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1.  Influenza vaccination acceptance among diverse pregnant women and its impact on infant immunization 
Human Vaccines & Immunotherapeutics  2013;9(12):2591-2602.
Objective: We examined pregnant women’s likelihood of vaccinating their infants against seasonal influenza via a randomized message framing study. Using Prospect Theory, we tested gain- and loss-frame message effects and demographic and psychosocial correlates of influenza immunization intention. We also explored interactions among pregnant women who viewed “Contagion” to understand cultural influences on message perception.
Methods: Pregnant women ages 18–50 participated in a randomized message framing study from September 2011 through May 2012 that included exposure to intervention or control messages, coupled with questionnaire completion. Venue-based sampling was used to recruit racial and ethnic minority female participants at locations throughout Atlanta, Georgia. Bivariate and multivariate analyses were conducted to evaluate key outcomes.
Results: The study population (n = 261) included many lower income (≤ $20 000/yearly household earnings) pregnant participants (69.2%, n = 171) inclusive of Black/African Americans (88.5%, n = 230), Hispanic/Latinas (7.3%, n = 19), and Other/Multicultural women (4.2%, n = 11). Both gain [OR = 2.13, 90% CI: (1.120, 4.048)] and loss-frame messages [OR = 2.02, 90% CI: (1.083, 3.787)] were significantly associated with infant influenza vaccination intention compared with the control condition. Intention to immunize against influenza during pregnancy had a strong effect on intent to immunize infants [OR = 10.83, 90%CI: (4.923, 23.825)]. Those who had seen the feature film “Contagion” (n = 54, 20.69%) viewed gain- and loss-framed messages as appealing (x2 = 6.03, p = 0.05), novel (x2 = 6.24, p = 0.03), and easy to remember (x2 = 16.33, P = 0.0003).
Conclusions: In this population, both gain- and loss-framed messages were positively associated with increased maternal intent to immunize infants against influenza. Message resonance was enhanced among those who saw the film “Contagion.” Additionally, history of immunization was strongly associated with infant immunization intention.
PMCID: PMC4162045  PMID: 24172064
message framing; prospect theory; influenza vaccination; immunization coverage; pregnant women; racial/ethnic minorities; contagion
2.  Autophagy may promote carcinoma cell invasion and correlate with poor prognosis in cholangiocarcinoma 
The role of autophagy in cholangiocarcinoma is poorly understood. This study investigated its involvement in cholangiocarcinoma, focusing on carcinoma cell invasion and prognostic significance using cholangiocarcinoma cell lines, CCKS1 and HuCCT1, and human tissues of hilar and extrahepatic cholangiocarcinoma. Nutrient starvation induced the expression of LC3-II and the formation of LC3 puncta in both CCKS1 and HuCCT1, suggesting the occurrence of autophagy. The induction of autophagy was accompanied by the increased expression of an autophagy-related protein, Ambra1, in the cells. Under starvation conditions, the invasive activity of both cells was significantly increased, and a lysosomal inhibitor, chloroquine, attenuated this increased invasive activity. Transforming growth factor-β1 (TGF-β1), known as an inducer of epithelial-mesenchymal transition (EMT), increased the invasive activity of both cells, and chloroquine also significantly reduced TGF-β1-induced cell invasion. Immunohistochemical staining using cholangiocarcinoma tissues showed that the expression of Ambra1 positively correlated with the expression of Snail, one of the major transcriptional factors of EMT. In addition, overexpression of Ambra1 significantly correlated with lymph node metastasis and poor survival rate of the patients. These results suggest that the occurrence of autophagy may be associated with a malignant phenotype and poor prognosis in cholangiocarcinoma, and autophagy is possibly involved in EMT-related cholangiocarcinoma cell invasion.
PMCID: PMC4152052  PMID: 25197362
Cholangiocarcinoma; autophagy; Ambra1; EMT; prognosis
3.  BRG1 variant rs1122608 on chromosome 19p13.2 confers protection against stroke and regulates expression of pre-mRNA-splicing factor SFRS3 
Human genetics  2013;133(5):499-508.
