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author:("Wang, guolin")
1.  Modeling of the Bacillus subtilis Bacterial Biofilm Growing on an Agar Substrate 
Bacterial biofilms are organized communities composed of millions of microorganisms that accumulate on almost any kinds of surfaces. In this paper, a biofilm growth model on an agar substrate is developed based on mass conservation principles, Fick's first law, and Monod's kinetic reaction, by considering nutrient diffusion between biofilm and agar substrate. Our results show biofilm growth evolution characteristics such as biofilm thickness, active biomass, and nutrient concentration in the agar substrate. We quantitatively obtain biofilm growth dependence on different parameters. We provide an alternative mathematical method to describe other kinds of biofilm growth such as multiple bacterial species biofilm and also biofilm growth on various complex substrates.
PMCID: PMC4556878  PMID: 26355542
2.  Comparative efficacy and acceptability of five anti-tubercular drugs in treatment of multidrug resistant tuberculosis: a network meta-analysis 
Multidrug resistant tuberculosis (MDR-TB) is a serious form of tuberculosis (TB). There is no recognized effective treatment for MDR-TB, although there are a number of publications that have reported positive results for MDR-TB. We performed a network meta-analysis to assess the efficacy and acceptability of potential antitubercular drugs. We conducted a network meta-analysis of randomized controlled clinical trials to compare the efficacy and acceptability of five antitubercular drugs, bedaquiline, delamanid, levofloxacin, metronidazole and moxifloxacin in the treatment of MDR-TB. We included eleven suitable trials from nine journal articles and six clinical trials from, with data for 1472 participants. Bedaquiline (odds ratio [OR] 2.69, 95% CI 1.02-7.43), delamanid (OR 2.45, 95% CI 1.36-4.89) and moxifloxacin (OR 2.47, 95% CI 1.01, 7.31) were significantly more effective than placebo. For efficacy, the results indicated no statistical significance between each antitubercular drug. For acceptability, the results indicated no statistically significant difference between each compared intervention. There is insufficient evidence to suggest that any one of the five antitubercular drugs (bedaquiline, delamanid, levofloxacin, metronidazole and moxifloxacin) has superior efficacy compared to the others.
Electronic supplementary material
The online version of this article (doi:10.1186/s13336-015-0020-x) contains supplementary material, which is available to authorized users.
PMCID: PMC4416256  PMID: 25937888
Network meta-analysis; Antitubercular drugs; Multidrug-resistant tuberculosis
3.  Persistence of Smoking-Induced Dysregulation of MiRNA Expression in the Small Airway Epithelium Despite Smoking Cessation 
PLoS ONE  2015;10(4):e0120824.
Even after quitting smoking, the risk of the development of chronic obstructive pulmonary disease (COPD) and lung cancer remains significantly higher compared to healthy nonsmokers. Based on the knowledge that COPD and most lung cancers start in the small airway epithelium (SAE), we hypothesized that smoking modulates miRNA expression in the SAE linked to the pathogenesis of smoking-induced airway disease, and that some of these changes persist after smoking cessation. SAE was collected from 10th to 12th order bronchi using fiberoptic bronchoscopy. Affymetrix miRNA 2.0 arrays were used to assess miRNA expression in the SAE from 9 healthy nonsmokers and 10 healthy smokers, before and after they quit smoking for 3 months. Smoking status was determined by urine nicotine and cotinine measurement. There were significant differences in the expression of 34 miRNAs between healthy smokers and healthy nonsmokers (p<0.01, fold-change >1.5), with functions associated with lung development, airway epithelium differentiation, inflammation and cancer. After quitting smoking for 3 months, 12 out of the 34 miRNAs did not return to normal levels, with Wnt/β-catenin signaling pathway being the top identified enriched pathway of the target genes of the persistent dysregulated miRNAs. In the context that many of these persistent smoking-dependent miRNAs are associated with differentiation, inflammatory diseases or lung cancer, it is likely that persistent smoking-related changes in SAE miRNAs play a role in the subsequent development of these disorders.
PMCID: PMC4401720  PMID: 25886353
4.  Transcription Factors and microRNA-Co-Regulated Genes in Gastric Cancer Invasion in Ex Vivo 
PLoS ONE  2015;10(4):e0122882.
