Spatiotemporal Dynamics of Hand-Foot-Mouth Disease and Its Relationship with Meteorological Factors in Jiangsu Province, China 
PLoS ONE  2015;10(6):e0131311.
Hand, foot and mouth disease (HFMD) is an important public health issue in mainland China, including Jiangsu Province. The main purpose of this study was to depict the epidemiological characteristics of HFMD and evaluate the effects of meteorological variables on its dynamics via spatiotemporal analytic methods, which is essential for formulating scientific and effective prevention and control strategies and measures. In total, 497,910 cases of HFMD occurred in the 2009-2013 period, with an average annual incidence of 126.3 per 100,000 in Jiangsu. Out of these, 87.7% were under 5 years old with a male-to-female incidence ratio of 1.4. The dominant pathogens of the laboratory-confirmed cases were EV71 and CoxA16, accounting for 44.8% and 30.6% of all cases, respectively. Two incidence peaks were observed in each year, the higher occurring between April and June, the lower between November and December. The incidence ranged between 16.8 and 233.5 per 100,000 at the county level. The incidence in the South of the province was generally higher than that in the northern regions. The most likely spatiotemporal cluster detected by space–time scan analysis occurred in May-June of 2012 in the southern region. Average temperature and rainfall were positively correlated with HFMD incidence, while the number of days with rainfall ≥ 0.1mm, low temperature, high temperature and hours of sunshine were negatively related. Particularly, relative humidity had no relationship. In conclusion, the prevalence of HFMD in Jiangsu Province has an obvious feature of seasonality. The etiological composition changed dynamically and might be a latent driving force for the temporal variation of the incidence of HFMD. A moderately warm environment promotes the transmission of the HFMD viruses, while particularly cold and hot climate conditions restrain their transmission.
PMCID: PMC4488144  PMID: 26121573
9.  Association of endothelial lipase gene−384A/C with coronary artery disease in Han Chinese people 
BMJ Open  2015;5(6):e007621.
The endothelial lipase gene (LIPG) is one of the important genes in the metabolism of high-density lipoprotein cholesterol (HDL-C) and may be involved in the pathogenesis of coronary artery disease (CAD).
Materials and methods
To investigate the relationship between the common single nucleotide polymorphisms (SNPs) 584C/T (rs2000813) and −384A/C (rs3813082) in the LIPG gene and CAD, allele and genotype frequencies of the two SNPs were analysed in 287 Chinese patients with CAD and 367 controls by the high-resolution melting curve (HRM) method.
For 584C/T, no significant difference in polymorphic distribution was observed between patients and controls. However, the frequencies of allele C (20.2% vs 15%, p=0.013, OR=1.437, 95% CI 1.078 to 1.915) at −384A/C were significantly increased in patients compared with controls. Haplotype analysis also showed that haplotype CT (12.37% vs 8.72%, p=0.035, OR=1.478, 95% CI 1.034 to 2.112) was significantly higher in patients compared with controls.
These results suggested that the SNP −384A/C in the LIPG gene may be associated with risk for CAD and the LIPG gene may play a role in CAD in the Han Chinese.
PMCID: PMC4486941  PMID: 26124511
Single nucleotide polymorphism (SNP); Endothelial lipase gene (LIPG); Association
10.  MODIS Based Estimation of Forest Aboveground Biomass in China 
PLoS ONE  2015;10(6):e0130143.
Accurate estimation of forest biomass C stock is essential to understand carbon cycles. However, current estimates of Chinese forest biomass are mostly based on inventory-based timber volumes and empirical conversion factors at the provincial scale, which could introduce large uncertainties in forest biomass estimation. Here we provide a data-driven estimate of Chinese forest aboveground biomass from 2001 to 2013 at a spatial resolution of 1 km by integrating a recently reviewed plot-level ground-measured forest aboveground biomass database with geospatial information from 1-km Moderate-Resolution Imaging Spectroradiometer (MODIS) dataset in a machine learning algorithm (the model tree ensemble, MTE). We show that Chinese forest aboveground biomass is 8.56 Pg C, which is mainly contributed by evergreen needle-leaf forests and deciduous broadleaf forests. The mean forest aboveground biomass density is 56.1 Mg C ha−1, with high values observed in temperate humid regions. The responses of forest aboveground biomass density to mean annual temperature are closely tied to water conditions; that is, negative responses dominate regions with mean annual precipitation less than 1300 mm y−1 and positive responses prevail in regions with mean annual precipitation higher than 2800 mm y−1. During the 2000s, the forests in China sequestered C by 61.9 Tg C y−1, and this C sink is mainly distributed in north China and may be attributed to warming climate, rising CO2 concentration, N deposition, and growth of young forests.