A single nucleotide polymorphism (SNP) rs1122608 on chromosome 19p13.2 and in the BRG1/SMARCA4 gene was previously associated with coronary artery disease (CAD). CAD and ischemic stroke are both associated with atherosclerosis. Thus, we tested the hypothesis that rs1122608 is associated with ischemic stroke. Further studies were used to identify the most likely mechanism by which rs1122608 regulates atherosclerosis. For case–control association studies, two independent Chinese Han GeneID cohorts were used, including a Central cohort with 1,075 cases and 2,685 controls and the Northern cohort with 1,208 cases and 824 controls. eQTL and real-time RT-PCR analyses were used to identify the potential candidate gene(s) affected by rs1122608. The minor allele T of SNP rs1122608 showed significant association with a decreased risk of ischemic stroke in the Central GeneID cohort (adjusted Padj = 2.1 × 10−4, OR 0.61). The association was replicated in an independent Northern GeneID cohort (Padj = 6.00 × 10−3, OR 0.69). The association became more significant in the combined population (Padj = 7.86 × 10−5, OR 0.73). Allele T of SNP rs1122608 also showed significant association with a decreased total cholesterol level (Padj = 0.013). Allele T of rs1122608 was associated with an increased expression level of SFRS3 encoding an mRNA splicing regulator, but not with the expression of BRG1/SMARCA4 or LDLR (located 36 kb from rs1122608). Increased expression of SFSR3 may decrease IL-1β expression and secretion, resulting in reduced risk of atherosclerosis and stroke. This is the first study that demonstrates that rs1122608 confers protection against ischemic stroke and implicates splicing factor SFSR3 in the disease process.
PMCID: PMC3988217  PMID: 24190014
4.  What Are the Precursor and Early Lesions of Peripheral Intrahepatic Cholangiocarcinoma? 
Cholangiocarcinoma (CC) is divided into distal, perihilar, and intrahepatic CCs (ICCS), and are further subdivided into large bile duct ICC and peripheral ICC. In distal and perihilar CC and large duct ICC, biliary intraepithelial neoplasm (BilIN) and intraductal papillary neoplasm (IPN) have been proposed as precursor lesions. Peripheral ICC, bile duct adenoma (BDA), biliary adenofibroma (BAF), and von Meyenburg complexes (VMCs) are reportedly followed by development of ICCs. Herein, we surveyed these candidate precursor lesions in the background liver of 37 cases of peripheral ICC and controls (perihilar CC, 34 cases; hepatocellular carcinoma, 34 cases and combined hepatocellular cholangiocarcinoma, 25 cases). In the background liver of peripheral ICC, BDA and BAF were not found, but there were not infrequently foci of BDA-like lesions and atypical bile duct lesions involving small bile ducts (32.4% and 10.8%, resp.). VMCs were equally found in peripheral CCs and also control CCs. In conclusion, BDA, BAF, and VMCs are a possible precursor lesion of a minority of peripheral CCs, and BDA-like lesions and atypical bile duct lesions involving small bile ducts may also be related to the development of peripheral ICC. Further pathologic studies on these lesions are warranted for analysis of development of peripheral ICCs.
PMCID: PMC4016917  PMID: 24860673
5.  A Spodoptera exigua Cadherin Serves as a Putative Receptor for Bacillus thuringiensis Cry1Ca Toxin and Shows Differential Enhancement of Cry1Ca and Cry1Ac Toxicity 
Applied and Environmental Microbiology  2013;79(18):5576-5583.
Crystal toxin Cry1Ca from Bacillus thuringiensis has an insecticidal spectrum encompassing lepidopteran insects that are tolerant to current commercially used B. thuringiensis crops (Bt crops) expressing Cry1A toxins and may be useful as a potential bioinsecticide. The mode of action of Cry1A is fairly well understood. However, whether Cry1Ca interacts with the same receptor proteins as Cry1A remains unproven. In the present paper, we first cloned a cadherin-like gene, SeCad1b, from Spodoptera exigua (relatively susceptible to Cry1Ca). SeCad1b was highly expressed in the larval gut but scarcely detected in fat body, Malpighian tubules, and remaining carcass. Second, we bacterially expressed truncated cadherin rSeCad1bp and its interspecific homologue rHaBtRp from Helicoverpa armigera (more sensitive to Cry1Ac) containing the putative toxin-binding regions. Competitive binding assays showed that both Cry1Ca and Cry1Ac could bind to rSeCad1bp and rHaBtRp, and they did not compete with each other. Third, Cry1Ca ingestion killed larvae and decreased the weight of surviving larvae. Dietary introduction of SeCad1b double-stranded RNA (dsRNA) reduced approximately 80% of the target mRNA and partially alleviated the negative effect of Cry1Ca on larval survival and growth. Lastly, rSeCad1bp and rHaBtRp differentially enhanced the negative effects of Cry1Ca and Cry1Ac on the larval mortalities and growth of S. exigua and H. armigera. Thus, we provide the first lines of evidence to suggest that SeCad1b from S. exigua is a functional receptor of Cry1Ca.
PMCID: PMC3754171  PMID: 23835184
6.  Activation of the PI3K/mTOR Pathway Is Involved in Cystic Proliferation of Cholangiocytes of the PCK Rat 
PLoS ONE  2014;9(1):e87660.