Aberrant miRNA expression abnormally modulates gene expression in cells and can contribute to tumorigenesis in humans. This study identified functionally relevant differentially expressed genes using the transcription factors and miRNA-co-regulated network analysis for gastric cancer. The TF-miRNA co-regulatory network was constructed based on data obtained from cDNA microarray and miRNA expression profiling of gastric cancer tissues. The network along with their co-regulated genes was analyzed using Database for Annotation, Visualization and Integrated Discovery (DAVID) and Transcriptional Regulatory Element Database (TRED). We found eighteen (17 up-regulated and 1 down-regulated) differentially expressed genes that were co-regulated by transcription factors and miRNAs. KEGG pathway analysis revealed that these genes were part of the extracellular matrix-receptor interaction and focal adhesion signaling pathways. In addition, qRT- PCR and Western blot data showed an increase in COL1A1 and decrease in NCAM1 mRNA and protein levels in gastric cancer tissues. Thus, these data provided the first evidence to illustrate that altered gene network was associated with gastric cancer invasion. Further study with a large sample size and more functional experiments is needed to confirm these data and contribute to diagnostic and treatment strategies for gastric cancer.
PMCID: PMC4393113  PMID: 25860484
5.  Isolation and genetic characterization of enterovirus in patients with febrile rash illness 
Biomedical Reports  2015;3(3):375-378.
Measles and rubella virus are usually considered as the causative agents in patients with febrile rash illness (FRI). However, investigators have identified that enteroviruses are also associated with FRI, and the present study was undertaken to investigate this association. In the study, 20 throat swab samples were collected from patients suffering from rash and fever between April and July in 2013. The 20 samples tested negative for measles virus, but all were positive when reverse transcription-polymerase chain reaction was performed using enterovirus universal primers. Specifically, five tested positive for Coxsackie B3 virus (CVB3). The titers of the five CVB3 isolates were 106.5, 106.4, 107.5, 106.5 and 106.5 tissue culture infectious dose50/100 µl respectively. The partial VP1 sequences of the five CVB3 isolates were identical to each other and were closely associated with the CVB3/MKP and CVB3/Macocy strains, which are known to induce myocarditis and neonatal diseases of the central nervous system. In conclusion, CVB3 may cause symptoms of fever and rash and should be differentiated from measles, rubella and other infectious pathogens. The five CVB3 isolates described in the study were genetically similar to each other and to other local CVB3 strains. The results provide further data on the viral pathogen spectrum associated with FRI.
PMCID: PMC4467221  PMID: 26137239
febrile rash illness; enterrovius; CVB3; VP1; China
6.  Overexpression of E2F mRNAs Associated with Gastric Cancer Progression Identified by the Transcription Factor and miRNA Co-Regulatory Network Analysis 
PLoS ONE  2015;10(2):e0116979.
Gene expression is regulated at the transcription and translation levels; thus, both transcription factors (TFs) and microRNAs (miRNA) play roles in regulation of gene expression. This study profiled differentially expressed mRNAs and miRNAs in gastric cancer tissues to construct a TF and miRNA co-regulatory network in order to identify altered genes in gastric cancer progression. A total of 70 cases gastric cancer and paired adjacent normal tissues were subjected to cDNA and miRNA microarray analyses. We obtained 887 up-regulated and 93 down-regulated genes and 41 down-regulated and 4 up-regulated miRNAs in gastric cancer tissues. Using the Transcriptional Regulatory Element Database, we obtained 105 genes that are regulated by the E2F family of genes and using Targetscan, miRanda, miRDB and miRWalk tools, we predicted potential targeting genes of these 45 miRNAs. We then built up the E2F-related TF and miRNA co-regulatory gene network and identified 9 hub-genes. Furthermore, we found that levels of E2F1, 2, 3, 4, 5, and 7 mRNAs associated with gastric cancer cell invasion capacity, and has associated with tumor differentiation. These data showed Overexpression of E2F mRNAs associated with gastric cancer progression.
PMCID: PMC4315469  PMID: 25646628
7.  Association study of stuttering candidate genes GNPTAB, GNPTG and NAGPA with dyslexia in Chinese population 
BMC Genetics  2015;16:7.
Dyslexia is a polygenic speech and language disorder characterized by an unexpected difficulty in reading in children and adults despite normal intelligence and schooling. Increasing evidence reveals that different speech and language disorders could share common genetic factors. As previous study reported association of GNPTAB, GNPTG and NAGPA with stuttering, we investigated these genes with dyslexia through association analysis.
The study was carried out in an unrelated Chinese cohort with 502 dyslexic individuals and 522 healthy controls. In all, 21 Tag SNPs covering GNPTAB, GNPTG and NAGPA were subjected to genotyping. Association analysis was performed on all SNPs. Significant association of rs17031962 in GNPTAB and rs882294 in NAGPA with developmental dyslexia was identified after FDR correction for multiple comparisons.