PMCID: PMC4482713  PMID: 26115195
11.  mTORC1 Down-Regulates Cyclin-Dependent Kinase 8 (CDK8) and Cyclin C (CycC) 
PLoS ONE  2015;10(6):e0126240.
In non-alcoholic fatty liver disease (NAFLD) and insulin resistance, hepatic de novo lipogenesis is often elevated, but the underlying mechanisms remain poorly understood. Recently, we show that CDK8 functions to suppress de novo lipogenesis. Here, we identify the mammalian target of rapamycin complex 1 (mTORC1) as a critical regulator of CDK8 and its activating partner CycC. Using pharmacologic and genetic approaches, we show that increased mTORC1 activation causes the reduction of the CDK8-CycC complex in vitro and in mouse liver in vivo. In addition, mTORC1 is more active in three mouse models of NAFLD, correlated with the lower abundance of the CDK8-CycC complex. Consistent with the inhibitory role of CDK8 on de novo lipogenesis, nuclear SREBP-1c proteins and lipogenic enzymes are accumulated in NAFLD models. Thus, our results suggest that mTORC1 activation in NAFLD and insulin resistance results in down-regulation of the CDK8-CycC complex and elevation of lipogenic protein expression.
PMCID: PMC4456374  PMID: 26042770
12.  EETs Attenuate Ox-LDL-Induced LTB4 Production and Activity by Inhibiting p38 MAPK Phosphorylation and 5-LO/BLT1 Receptor Expression in Rat Pulmonary Arterial Endothelial Cells 
PLoS ONE  2015;10(6):e0128278.
Cytochrome P-450 epoxygenase (EPOX)-derived epoxyeicosatrienoic acids (EETs), 5-lipoxygenase (5-LO), and leukotriene B4 (LTB4), the product of 5-LO, all play a pivotal role in the vascular inflammatory process. We have previously shown that EETs can alleviate oxidized low-density lipoprotein (ox-LDL)-induced endothelial inflammation in primary rat pulmonary artery endothelial cells (RPAECs). Here, we investigated whether ox-LDL can promote LTB4 production through the 5-LO pathway. We further explored how exogenous EETs influence ox-LDL-induced LTB4 production and activity. We found that treatment with ox-LDL increased the production of LTB4 and further led to the expression and release of both monocyte chemoattractant protein-1 (MCP-1/CCL2) and intercellular adhesion molecule-1 (ICAM-1). All of the above ox-LDL-induced changes were attenuated by the presence of 11,12-EET and 14,15-EET, as these molecules inhibited the 5-LO pathway. Furthermore, the LTB4 receptor 1 (BLT1 receptor) antagonist U75302 attenuated ox-LDL-induced ICAM-1 and MCP-1/CCL2 expression and production, whereas LY255283, a LTB4 receptor 2 (BLT2 receptor) antagonist, produced no such effects. Moreover, in RPAECs, we demonstrated that the increased expression of 5-LO and BLT1 following ox-LDL treatment resulted from the activation of nuclear factor-κB (NF-κB) via the p38 mitogen-activated protein kinase (MAPK) pathway. Our results indicated that EETs suppress ox-LDL-induced LTB4 production and subsequent inflammatory responses by downregulating the 5-LO/BLT1 receptor pathway, in which p38 MAPK phosphorylation activates NF-κB. These results suggest that the metabolism of arachidonic acid via the 5-LO and EPOX pathways may present a mutual constraint on the physiological regulation of vascular endothelial cells.
PMCID: PMC4452698  PMID: 26035589
13.  MiR-506: A Multitasker in Suppression of the Epithelial-to-Mesenchymal Transition 
RNA & disease (Houston, Tex.)  2014;1(1):e447-.
MiRNAs emerge as important regulators of epithelial-to-mesenchymal transition (EMT). The Best known EMT regulatory miRNAs are targeting the transcriptional repressors of E-cadherin (E-cad). We identified miR-506 as a key EMT inhibitor through directly targeting the E-cad transcriptional repressor, SNAI2. Our recent studies showed that miR-506 simultaneously suppresses vimentin and N-cad. Thus, miR-506 possesses a multitasking property in the suppression of EMT and metastasis and thus may represent a promising tool in cancer therapeutics.