The polycystic kidney (PCK) rat is an animal model of Caroli’s disease as well as autosomal recessive polycystic kidney disease (ARPKD). The signaling pathways involving the mammalian target of rapamycin (mTOR) are aberrantly activated in ARPKD. This study investigated the effects of inhibitors for the cell signaling pathways including mTOR on cholangiocyte proliferation of the PCK rat. Cultured PCK cholangiocytes were treated with rapamycin and everolimus [inhibitors of mTOR complex 1 (mTOC1)], LY294002 [an inhibitor of phosphatidylinositol 3-kinase (PI3K)] and NVP-BEZ235 (an inhibitor of PI3K and mTORC1/2), and the cell proliferative activity was determined in relation to autophagy and apoptosis. The expression of phosphorylated (p)-mTOR, p-Akt, and PI3K was increased in PCK cholangiocytes compared to normal cholangiocytes. All inhibitors significantly inhibited the cell proliferative activity of PCK cholangiocytes, where NVP-BEZ235 had the most prominent effect. NVP-BEZ235, but not rapamycin and everolimus, further inhibited biliary cyst formation in the three-dimensional cell culture system. Rapamycin and everolimus induced apoptosis in PCK cholangiocytes, whereas NVP-BEZ235 inhibited cholangiocyte apoptosis. Notably, the autophagic response was significantly induced following the treatment with NVP-BEZ235, but not rapamycin and everolimus. Inhibition of autophagy using siRNA against protein-light chain3 and 3-methyladenine significantly increased the cell proliferative activity of PCK cholangiocytes treated with NVP-BEZ235. In vivo, treatment of the PCK rat with NVP-BEZ235 attenuated cystic dilatation of the intrahepatic bile ducts, whereas renal cyst development was unaffected. These results suggest that the aberrant activation of the PI3K/mTOR pathway is involved in cystic proliferation of cholangiocytes of the PCK rat, and inhibition of the pathway can reduce cholangiocyte proliferation via the mechanism involving apoptosis and/or autophagy.
PMCID: PMC3907540  PMID: 24498161
7.  Participation of peribiliary glands in biliary tract pathophysiologies 
World Journal of Hepatology  2013;5(8):425-432.
AIM: To investigate the roles of peribiliary glands around the bile ducts in the pathophysiology of the biliary tract.
METHODS: The expression of fetal pancreatic markers, pancreatic duodenal homeobox factor 1 (PDX1) and hairy and enhancer of split 1 (HES1) and endodermal stem/progenitor (S/P) cell markers [CD44s, chemokine receptor type 4 (CXCR4), SOX9 and epithelial cell adhesion molecule (EpCAM)] were examined immunohistochemically in 32 normal adult livers (autopsy livers) and 22 hepatolithiatic livers (surgically resected livers). The latter was characterized by the proliferation of the peribiliary glands. Immunohistochemistry was performed using formalin-fixed, paraffin-embedded tissue sections after deparaffinization. Although PDX1 and HES1 were expressed in both the nucleus and cytoplasm of epithelial cells, only nuclear staining was evaluated. SOX9 was expressed in the nucleus, while CD44s, CXCR4 and EpCAM were expressed in the cell membranes. The frequency and extent of the expression of these molecules in the lining epithelia and peribiliary glands were evaluated semi-quantitatively based on the percentage of positive cells: 0, 1+ (focal), 2+ (moderate) and 3+ (extensive).
RESULTS: In normal livers, PDX1 was infrequently expressed in the lining epithelia, but was frequently expressed in the peribiliary glands. In contrast, HES1 was frequently expressed in the lining epithelia, but its expression in the peribiliary glands was focal, suggesting that the peribiliary glands retain the potential of differentiation toward the pancreas and the lining epithelia exhibit properties to inhibit such differentiation. This unique combination was also seen in hepatolithiatic livers. The expression of endodermal S/P cell markers varied in the peribiliary glands in normal livers: SOX9 and EpCAM were frequently expressed, CD44s infrequently, and CXCR4 almost not at all. The expression of these markers, particularly CD44s and CXCR4, increased in the peribiliary glands and lining epithelia in hepatolithiatic livers. This increased expression of endodermal S/P cell markers may be related to the increased production of intestinal and gastric mucin and also to the biliary neoplasia associated with the gastric and intestinal phenotypes reported in hepatolithiasis.
CONCLUSION: The unique expression pattern of PDX1 and HES1 and increased expression of endodermal S/P cell markers in the peribiliary glands may be involved in biliary pathophysiologies.
PMCID: PMC3767841  PMID: 24023981
Biliary tree; Peribiliary glands; Pancreatic duodenal homeobox factor 1; Stem cells; Differentiation; Pancreas
8.  Cell adaptation to a physiologically relevant ECM mimic with different viscoelastic properties 
Biomaterials  2006;28(4):671-679.