Our results revealed that the stuttering risk genes GNPTAB and NAGPA might also associate with developmental dyslexia in the Chinese population.
Electronic supplementary material
The online version of this article (doi:10.1186/s12863-015-0172-5) contains supplementary material, which is available to authorized users.
PMCID: PMC4342093  PMID: 25643770
Developmental dyslexia; GNPTAB; GNPTG; NAGPA; SNPs
8.  An empirical Bayes normalization method for connectivity metrics in resting state fMRI 
Functional connectivity analysis using resting-state functional magnetic resonance imaging (rs-fMRI) has emerged as a powerful technique for investigating functional brain networks. The functional connectivity is often quantified by statistical metrics (e.g., Pearson correlation coefficient), which may be affected by many image acquisition and preprocessing steps such as the head motion correction and the global signal regression. The appropriate quantification of the connectivity metrics is essential for meaningful and reproducible scientific findings. We propose a novel empirical Bayes method to normalize the functional brain connectivity metrics on a posterior probability scale. Moreover, the normalization function maps the original connectivity metrics to values between zero and one, which is well-suited for the graph theory based network analysis and avoids the information loss due to the (negative value) hard thresholding step. We apply the normalization method to a simulation study and the simulation results show that our normalization method effectively improves the robustness and reliability of the quantification of brain functional connectivity and provides more powerful group difference (biomarkers) detection. We illustrate our method on an analysis of a rs-fMRI dataset from the Autism Brain Imaging Data Exchange (ABIDE) study.
PMCID: PMC4584951  PMID: 26441493
anticorrelation; connectivity; fMRI; network; normalization; resting state
9.  Stuttering candidate genes DRD2 but not SLC6A3 is associated with developmental dyslexia in Chinese population 
Dyslexia is a polygenic developmental disorder characterized by difficulties in reading and spelling despite normal intelligence, educational backgrounds and perception. Increasing evidences indicated that dyslexia may share similar genetic mechanisms with other speech and language disorders. We proposed that stuttering candidate genes, DRD2 and SLC6A3, might be associated with dyslexia.
Methods and results
The study was conducted in an unrelated Chinese cohort with 502 dyslexic cases and 522 healthy controls. In total, 23 Tag SNPs covering the two genes were selected for genotyping through Tagger program. Association analysis was performed on each SNP alone and in haplotypes. One SNP markers in DRD2 showed significant association with developmental dyslexia.
These findings indicate that polymorphism of DRD2 gene may be a risk factor of developmental dyslexia in the Chinese population.
PMCID: PMC4236612  PMID: 25178928
Dyslexia; Dopamine D2 receptor (DRD2); Solute carrier family 6, member 3 (SLC6A3); Linkage study
10.  Solitary fibrous tumors of the pleura with Doege-Potter syndrome: a case report and three-decade review of the literature 
BMC Research Notes  2014;7:515.
No case of solitary fibrous tumor of the pleura with Doege-Potter syndrome has been reported in China. This study was to report a rare repeatedly recurrent case of solitary fibrous tumor of the pleura with Doege-Potter syndrome diagnosed in China and a three-decade literature review of solitary fibrous tumor of the pleura with Doege-Potter syndrome worldwide.
Case presentation
A rare case of solitary fibrous tumor of the pleura with Doege-Potter syndrome was diagnosed in 2005 with follow-up to 2011. All medical records were collected and literature of solitary fibrous tumor of the pleura with Doege-Potter syndrome from 1979 to 2011 was obtained through Medline. This typical case, diagnosed and confirmed by histopathologic results, was a 72-year-old Chinese woman who had a complaint of night sweat for a month. A localized mass 12 cm × 11 cm × 8 cm in size was found associated with pleural effusion in her left low chest cavity, and blood tests showed severe hypoglycemia. Removal of the mass solved the hypoglycemia. The case was repeatedly recurrent in April, 2010 and March, 2011 and had no signs of recurrence up to the end of 2011 after surgery. A review of 45 cases of solitary fibrous tumor of the pleura with Doege-Potter syndrome compared and summarized clinical characteristics, treatments, and outcomes by benign and malignant tumor nature.
Incidence of solitary fibrous tumor of the pleura with Doege-Potter syndrome is similar between genders. There are no significant differences in clinical characteristics between benign and malignant cases. Surgery is the first effective treatment for solitary fibrous tumor of the pleura with Doege-Potter syndrome and the completeness of the initial resection is the key to preventing recurrence. Routine follow-up examinations are recommended for early detection of recurrence.