PMCID: PMC4447487  PMID: 26029740
miR-506; epithelial-to-mesenchymal transition; vimentin; N-cadherin; epithelial ovarian cancer; nanoparticle
14.  Gene cloning of an important eukaryotic translation initiation factor family, eIF2A gene in halophytic Leymus chinensis (Trin.) 
Eukaryotic initiation factors eIF2A and eIF2 both play important roles in the mRNA translation of protein synthesis, whereas the functions of eIF2A are usually overlooked, as both functions of binding methyionly-tRNAi (Met-tRNAi) to 40S are similar under the same complementary factor and nucleotide requirements. Recently, the functions of eIF2A were reported to differ from those of eIF2 in manners when binding Met-tRNAi to 40S. Given that eukaryotic initiation factor eIF2 has been well known, eIF2A was still deficient in understanding of its sequence, structure and functions. In this work, we collected a high salt-tolerant grass Leymus chinensis (Trin.) as the object of study, and cloned and sequenced the eIF2A gene from this species. Based on the DNA alignment and analysis of eIF2A gene sequences from other organisms, an effective primer set was newly designed. Using this primer set, a DNA fragment with length of about 500 bp was obtained, and we have submitted this sequencing result to NCBI GenBank database (accession number: KF279515). The Basic Local Alignment Search Tool (BLAST) result showed that our sequence is highly identical to eIF2A gene sequences that existed in NCBI GenBank database. This work would help to further understand the function of eIF2A, and provide more potential target genes for studying their functions in relation to stress tolerance mechanisms.
PMCID: PMC4433946  PMID: 26019549
Leymus chinensis; eukaryotic translation initiation factor; eIF2A; gene cloning
15.  Genetic relationship in mulberry (Morus L.) inferred through PCR–RFLP and trnD-trnT sequence data of chloroplast DNA 
Ten universal primer pairs of the plant chloroplast genome were used to amplify the chloroplast DNA (cpDNA) non-coding regions in eight mulberry (Morus spp.) genotypes, including M. mongolica, M. bombycis, M. alba, M. atropurpurea and M. multicaulis. Subsequently, the polymerase chain reaction (PCR) products were digested by seven restriction enzymes and the trnD-trnT fragment for sequence alignment, and the variations were expected to provide the genetic information for system classification. The results from this study showed that: (1) 10 cpDNA primer pairs could be used for successful amplification in the tested materials, with approximately 17.1 kb of the chloroplast genome analysed. The 152 marker loci were detected by 70 primer/restriction endonuclease combinations, among which the trnD-trnT non-coding region digested by AluI, HinfI, MvaI and RsaI was detected by visible fragment length variation in different genotypes of the genus Morus. (2) eight Morus L. genotypes were divided into two groups based on the digesting pattern discrepancy through cpDNA. The M. multicaulis genotypes displayed diversity on an intraspecies level. ‘Nongsang No.12’ was identical with the female parent ‘Beiqu No.1’ (M. atropurpurea) in the surveyed sequence, but different from the male parent ‘Tongxiangqing’ (M. multicaulis), suggesting that the cpDNA was maternal inheritance in Morus L. (3) There were two deletion fragments (451–456 bp; 840–863bp) and six base point mutations in the trnD-trnT region based on homologous sequence alignment. The sequence of trnD-trnT in the cpDNA of mulberry could provide more genetic information for phylogenetic analysis and pedigree identification.
PMCID: PMC4433829  PMID: 26019528
Morus L.; cpDNA; PCR-RFLP; trnD-trnT sequence; genetic analysis
16.  Downregulation of Endogenous Hydrogen Sulfide Pathway Is Involved in Mitochondrion-Related Endothelial Cell Apoptosis Induced by High Salt 
Background. The study aimed to investigate whether endogenous H2S pathway was involved in high-salt-stimulated mitochondria-related vascular endothelial cell (VEC) apoptosis. Methods. Cultured human umbilical vein endothelial cells (HUVECs) were used in the study. H2S content in the supernatant was detected. Western blot was used to detect expression of cystathionine gamma-lyase (CSE), cleaved-caspase-3, and mitochondrial and cytosolic cytochrome c (cytc). Fluorescent probes were used to quantitatively detect superoxide anion generation and measure the in situ superoxide anion generation in HUVEC. Mitochondrial membrane pore opening, mitochondrial membrane potential, and caspase-9 activities were measured. The cell apoptosis was detected by cell death ELISA and TdT-mediated dUTP nick end labeling (TUNEL) methods. Results. High-salt treatment downregulated the endogenous VEC H2S/CSE pathway, in association with increased generation of oxygen free radicals, decreased mitochondrial membrane potential, enhanced the opening of mitochondrial membrane permeability transition pore and leakage of mitochondrial cytc, activated cytoplasmic caspase-9 and caspase-3 and subsequently induced VEC apoptosis. However, supplementation of H2S donor markedly inhibited VEC oxidative stress and mitochondria-related VEC apoptosis induced by high salt. Conclusion. H2S/CSE pathway is an important endogenous defensive system in endothelial cells antagonizing high-salt insult. The protective mechanisms for VEC damage might involve inhibiting oxidative stress and protecting mitochondrial injury.