To successfully induce tissue repair or regeneration in vivo, bioengineered constructs must possess both optimal bioactivity and mechanical strength. This is because cell interaction with the extracellular matrix (ECM) produces two different but concurrent signaling mechanisms: ligation-induced signaling, which depends on ECM biological stimuli, and traction-induced signaling, which depends on ECM mechanical stimuli. In this report, we provide a fundamental understanding of how alterations in mechanical stimuli alone, produced by varying the viscoelastic properties of our bioengineered construct, modulate phenotypic behavior at the whole-cell level. Using a physiologically-relevant ECM mimic composed of hyaluronan and fibronectin, we found that adult human dermal fibroblasts modify their mechanical response in order to match substrate stiffness. More specifically, the cells on stiffer substrates had higher modulus and a more stretched and organized actin cytoskeleton (and vice versa), which translated into larger traction forces exerted on the substrate. This modulation of cellular mechanics had contrasting effects on migration and proliferation, where cells migrated faster on softer substrates while proliferating preferentially on the stiffer ones. These findings implicate substrate rigidity as a critical design parameter in the development of bioengineered constructs aimed at eliciting maximal cell and tissue function.
PMCID: PMC3625367  PMID: 17049594
9.  Validation of reference genes for expression analysis by quantitative real-time PCR in Leptinotarsa decemlineata (Say) 
BMC Research Notes  2013;6:93.
L. decemlineata is an exotic invasive insect pest, and invaded in Xinjiang Uygur autonomous region in China in the 1990s from Kazakhstan. It is a notorious defoliator of potato throughout most of the northern Xinjiang in current, and often causes extremely large yield losses of potato.
The expression stability of nine L. decemlineata house-keeping genes (Actin, ACT1 and ACT2; ADP-ribosylation factor, ARF1 and ARF4; TATA box binding protein, TBP1 and TBP2; ribosomal protein RP4 and RP18; translation elongation factor 1α EF1α) was evaluated by quantitative real-time polymerase chain reaction (qRT-PCR) in seven developmental stages, three larval tissues and two insecticide treatments. The results were analyzed using three software programs: geNorm, NormFinder and BestKeeper. Although there was no consistent ranking observed among the house-keeping genes across the samples, the overall analysis revealed that RP18, RP4, ARF1, and ARF4 were the four most stable house-keeping genes. In contrast, ACT1 and ACT2, two of the most widely used reference genes, had the least stability. Our results suggest that the combined use of the four most stably expressed genes may produce optimal normalization for qRT-PCR.
The expression stability of the house-keeping genes varies among different developing stages, in different tissues and under different experimental conditions. Our results will enable a more accurate and reliable normalization of qRT-PCR data in L. decemlineata.
PMCID: PMC3600673  PMID: 23497596
L. decemlineata; Quantitative real-time PCR; Reference gene; Normalization
10.  A Laboratory Evaluation of Medicinal Herbs Used in China for the Treatment of Hand, Foot, and Mouth Disease 
Enterovirus 71 (EV71) and coxsackievirus A16 (CVA16) are the causative agents of hand, foot, and mouth disease (HFMD). During recent epidemics of HFMD in China, medicinal herbals and preparations containing herbal extracts have demonstrated therapeutic efficacy with relative safety profiles. There have been no microbiological studies to validate their usefulness for HFMD. We selected 12 commonly used herbs for HFMD from government recommended guidelines as well as published reports and tested for their antiviral activity and anti-inflammatory activity. A water extract of Houttuynia cordata Thunb. (HCT) inhibited EV71 infection significantly and was marginally active against CVA16 infection. The IC50 (concentration to have 50% inhibitory effect) values of HCT against a Fuyang strain and a BrCr strain of EV71 were determined at 8.9 μg/mL and 20.6 μg/mL, respectively. Mentha haplocalyx Briq. (MHB) water extract was active against CVA16, with an IC50 value of 70.3 μg/mL. The extract did not exhibit activity against EV71 infection. Although the majority of the extracts showed no activity against viral infection, several extracts demonstrated activity in blocking proinflammatory response by viral infection. This study therefore validates the effectiveness of Chinese herbs for HFMD since some formulations containing the correct combination of the herbs can block viral replication as well as proinflammatory response of HFMD.
PMCID: PMC3608275  PMID: 23554831
11.  Novel cancerization marker, TP53, and its role in distinguishing normal tissue adjacent to cancerous tissue from normal tissue adjacent to benign tissue 
The histopathological and molecular heterogeneity of normal tissue adjacent to cancerous tissue (NTAC) and normal tissue adjacent to benign tissue (NTAB), and the availability of limited specimens make deciphering the mechanisms of carcinogenesis challenging. Our goal was to identify histogenetic biomarkers that could be reliably used to define a transforming fingerprint using RNA in situ hybridization.