PMCID: PMC4267432  PMID: 25113505
Solitary fibrous tumors of pleura; Doege-Potter syndrome; Surgery; Case report review
11.  Role of MicroRNAs in Hepatocellular Carcinoma 
Hepatitis Monthly  2014;14(8):e18672.
MicroRNAs (miRNAs) are small, noncoding RNAs that play an important role in posttranscriptional gene regulation and function as negative gene regulators. They are an abundant class of RNA, each of which can control hundreds of gene targets and regulate diverse biological processes such as hematopoiesis, organogenesis, apoptosis and cell proliferation. Aberrant miRNA expression contributes to tumorigenesis and cancer progression.
Evidence Acquisition:
In this study we provided a summarized review of the most important new data available on hepatocellular carcinoma (HCC)-associated miRNAs. The data were collected through searching the related keywords and were categorized and summarized in different sections.
Researchers have reported that miRNAs can repress the expression of important cancer-related genes and might be helpful in the diagnosis and treatment of cancer. During the past two decades, numerous studies have shown that miRNAs play an essential role in inhibiting HCC via several different pathways. Deregulated miRNAs may contribute to carcinogenesis, indicating that miRNAs can act as tumor suppressors and oncogenes.
In this mini review, we highlight current findings and discuss recent work to determine the contribution of miRNA expression to the maintenance and growth of HCC, thereby providing a significant source of hope that miRNAs could serve as therapeutic targets.
PMCID: PMC4199151  PMID: 25337143
Hepatocellular Carcinoma; MicroRNAs; Regulation; Therapeutic Targets
12.  A comparison of ARMS and mutation specific IHC for common activating EGFR mutations analysis in small biopsy and cytology specimens of advanced non small cell lung cancer 
We have compared mutation analysis by Amplification Refractory Mutation System (ARMS) and epidermal growth factor receptor (EGFR) mutant-specific antibodies for their ability to detect two common activating EGFR mutations in a cohort of 115 advanced non-small cell lung cancer (NSCLC), including cytology material, core biopsy, and bronchoscopic biopsies. Assessment of EGFR mutation status was performed by using antibodies and ARMS assay specific to the two major forms of mutant EGFR, exon 19 deletion E746-A750 (c.2235_2249del15 or c.2236_2250del15, p. Glu746_Ala750 del) and exon 21 L858R point mutation (c.2573T>G, p.Leu858Arg). In this study the optimal buffer for antigen retrieval was sodium citrate (pH 6.0). Q score was used to evaluate the specific mutant EGFR proteins expression. Validation using clinical material showed deletions in exon 19 were detected in 19.1% and L858R mutation in 20% of all cases by ARMS assay. A cutoff value of score 1 was used as positive by IHC. No wild type cases were immuno-reactive. The antibodies performed well in cytology, core biopsies and bronchoscopic biopsies. There were only one false positive case using L858R IHC (sensitivity 100%, specificity 98.5%, positive predictive value 96%, negative predictive value 100%). All 23 E746-A750 exon 19 deletions identified by mutation analysis were positive by IHC. The sensitivity of exon 19 IHC for E746-A750 was 100%, specificity 100%, positive predictive value 100% and negative predictive value 100%. The result of the IHC stains was finely correlated with mutations status determined by ARMS assay. Although inferior to molecular genetic analysis of the EGFR gene, IHC is highly specific and sensitive for the targeted EGFR mutations. The antibodies are likely to be of clinical value in cases especially where limited tumor material is available, or in situations where molecular genetic analysis is not readily available.
PMCID: PMC4129049  PMID: 25120814
NSCLC; cytology; EGFR mutation; immunohistochemistry
13.  Altered Expression of Hypoxia-Inducible Factor-1α (HIF-1α) and Its Regulatory Genes in Gastric Cancer Tissues 
PLoS ONE  2014;9(6):e99835.