PMCID: PMC4442413  PMID: 26078816
17.  The cis and trans effects of the risk variants of coronary artery disease in the Chr9p21 region 
BMC Medical Genomics  2015;8:21.
Recent genome-wide association studies (GWAS) have shown that single nucleotide polymorphisms (SNPs) in the Chr9p21 region are associated with coronary artery disease (CAD). Most of the SNPs identified in this region are non-coding SNPs, suggesting that they may influence gene expression by cis or trans mechanisms to affect disease susceptibility. Since all cells from an individual have the same DNA sequence variations, levels of gene expression in immortalized cell lines can reflect the functional effects of DNA sequence variations that influence or regulate gene expression. The objective of this study is to evaluate the functional consequences of the risk variants in the Chr9p21 region on gene expression.
We examined the association between the variants in the Chr9p21 region and the transcript-level mRNA expression of the adjacent genes (cis) as well as all other genes across the whole genome (trans) from transformed beta-lymphocytes in 801 non-Hispanic white participants from The Genetic Epidemiology Network of Arteriopathy (GENOA) study.
We found that the CAD risk variants in the Chr9p21 region were significantly associated with the mRNA expression of the ANRIL transcript ENST00000428597 (p = 8.58e-06). Importantly, a few distant transcripts were also found to be associated with the variants in this region, including the well-known CAD risk gene ABCA1 (p = 1.01e-05). Gene enrichment testing suggests that retinol metabolism, N-Glycan biosynthesis, and TGF signaling pathways may be involved.
These results suggest that the effect of risk variants in the Chr9p21 region on susceptibility to CAD is likely to be mediated through both cis and trans mechanisms.
Electronic supplementary material
The online version of this article (doi:10.1186/s12920-015-0094-0) contains supplementary material, which is available to authorized users.
PMCID: PMC4432789  PMID: 25958224
GENOA; Gene expression; SNP; CAD; Chr9p21
18.  Association analysis of polymorphisms of the CRHR1 gene with infantile spasms 
Molecular Medicine Reports  2015;12(2):2539-2546.
While >200 types of etiologies have been shown to be involved in the pathogenesis of infantile spasms, the pathophysiology of infantile spasms remains largely elusive. Pre-natal stress and hypothalamic-pituitary-adrenal axis dysfunction were shown to be involved in the development of infantile spasms. To test the genetic association between the CRHR1 gene, which encodes the corticotrophin-releasing hormone (CRH) receptor, and infantile spasms, five single nucleotide polymorphisms (SNPs) in the CRHR1 gene were genotyped in a sample set of 128 cases with infantile spasms and 131 healthy controls. Correlation analysis was performed on the genotyped data. Under the assumption of the dominant model, the selected five SNPs, rs4458044, rs171440, rs17689966, rs28364026 and rs242948, showed no association with the risk of infantile spasms and the effectiveness of adrenocorticotropic hormone treatment. In addition, subsequent haplotype analysis suggested none of them was associated with infantile spasms. In conclusion, the experimental results of the present study suggested no association between the CRHR1 gene and infantile spasms in a Chinese population.
PMCID: PMC4464474  PMID: 25954915
infantile spasms; CRHR1 gene; single nucleotide polymorphism; haplotype
19.  Overexpression of Notch1 is associated with the progression of cervical cancer 
Oncology Letters  2015;9(6):2750-2756.