We evaluated 15 tumor-related RNA in situ hybridization biomarkers using tumor microarray and samples of seven tumor-adjacent normal tissues from 314 patients. Biomarkers were determined using comprehensive statistical methods (significance of support vector machine-based artificial intelligence and area under curve scoring of classification distribution).
TP53 was found to be a most reliable index (P <10-7; area under curve >87%) for distinguishing NTAC from NTAB, according to the results of a significance panel (BCL10, BECN1, BRCA2, FITH, PTCH11 and TP53).
The genetic alterations in TP53 between NTAC and NTAB may provide new insight into the field of cancerization and tumor transformation.
PMCID: PMC3544683  PMID: 23170979
Cancerization; Genetic biomarkers; Normal tissue adjacent to benign; Normal tissue adjacent to cancer; Tissue microarray
12.  Isochromophilones from an endophytic fungus Diaporthe sp. 
Three new azaphilone compounds, isochromophilones X–XII (1–3), together with two known ones sclerotioramine (4) and isochromophilone VI (5) were isolated from the cultures of an endophytic fungus Diaporthe sp. The structures were elucidated by extensive HRESIMS and NMR spectroscopic analyses. All compounds were tested for their cytotoxicities against five human cancer cell lines by MTT method, among which compound 1 showed moderate inhibitory effects on these cell lines. This was the first report of azaphilones isolated from Diaporthe sp.
Electronic Supplementary Material
Supplementary material is available for this article at 10.1007/s13659-012-0023-2 and is accessible for authorized users.
PMCID: PMC4131592
azaphilone; endophyte; Diaporthe sp.; cytotoxicity
13.  Predicting Residue-Residue Contacts and Helix-Helix Interactions in Transmembrane Proteins Using an Integrative Feature-Based Random Forest Approach 
PLoS ONE  2011;6(10):e26767.
Integral membrane proteins constitute 25–30% of genomes and play crucial roles in many biological processes. However, less than 1% of membrane protein structures are in the Protein Data Bank. In this context, it is important to develop reliable computational methods for predicting the structures of membrane proteins. Here, we present the first application of random forest (RF) for residue-residue contact prediction in transmembrane proteins, which we term as TMhhcp. Rigorous cross-validation tests indicate that the built RF models provide a more favorable prediction performance compared with two state-of-the-art methods, i.e., TMHcon and MEMPACK. Using a strict leave-one-protein-out jackknifing procedure, they were capable of reaching the top L/5 prediction accuracies of 49.5% and 48.8% for two different residue contact definitions, respectively. The predicted residue contacts were further employed to predict interacting helical pairs and achieved the Matthew's correlation coefficients of 0.430 and 0.424, according to two different residue contact definitions, respectively. To facilitate the academic community, the TMhhcp server has been made freely accessible at
PMCID: PMC3203928  PMID: 22046350
14.  Natural orifice transluminal endoscopic surgery: New minimally invasive surgery come of age 
Although in the past two decades, laparoscopic surgery, considered as a great revolution in the minimally invasive surgery field, has undergone major development worldwide, another dramatic surgical revolution has quietly appeared in recent years. Ever since Kalloo’s first report on transgastric peritoneoscopy in a porcine model in 2004, interest in a new surgical procedure named natural orifice transluminal endoscopic surgery (NOTES) has blossomed worldwide. Considering that a NOTES procedure could theoretically avoid any abdominal incision, operation-related pain and scarring, many surgeons and endoscopists have been enthusiastic in their study of this new technique. In recent years, several NOTES studies have been carried out on porcine models and even on humans, including transvaginal cholecystectomy, transgastric appendectomy, transvaginal appendectomy, and transvesical peritoneoscopy. So what is the current situation of NOTES and how many challenges do we still face? This review discusses the current research progress in NOTES.
PMCID: PMC3218151  PMID: 22110263
Laparoscopic surgery; Natural orifice transluminal endoscopic surgery; Endoscopy
15.  Prediction of Ubiquitination Sites by Using the Composition of k-Spaced Amino Acid Pairs 
PLoS ONE  2011;6(7):e22930.
As one of the most important reversible protein post-translation modifications, ubiquitination has been reported to be involved in lots of biological processes and closely implicated with various diseases. To fully decipher the molecular mechanisms of ubiquitination-related biological processes, an initial but crucial step is the recognition of ubiquitylated substrates and the corresponding ubiquitination sites. Here, a new bioinformatics tool named CKSAAP_UbSite was developed to predict ubiquitination sites from protein sequences. With the assistance of Support Vector Machine (SVM), the highlight of CKSAAP_UbSite is to employ the composition of k-spaced amino acid pairs surrounding a query site (i.e. any lysine in a query sequence) as input. When trained and tested in the dataset of yeast ubiquitination sites (Radivojac et al, Proteins, 2010, 78: 365–380), a 100-fold cross-validation on a 1∶1 ratio of positive and negative samples revealed that the accuracy and MCC of CKSAAP_UbSite reached 73.40% and 0.4694, respectively. The proposed CKSAAP_UbSite has also been intensively benchmarked to exhibit better performance than some existing predictors, suggesting that it can be served as a useful tool to the community. Currently, CKSAAP_UbSite is freely accessible at Moreover, we also found that the sequence patterns around ubiquitination sites are not conserved across different species. To ensure a reasonable prediction performance, the application of the current CKSAAP_UbSite should be limited to the proteome of yeast.