Tissue hypoxia induces reprogramming of cell metabolism and may result in normal cell transformation and cancer progression. Hypoxia-inducible factor 1-alpha (HIF-1α), the key transcription factor, plays an important role in gastric cancer development and progression. This study aimed to investigate the underlying regulatory signaling pathway in gastric cancer using gastric cancer tissue specimens. The integration of gene expression profile and transcriptional regulatory element database (TRED) was pursued to identify HIF-1α ↔ NFκB1 → BRCA1 → STAT3 ← STAT1 gene pathways and their regulated genes. The data showed that there were 82 differentially expressed genes that could be regulated by these five transcription factors in gastric cancer tissues and these genes formed 95 regulation modes, among which seven genes (MMP1, TIMP1, TLR2, FCGR3A, IRF1, FAS, and TFF3) were hub molecules that are regulated at least by two of these five transcription factors simultaneously and were associated with hypoxia, inflammation, and immune disorder. Real-Time PCR and western blot showed increasing of HIF-1α in mRNA and protein levels as well as TIMP1, TFF3 in mRNA levels in gastric cancer tissues. The data are the first study to demonstrate HIF-1α-regulated transcription factors and their corresponding network genes in gastric cancer. Further study with a larger sample size and more functional experiments is needed to confirm these data and then translate into clinical biomarker discovery and treatment strategy for gastric cancer.
PMCID: PMC4057318  PMID: 24927122
14.  The whole genome sequence of Coxsackievirus B3 MKP strain leading to myocarditis and its molecular phylogenetic analysis 
Virology Journal  2014;11:33.
In recent years, the reported infection cases by coxsackievirus (CV) have been on the rise. In order to reveal the relationship between the nucleotide and amino acid sequences and the viral virulence of the CVB3/MKP strain causing myocarditis, we initially confirmed the virulence of the strain in myocardial tissue and then carried out the whole genome sequencing of CVB3/MKP strain and performed a phylogenetic analysis among different CVB3 strains.
CVB3/MKP infected mouse model was established to check lesions of myocardial tissue in mice using immunohistochemical detection at different periods. RT-PCR analysis was used to amplify seven fragments covering the whole viral sequence and comparable analysis was performed.
The immunohistochemical results showed that particles of CVB3/MKP virus persisted in the cardiac tissue and caused severe pathology. The length of whole genome sequence of CVB3/MKP strain was 7400 bp. CVB3/MKP had 99.7% and 99.6% homology in nucleotide sequence with CVB3/28 and non-virulent CVB3/0, respectively. The former can induce pancreatitis and myocarditis. The nucleotide sequence in the 5′untranslated region of CVB3/MKP strain shared 99.6% and 99.5% homology with CVB3/20 and CVB3/Nancy, respectively.
We confirmed in our animal experiments that CVB3/MKP had cardiotoxicity. CVB3/MKP, CVB3/28, and CVB3/0 may share evolutionary convergence and the 5′untranslated region (5′UTR) may be associated with virulence phenotype. Our findings will provide a basis for identifying the genomic determinant of viral virulence of CVB3/MKP strain and phylogenetic relationship among different CVB3 strains.
PMCID: PMC3996064  PMID: 24555514
Coxsackievirus B3/MKP; Myocarditis; Phylogenetic analysis; Functional genomics
15.  A novel molecular typing method of Mycobacteria based on DNA barcoding visualization 
Different subtypes of Mycobacterium tuberculosis (MTB) may induce diverse severe human infections, and some of their symptoms are similar to other pathogenes, e.g. Nontuberculosis mycobacteria (NTM). So determination of mycobacterium subtypes facilitates the effective control of MTB infection and proliferation. This study exploits a novel DNA barcoding visualization method for molecular typing of 17 mycobacteria genomes published in the NCBI prokaryotic genome database. Three mycobacterium genes (Rv0279c, Rv3508 and Rv3514) from the PE/PPE family of MT Band were detected to best represent the inter-strain pathogenetic variations. An accurate and fast MTB substrain typing method was proposed based on the combination of the aforementioned three biomarker genes and the 16S rRNA gene. The protocol of establishing a bacterial substrain typing system used in this study may also be applied to the other pathogenes.
PMCID: PMC3931916  PMID: 24555538
Mycobacterium; Molecular typing; Typing biomarker; Bioinformatics; Differential diagnosis of mycobacteria
16.  The Laboratory of Genetics and Physiology 2: Emerging Insights into the Controversial Functions of This RIG-I-Like Receptor 
BioMed Research International  2014;2014:960190.