Cervical cancer is the third most common malignancy worldwide, accounting for 250,000 mortalities annually. Notch1, an important regulator of cell-fate decisions and differentiation, has been found to be overexpressed in certain types of cancer. However, the role of Notch1 in cervical carcinogenesis remains unclear. In the present study, immunohistochemical staining and western blot analysis revealed that Notch1 expression was significantly higher in cervical cancer tissues than that in normal cervical tissues. Furthermore, statistical analysis revealed that Notch1 expression was significantly associated with tumor differentiation and tumor stage. These findings indicated that Notch1 expression was associated with the progression of cervical cancer. The western blot assay also identified a positive correlation between Notch1 and Ki67 expression in cervical cancer tissues, which suggested that Notch1 expression may be associated with the proliferation of cervical cancer. In order to further evaluate the specific role of Notch1 in cervical cancer progression, its expression in SiHa and C33A cells was knocked down using small interfering RNA. It was revealed that the knockdown of Notch1 in SiHa and C33A cells resulted in significant inhibition of cell proliferation and colony formation in vitro. These results indicated that Notch1 was able to promote cell proliferation in cervical cancer. In conclusion, the results of the present study indicated that Notch1 may function as a promoter in cervical carcinogenesis.
PMCID: PMC4473684  PMID: 26137140
cervical cancer; Notch1; immunohistochemical staining
20.  Highly Immunostimulatory RNA Derived from a Sendai Virus Defective Viral Genome 
Vaccine  2013;31(48):5713-5721.
Defective viral genomes (DVGs) are generated during virus replication. DVGs bearing complementary ends are strong inducers of dendritic cell (DC) maturation and of the expression of antiviral and pro-inflammatory cytokines by triggering signaling of the RIG-I family of intracellular pattern recognition receptors. Our data show that DCs stimulated with virus containing DVGs have an enhanced ability to activate human T cells and can induce adaptive immunity in mice. In addition, we describe the generation of a short Sendai virus (SeV)-derived DVG RNA (DVG-324) that maintains strong immunostimulatory activity in vitro and in vivo. DVG-324 induced high levels of IFN-β expression when transfected into cells and triggered fast expression of pro-inflammatory cytokines and mobilization of dendritic cells when injected into the footpad of mice. Importantly, DVG-324 enhanced the production of antibodies to a prototypic vaccine after a single intramuscular immunization in mice. Notably, the proinflammatory cytokine profile induced by DVG-324 was different from that induced by poly I:C, the only viral RNA analogue currently used as an immunostimulant in vivo, suggesting a distinct mechanism of action. SeV-derived oligonucleotides represent novel alternatives to be harnessed as potent adjuvants for vaccination.
PMCID: PMC4406099  PMID: 24099876
Adjuvant; Sendai virus; defective genomes; dendritic cells; immunization
21.  Functional Polymorphisms in COX-2 Gene Are Correlated with the Risk of Oral Cancer 
BioMed Research International  2015;2015:580652.
Background. This meta-analysis investigated the association between functional COX-2 gene polymorphisms and the risk of oral cancer. Methods. Several electronic databases were searched for published studies using combinations of keywords related to COX-2 gene polymorphisms and oral cancer. After selection of relevant studies, following strict inclusion and exclusion criteria, data was performed using STATA 12.0 software. Results. We retrieved 83 studies from database search using specific search terms. After multiple rounds of selection and elimination, 7 studies were finally identified as suitable to be included in our present meta-analysis, based on their relevance and data integrity. These 7 studies contained a combined total of 2,296 oral cancer patients and 3,647 healthy controls. Our findings demonstrated that +837 T > C (rs5275) polymorphism in COX-2 showed statistically significant differences in gene frequencies in case and control groups in allele model and dominant model. Similar results were obtained with COX-2 gene polymorphism 765 G > C (rs20417). On the other hand, 1195 A > G (rs689466) polymorphism in COX-2 did not confer susceptibility to oral cancers. Conclusion. Based on our results, COX-2 gene polymorphisms, +837 T > C (rs5275) and −765G > C (rs20417), showed clear links with oral cancer susceptibility, and the 1195A > G (rs689466) polymorphism did not show such a correlation.
PMCID: PMC4419230  PMID: 25977924
22.  Strengthening core public health capacity based on the implementation of the International Health Regulations (IHR) (2005): Chinese lessons 
As an international legal instrument, the International Health Regulations (IHR) is internationally binding in 196 countries, especially in all the member states of the World Health Organization (WHO). The IHR aims to prevent, protect against, control, and respond to the international spread of disease and aims to cut out unnecessary interruptions to traffic and trade. To meet IHR requirements, countries need to improve capacity construction by developing, strengthening, and maintaining core response capacities for public health risk and Public Health Emergency of International Concern (PHEIC). In addition, all the related core capacity requirements should be met before June 15, 2012. If not, then the deadline can be extended until 2016 upon request by countries. China has promoted the implementation of the IHR comprehensively, continuingly strengthening the core public health capacity and advancing in core public health emergency capacity building, points of entry capacity building, as well as risk prevention and control of biological events (infectious diseases, zoonotic diseases, and food safety), radiological, nuclear, and chemical events, and other catastrophic events. With significant progress in core capacity building, China has dealt with many public health emergencies successfully, ensuring that its core public health capacity has met the IHR requirements, which was reported to WHO in June 2014. This article describes the steps, measures, and related experiences in the implementation of IHR in China.