PMCID: PMC3146527  PMID: 21829559
16.  Fibronectin Growth Factor-Binding Domains Are Required for Fibroblast Survival 
Fibronectin (FN) is required for embryogenesis, morphogenesis, and wound repair, and its Arg–Gly–Asp-containing central cell-binding domain (CCBD) is essential for mesenchymal cell survival and growth. Here, we demonstrate that FN contains three growth factor-binding domains (FN-GFBDs) that bind platelet-derived growth factor-BB (PDGF-BB), a potent fibroblast survival and mitogenic factor. These sites bind PDGF-BB with dissociation constants of 10–100 nm. FN-null cells cultured on recombinant CCBD (FNIII8–11) without a FN-GFBD demonstrated minimal metabolism and underwent autophagy at 24 hours, followed by apoptosis at 72 hours, even in the presence of PDGF-BB. In contrast, FN-null cells plated on FNIII8–11 contiguous with FN-GFBD survived without, and proliferated with, PDGF-BB. FN-null cell survival on FNIII8–11 and noncontiguous arrays of FN-GFBDs required these domains to be adsorbed on the same surface, suggesting the existence of a mesenchymal cell-extracellular matrix synapse. Thus, fibroblast survival required GF stimulation in the presence of a FN-GFBD, as well as adhesion to FN through the CCBD. The findings that fibroblast survival is dependent on FN-GFBD underscore the critical importance of pericellular matrix for cell survival and have significant implications for cutaneous wound healing and regeneration.
PMCID: PMC3139177  PMID: 20811396
17.  Caroli's Disease: Current Knowledge of Its Biliary Pathogenesis Obtained from an Orthologous Rat Model 
Caroli's disease belongs to a group of hepatic fibropolycystic diseases and is a hepatic manifestation of autosomal recessive polycystic kidney disease (ARPKD). It is a congenital disorder characterized by segmental saccular dilatations of the large intrahepatic bile duct and is frequently associated with congenital hepatic fibrosis (CHF). The most viable theory explaining its pathogenesis suggests that it is related to ductal plate malformation. The development of the polycystic kidney (PCK) rat, an orthologous rodent model of Caroli's disease with CHF as well as ARPKD, has allowed the molecular pathogenesis of the disease and the therapeutic options for its treatment to be examined. The relevance of the findings of studies using PCK rats and/or the cholangiocyte cell line derived from them to the pathogenesis of human Caroli's disease is currently being analyzed. Fibrocystin/polyductin, the gene product responsible for ARPKD, is normally localized to primary cilia, and defects in the fibrocystin from primary cilia are observed in PCK cholangiocytes. Ciliopathies involving PCK cholangiocytes (cholangiociliopathies) appear to be associated with decreased intracellular calcium levels and increased cAMP concentrations, causing cholangiocyte hyperproliferation, abnormal cell matrix interactions, and altered fluid secretion, which ultimately result in bile duct dilatation. This article reviews the current knowledge about the pathogenesis of Caroli's disease with CHF, particularly focusing on studies of the mechanism responsible for the biliary dysgenesis observed in PCK rats.
PMCID: PMC3168917  PMID: 22007315
18.  Hopeahainol C monohydrate 
In the structure of the title compound, C28H16O6·H2O [systematic name 3,11-bis(4-hydroxyphenyl)-4,12-dioxapentacyclo[,5.013,17.09,18]octadeca-1(16),2,5(18),6,8,10,13(17),14-octaene-7,15-diol monohydrate], the hopeahainol C mol­ecule lies about an inversion center with the solvent water mol­ecule located on a crystallographic twofold axis. Hopeahainol C is an oligostillbenoid compound and was isolated from the bark of Shorea roxburghii G. Don. The five central fused rings are essentially planar with an r.m.s. deviation of 0.0173 (3) Å. The 4-hy­droxy­phenyl ring is twisted with respect to this plane, with the dihedral angle between the phenyl ring and the fused-ring system being 41.70 (10)°. The crystal features inter­molecular O—H⋯O hydrogen bonds. These inter­actions link the hopeahainol C mol­ecules into chains along the b axis. Water mol­ecules are located inter­stitially between the hopeahainol C mol­ecules linked by O(water)—H⋯O(hy­droxy) and O(hy­droxy)—H⋯O(water) hydrogen bonds. π–π inter­actions are also observed with centroid–centroid distances of 3.6056 (17) and 3.5622 (17) Å. Short O⋯O contacts [2.703 (2)–2.720 (3) Å] are also present in the crystal.