The laboratory of genetics and physiology 2 (LGP2) is a key component of the RNA helicase family of retinoic acid-inducible gene 1- (RIG-I-) like receptors (RLRs) and is widely involved in viral RNA recognition and regulation during innate immune responses. Unlike RIG-I and melanoma differentiation-associated 5, both RLR members, LGP2 lacks the caspase-recruitment domain (CARD), which is required for recruiting and interacting with downstream signaling proteins to activate a cascade of downstream signaling events. The absence of the CARD results in divergent functional performance for LGP2 compared to these other RLR members. Both negative and positive regulatory roles have been reported for LGP2 in antiviral immune responses. It is currently unclear how the unusual properties of LGP2 mediate opposing roles. Future studies should elucidate the molecular mechanism(s) of LGP2 action. This minireview provides a brief overview of LGP2 structure and functions, with an expanded discussion on the regulation mechanisms in response to viral infection, hopefully stimulating insight into the divergent roles of LGP2 in the regulation of antiviral immune responses.
PMCID: PMC3914343  PMID: 24551857
17.  Analysis of Risk Factors for First Seizure after Stroke in Chinese Patients 
BioMed Research International  2013;2013:702871.
The aim of this study is to assess related risk factors and predict early- and late-onset seizure after first-ever stroke. A total of 2474 consecutive patients with initial stroke in China from 1997 to 2007 were retrospectively investigated, in which, 24 clinical and radiological indexes were used for evaluation. Odds ratio (OR) and 95% confidence interval (CI) were calculated by logistic regression. A total of 232 (11.1%) of patients developed seizures during a mean follow-up period of 18 months, with 123 experiencing early-onset and 109 late-onset seizure. The independent risk factors for early-onset seizure were large lesion (OR = 9.36), subarachnoid hemorrhage (OR = 5.28), initial hyponatremia (OR = 2.10), and cortical involvement (OR = 1.33). The independent risk factors for late-onset seizure were cortical involvement (OR = 11.84) and large lesion (OR = 1.87). These results demonstrated that the risk factors for early seizure after stroke are large lesion, subarachnoid hemorrhage, and cortical involvement. Surprisingly, hyponatremia also predicts seizure in stroke patients. Cortical involvement is a major risk factor for late-onset seizure after stroke.
PMCID: PMC3835814  PMID: 24298553
18.  Clinical Evaluation and Cost-Effectiveness Analysis of Serum Tumor Markers in Lung Cancer 
BioMed Research International  2013;2013:195692.
The detection of serum tumor markers is valuable for the early diagnosis of lung cancer. Tumor markers are frequently used for the management of cancer patients. However, single markers are less efficient but marker combinations increase the cost, which is troublesome for clinics. To find an optimal serum marker combination panel that benefits the patients and the medical management system as well, four routine lung cancer serum markers (SCCA, NSE, CEA, and CYFRA21-1) were evaluated individually and in combination. Meanwhile, the costs and effects of these markers in clinical practice in China were assessed by cost-effectiveness analysis. As expected, combinations of these tumor markers improved their sensitivity for lung cancer and different combination panels had their own usefulness. NSE + CEA + CYFRA21-1 was the optimal combination panel with highest Youden's index (0.64), higher sensitivity (75.76%), and specificity (88.57%), which can aid the clinical diagnosis of lung cancer. Nevertheless, the most cost-effective combination was SCCA + CEA, which can be used to screen the high-risk group.
PMCID: PMC3792518  PMID: 24167812
19.  Airway Epithelial Expression of Toll-like Receptor 5 is Down-regulated in Healthy Smokers and Smokers with Chronic Obstructive Pulmonary Disease 
The toll-like receptors (TLRs) are important components of the respiratory epithelium host innate defense, enabling the airway surface to recognize and respond to a variety of insults in inhaled air. Based on the knowledge that smokers are more susceptible to pulmonary infection and that the airway epithelium of smokers with chronic obstructive pulmonary disease (COPD) is characterized by bacterial colonization and acute exacerbation of airway infections, we assessed whether smoking alters expression of TLRs in human small airway epithelium, the primary site of smoking-induced disease. Microarrays were used to survey the TLR family gene expression in small airway (10th–12th order) epithelium from healthy nonsmokers (n=60), healthy smokers (n=73) and smokers with COPD (n=36). Using the criteria of detection call of present in ≥50%, 6 of 10 TLRs (1, 2, 3, 4, 5 and 8) were expressed. Compared to nonsmokers, the most striking change was for TLR5, which was down-regulated in healthy smokers (1.4-fold, p<10−10) and smokers with COPD (1.6-fold, p<10−11). TaqMan RT-PCR confirmed these observations. Bronchial biopsy immunofluorescence studies showed that TLR5 was expressed mainly on the apical side of the epithelium and was decreased in healthy smokers and smokers with COPD. In vitro, the level of TLR5 downstream genes, IL-6 and IL-8, were highly induced by flagellin in TLR5 high-expressing cells compared to TLR5 low-expressing cells. In the context that TLR5 functions to recognize pathogens and activate innate immune responses, the smoking-induced down-regulation of TLR5 may contribute to smoking-related susceptibility to airway infection, at least for flagellated bacteria.