PMCID: PMC4450733  PMID: 26029897
International Health Regulations (IHR); Health Emergency; Core Public Health Capacity
23.  Treatment and prognosis of Masaoka stage 3 thymic carcinoma: a retrospective study of 32 cases 
OncoTargets and therapy  2015;8:699-702.
The aim of this study was to investigate the treatment and prognostic factors in patients with Masaoka stage 3 thymic carcinoma.
A retrospective review was conducted of the medical records of patients with Masaoka stage 3 thymic carcinoma between 2000 and 2012 in our institution. Clinical characteristics and prognostic factors were analyzed. Survival curves were plotted using the Kaplan–Meier method. The Cox proportional hazard model was used for multivariate analysis.
Thirty-two patients with Masaoka stage 3 thymic carcinoma, operated on in Zhejiang Cancer Hospital, were identified between 2000 and 2012. Among 32 patients, 24 achieved R0 resection. The most common histological subtypes were squamous cell carcinoma (n=15, 46.8%), followed by undifferentiated carcinoma (n=12, 37.5%), and other tumors (n=5, 15.7%). The 5-year disease-free survival and overall survival rates were 56.8% and 61.5%, respectively. Patients with incomplete resection had a significantly worse disease-free survival and overall survival as compared to complete resection with univariate analyses (P-value 0.006 and 0.034, respectively). Multivariate analysis revealed that complete resection was statistically associated with disease-free survival but not overall survival (P-value 0.025 and 0.076, respectively).
Our results indicated that complete resection could impact the disease-free survival of patients with stage 3 thymic carcinoma.
PMCID: PMC4396510  PMID: 25897244
thymic carcinoma; treatment; prognosis; Masaoka stage 3
24.  Aspergillus and Fusarium corneal infections are regulated by Th17 cells and IL-17 producing neutrophils 
Fusarium and Aspergillus species of mould are major causes of corneal infections in the USA and worldwide, resulting in severe visual impairment and blindness. As there is evidence for T cell responses to these pathogenic fungi in infected individuals, we examined the role of IL-17A (IL-17) and IFN-γ in murine models of fungal keratitis. We found that C57BL/6 mice given intratracheal or subcutaneous immunization of conidia prior to corneal infection exhibited enhanced fungal killing and lower corneal opacity compared with unimmunized mice. Protective immunity was associated with temporal recruitment of IL-17 producing neutrophils, Th17 and Th1 cells, and was dependent on production of IL-17 but not IFN-γ. Protection was also impaired in neutrophil depleted and in Rag2−/− mice. Together, the results of these studies identify an essential role for IL-17 producing neutrophils and Th17 cells in regulating the growth of fungal hyphae and the severity of corneal disease.
PMCID: PMC4020181  PMID: 24591369
Neutrophil; IL-17; Th17; fungal infection; Aspergillus; Fusarium; cornea; keratitis
25.  Human Pirh2 is A Novel Inhibitor of Prototype Foamy Virus Replication 
Viruses  2015;7(4):1668-1684.
Prototype foamy virus (PFV) is a member of the unconventional and nonpathogenic retroviruses. PFV causes lifelong chronic infections, which are partially attributable to a number of host cell factors that restrict viral replication. Herein, we identified human p53-induced RING-H2 protein (Pirh2) as a novel inhibitor of prototype foamy virus. Overexpression of Pirh2 decreased the replication of PFV, whereas knockdown of Pirh2 with specific siRNA increased PFV replication. Dual-luciferase assays and coimmunoprecipitation demonstrated that Pirh2 negatively influences the Tas-dependent transcriptional activation of the PFV long terminal repeat (LTR) and internal promoter (IP) by interacting with the transactivator Tas and down-regulating its expression. In addition, the viral inhibitory function of Pirh2 is N-terminal and RING domain dependent. Together, these results indicated that Pirh2 suppresses PFV replication by negatively impacting its transactivator Tas and the transcription of two viral promoters, which may contribute to the latency of PFV infection.
PMCID: PMC4411673  PMID: 25848801
PFV; Pirh2; replication; ubiquitination

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