PMCID: PMC3120350  PMID: 21754780
19.  Outer membrane proteins can be simply identified using secondary structure element alignment 
BMC Bioinformatics  2011;12:76.
Outer membrane proteins (OMPs) are frequently found in the outer membranes of gram-negative bacteria, mitochondria and chloroplasts and have been found to play diverse functional roles. Computational discrimination of OMPs from globular proteins and other types of membrane proteins is helpful to accelerate new genome annotation and drug discovery.
Based on the observation that almost all OMPs consist of antiparallel β-strands in a barrel shape and that their secondary structure arrangements differ from those of other types of proteins, we propose a simple method called SSEA-OMP to identify OMPs using secondary structure element alignment. Through intensive benchmark experiments, the proposed SSEA-OMP method is better than some well-established OMP detection methods.
The major advantage of SSEA-OMP is its good prediction performance considering its simplicity. The web server implements the method is freely accessible at
PMCID: PMC3072342  PMID: 21414186
20.  A Novel Neural Substrate for the Transformation of Olfactory Inputs into Motor Output 
PLoS Biology  2010;8(12):e1000567.
Anatomical and physiological experiments in the lamprey reveal the neural circuit involved in transforming olfactory inputs into motor outputs, which was previously unknown in a vertebrate.
It is widely recognized that animals respond to odors by generating or modulating specific motor behaviors. These reactions are important for daily activities, reproduction, and survival. In the sea lamprey, mating occurs after ovulated females are attracted to spawning sites by male sex pheromones. The ubiquity and reliability of olfactory-motor behavioral responses in vertebrates suggest tight coupling between the olfactory system and brain areas controlling movements. However, the circuitry and the underlying cellular neural mechanisms remain largely unknown. Using lamprey brain preparations, and electrophysiology, calcium imaging, and tract tracing experiments, we describe the neural substrate responsible for transforming an olfactory input into a locomotor output. We found that olfactory stimulation with naturally occurring odors and pheromones induced large excitatory responses in reticulospinal cells, the command neurons for locomotion. We have also identified the anatomy and physiology of this circuit. The olfactory input was relayed in the medial part of the olfactory bulb, in the posterior tuberculum, in the mesencephalic locomotor region, to finally reach reticulospinal cells in the hindbrain. Activation of this olfactory-motor pathway generated rhythmic ventral root discharges and swimming movements. Our study bridges the gap between behavior and cellular neural mechanisms in vertebrates, identifying a specific subsystem within the CNS, dedicated to producing motor responses to olfactory inputs.
Author Summary
Animal behaviors, including locomotion, can be driven by olfactory cues, such as pheromones or food sources. The neural substrate (neuroanatomical connections and physiological signals) that permits the transformation of olfactory inputs into locomotor responses is still unknown in vertebrates. In the present study, we identify such a neural substrate in the lamprey. Here, olfactory signals from the outside world are transmitted to the reticulospinal neurons in the lower brainstem, which provide the descending locomotor command to the spinal cord. We found that this circuit originates in the medial portion of the olfactory bulb and that connections are made in the posterior tuberculum, a ventral diencephalic structure. These inputs are then conveyed to the mesencephalic locomotor region, known to project extensively to brainstem reticulospinal neurons and thereby activate locomotion. Our results illuminate a specific dedicated neural substrate in the brain of lampreys that underlies olfactory-motor responses, which is activated by both food-related or pheromonal olfactory cues. It will be of interest to determine whether such a pathway is preserved in all vertebrates.
PMCID: PMC3006349  PMID: 21203583
21.  CADgene: a comprehensive database for coronary artery disease genes 
Nucleic Acids Research  2010;39(Database issue):D991-D996.
Coronary artery disease (CAD) is a complex, multifactorial disease and a leading cause of mortality world wide. Over the past decades, great efforts have been made to elucidate the underlying genetic basis of CAD and massive data have been accumulated. To integrate these data together and to provide a useful resource for researchers, we developed the CADgene, a comprehensive database for CAD genes. We manually extracted CAD-related evidence for more than 300 candidate genes for CAD from over 1300 publications of genetic studies. We classified these candidate genes into 12 functional categories based on their roles in CAD. For each gene, we extracted detailed information from related studies (e.g. the size of case–control, population, SNP, odds ratio, P-value, etc.) and made useful annotations, which include general gene information, Gene Ontology annotations, KEGG pathways, protein–protein interactions and others. Besides the statistical number of studies for each gene, CADgene also provides tools to search and show the most frequently studied candidate genes. In addition, CADgene provides cumulative data from 11 publications of CAD-related genome-wide association studies. CADgene has a user-friendly web interface with multiple browse and search functions. It is freely available at
PMCID: PMC3013698  PMID: 21045063
22.  Anti-proliferative and pro-apoptotic effects of tectorigenin on hepatic stellate cells 
AIM: To investigate the effect of tectorigenin on proliferation and apoptosis of hepatic stellate cells (HSC)-T6 cells.