PMCID: PMC3579667  PMID: 22855713
20.  Normalizing Electrocardiograms of Both Healthy Persons and Cardiovascular Disease Patients for Biometric Authentication 
PLoS ONE  2013;8(8):e71523.
Although electrocardiogram (ECG) fluctuates over time and physical activity, some of its intrinsic measurements serve well as biometric features. Considering its constant availability and difficulty in being faked, the ECG signal is becoming a promising factor for biometric authentication. The majority of the currently available algorithms only work well on healthy participants. A novel normalization and interpolation algorithm is proposed to convert an ECG signal into multiple template cycles, which are comparable between any two ECGs, no matter the sampling rates or health status. The overall accuracies reach 100% and 90.11% for healthy participants and cardiovascular disease (CVD) patients, respectively.
PMCID: PMC3748040  PMID: 23977063
21.  An analysis of the molecular evolution of Hepatitis B viral genotypes A/B/D using a Bayesian evolutionary method 
Virology Journal  2013;10:256.
Hepatitis B virus (HBV) infection is a major global health problem. The infectious virion contains an inner “core particle”, which is made of 180 or 240 copies of core protein, alternatively known as hepatitis B core antigen, or HBcAg which encloses the viral genome.
In this study, we characterized HBV genotypes and used Bayesian analyses to estimate date of emergence of the most recent common ancestor (TMRCA) of three HBV genotypes, A, B, and D.
We estimated that the rate of evolution of HBV core protein gene to be 1.127 (0.925–1.329, 95% HPD) substitutions per site per year. The TMRCA of HBV for genotypes A, B, D were 118 (54–194, 95% HPD) year, 184 (78–323, 95% HPD) year and 133 (65–230, 95% HPD) year, respectively. Demographic histories of the HBcAg gene showed that the relative genetic diversity had a sharp increase within the first 10 years of its emergence.
Using a bayesian evolutionary method to predict the outbreak trends of HBV through evolutionary trees of HBV, and provide theoretical foundations for clinical prevention and treatment of HBV.
PMCID: PMC3765096  PMID: 23937671
HBV; Genotypes; Bayesian analyses; TMRCA
22.  Aberrant expression of microRNAs in gastric cancer and biological significance of miR-574-3p 
International Immunopharmacology  2012;13(4):468-475.
The discovery of microRNAs (miRNAs) provides a new and powerful tool for studying the mechanisms, diagnosis and treatments of cancer. In this study, we employed AFFX miRNA expression chips to search for miRNAs that may be aberrantly expressed in gastric cancer tissues and to investigate the potential roles that miRNAs may play in the development and progression of gastric cancer. 14 miRNAs were found to be down-regulated and 2 miRNAs up-regulated in gastric cancer tissues compared to the normal gastric tissues. Among the aberrantly expressed miRNAs, miR-574-3p was selected to further study its expression features and functional roles. Interestingly, the reduced expression of miR-574-3p occurred mainly in the early stages of gastric cancer or in cancers with high level of differentiation, suggesting that it can be used as a marker for a mild case of gastric cancer. Functional study revealed that cell proliferation, migration and invasion were significantly inhibited in miR-574-3p-transfected gastric cancer SGC7901 cells. Computational prediction and experimental validation suggest that Cullin2 may be one of the targets of miR-574-3p. Overall our study suggests that the aberrantly expressed miRNAs may play regulatory and functional roles in the development and progression of gastric cancer.
PMCID: PMC3389336  PMID: 22683180
microRNA; gastric cancer; target gene; proliferation; invasion
23.  Empirical Bayes conditional independence graphs for regulatory network recovery 
Bioinformatics  2012;28(15):2029-2036.
Motivation: Computational inference methods that make use of graphical models to extract regulatory networks from gene expression data can have difficulty reconstructing dense regions of a network, a consequence of both computational complexity and unreliable parameter estimation when sample size is small. As a result, identification of hub genes is of special difficulty for these methods.
Methods: We present a new algorithm, Empirical Light Mutual Min (ELMM), for large network reconstruction that has properties well suited for recovery of graphs with high-degree nodes. ELMM reconstructs the undirected graph of a regulatory network using empirical Bayes conditional independence testing with a heuristic relaxation of independence constraints in dense areas of the graph. This relaxation allows only one gene of a pair with a putative relation to be aware of the network connection, an approach that is aimed at easing multiple testing problems associated with recovering densely connected structures.
Results: Using in silico data, we show that ELMM has better performance than commonly used network inference algorithms including GeneNet, ARACNE, FOCI, GENIE3 and GLASSO. We also apply ELMM to reconstruct a network among 5492 genes expressed in human lung airway epithelium of healthy non-smokers, healthy smokers and individuals with chronic obstructive pulmonary disease assayed using microarrays. The analysis identifies dense sub-networks that are consistent with known regulatory relationships in the lung airway and also suggests novel hub regulatory relationships among a number of genes that play roles in oxidative stress and secretion.
Availability and implementation: Software for running ELMM is made available at
Contact: or
Supplementary information: Supplementary data are available at Bioinformatics online.
PMCID: PMC3400959  PMID: 22685074
24.  High-throughput screen of essential gene modules in Mycobacterium tuberculosis: a bibliometric approach 
BMC Infectious Diseases  2013;13:227.
Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (M. tuberculosis). The annotation of functional genome and signaling network in M. tuberculosis are still not systematic. Essential gene modules are a collection of functionally related essential genes in the same signaling or metabolic pathway. The determination of essential genes and essential gene modules at genomic level may be important for better understanding of the physiology and pathology of M. tuberculosis, and also helpful for the development of drugs against this pathogen. The establishment of genomic operon database (DOOR) and the annotation of gene pathways have felicitated the genomic analysis of the essential gene modules of M. tuberculosis.
Bibliometric approach has been used to perform a High-throughput screen for essential genes of M. tuberculosis strain H37Rv. Ant colony algorithm were used to identify the essential genes in other M. tuberculosis reference strains. Essential gene modules were analyzed by operon database DOOR. The pathways of essential genes were assessed by Biocarta, KEGG, NCI-PID, HumanCyc and Reactome. The function prediction of essential genes was analyzed by Pfam.
A total approximately 700 essential genes were identified in M. tuberculosis genome. 40% of operons are consisted of two or more essential genes. The essential genes were distributed in 92 pathways in M. tuberculosis. In function prediction, 61.79% of essential genes were categorized into virulence, intermediary metabolism/respiration,cell wall related and lipid metabolism, which are fundamental functions that exist in most bacteria species.
We have identified the essential genes of M. tuberculosis using bibliometric approach at genomic level. The essential gene modules were further identified and analyzed.
PMCID: PMC3680244  PMID: 23687949
Mycobacterium tuberculosis; Essential gene modules; Operon; Pathway
25.  The endothelial lipase protein is promising urinary biomarker for diagnosis of gastric cancer 
Diagnostic Pathology  2013;8:45.
Gastric cancer is one of the most common malignant tumors in the world. Finding effective diagnostic biomarkers in urine or serum would represent the most ideal solution to detecting gastric cancer during annual physical examination. This study was to evaluate the potential of endothelial lipase (EL) as a urinary biomarker for diagnosis of gastric cancer.
The expression levels of EL was measured using Western blotting and immunohistochemical staining experiments on (tissue, serum, and urine) samples of gastric cancer patients versus healthy people. We also checked the EL levels in the urine samples of other cancer types (lung, colon and rectum cancers) and benign lesions (gastritis and gastric leiomyoma) to check if EL was specific to gastric cancer.
We observed a clear separation between the EL expression levels in the urine samples of 90 gastric cancer patients and of 57 healthy volunteers. It was approximately 9.9 fold average decrease of the EL expression levels in the urine samples of gastric cancer compared to the healthy controls (P <0.0001), achieving a 0.967 AUC value for the ROC (receiver operating characteristic) curve, demonstrating it’s highly accurate as a diagnostic marker for gastric cancer. Interestingly, the expression levels of EL in tissue and serum samples were not nearly as discriminative as in urine samples (P = 0.90 and P = 0.79). In immunohistochemical experiments, positive expression of the EL protein was found in 67% (8/12) of gastric adjacent noncancerous and in 58% (7/12) of gastric cancer samples. There was no significant statistical in the expression levels of this protein between the gastric cancer and the matching noncancerous tissues (P =0.67).
The urinary EL as a highly accurate gastric cancer biomarker that is potentially applicable to the general screening with high sensitivity and specificity.
Virtual Slides
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PMCID: PMC3621381  PMID: 23510199
Endothelial lipase; Biomarker; Gastric cancer; Diagnosis

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