METHODS: HSC-T6 cells were incubated with tectorigenin at different concentrations, and their proliferation was assessed by bromodeoxyuridine incorporation assay. Apoptosis was detected by flow cytometry assay with Hoechst 33342 staining. Also, generation of reactive oxygen species (ROS), intracellular [Ca2+]i, potential of mitochondrial membrane, activities of cytochrome c and caspase-9 and -3 were investigated to explore a conceivable apoptotic pathway.
RESULTS: Tectorigenin suppressed the proliferation of HSC-T6 cells and induced apoptosis of HSC-T6 cells in a time- and dose-dependent manner. Tectorigenin at the concentration of 100 μg/mL greatly inhibited the viability of HSC-T6 cells and induced the condensation of chromatin and fragmentation of nuclei. When treated for 48 h, the percentage of cell growth and apoptosis reached 46.3% ± 2.37% (P = 0.004) and 50.67% ± 3.24% (P = 0.003), respectively. Furthermore, tectorigenin-induced apoptosis of HSC-T6 cells was associated with the generation of ROS, increased intracellular [Ca2+]i, loss of mitochondrial membrane potential, translocation of cytochrome c, and activation of caspase-9 and -3.
CONCLUSION: Tectorigenin inhibits proliferation of HSC-T6 cells and induces apoptosis of HSC-T6 cells.
PMCID: PMC2923765  PMID: 20712052
Tectorigenin; Apoptosis; Hepatic stellate cells; Hepatic fibrosis; Mitochondria; Proliferation
23.  TIM-Finder: A new method for identifying TIM-barrel proteins 
The triosephosphate isomerase (TIM)-barrel fold occurs frequently in the proteomes of different organisms, and the known TIM-barrel proteins have been found to play diverse functional roles. To accelerate the exploration of the sequence-structure protein landscape in the TIM-barrel fold, a computational tool that allows sensitive detection of TIM-barrel proteins is required.
To develop a new TIM-barrel protein identification method in this work, we consider three descriptors: a sequence-alignment-based descriptor using PSI-BLAST e-values and bit scores, a descriptor based on secondary structure element alignment (SSEA), and a descriptor based on the occurrence of PROSITE functional motifs. With the assistance of Support Vector Machine (SVM), the three descriptors were combined to obtain a new method with improved performance, which we call TIM-Finder. When tested on the whole proteome of Bacillus subtilis, TIM-Finder is able to detect 194 TIM-barrel proteins at a 99% confidence level, outperforming the PSI-BLAST search as well as one existing fold recognition method.
TIM-Finder can serve as a competitive tool for proteome-wide TIM-barrel protein identification. The TIM-Finder web server is freely accessible at
PMCID: PMC2803183  PMID: 20003393
24.  DescFold: A web server for protein fold recognition 
BMC Bioinformatics  2009;10:416.
Machine learning-based methods have been proven to be powerful in developing new fold recognition tools. In our previous work [Zhang, Kochhar and Grigorov (2005) Protein Science, 14: 431-444], a machine learning-based method called DescFold was established by using Support Vector Machines (SVMs) to combine the following four descriptors: a profile-sequence-alignment-based descriptor using Psi-blast e-values and bit scores, a sequence-profile-alignment-based descriptor using Rps-blast e-values and bit scores, a descriptor based on secondary structure element alignment (SSEA), and a descriptor based on the occurrence of PROSITE functional motifs. In this work, we focus on the improvement of DescFold by incorporating more powerful descriptors and setting up a user-friendly web server.
In seeking more powerful descriptors, the profile-profile alignment score generated from the COMPASS algorithm was first considered as a new descriptor (i.e., PPA). When considering a profile-profile alignment between two proteins in the context of fold recognition, one protein is regarded as a template (i.e., its 3D structure is known). Instead of a sequence profile derived from a Psi-blast search, a structure-seeded profile for the template protein was generated by searching its structural neighbors with the assistance of the TM-align structural alignment algorithm. Moreover, the COMPASS algorithm was used again to derive a profile-structural-profile-alignment-based descriptor (i.e., PSPA). We trained and tested the new DescFold in a total of 1,835 highly diverse proteins extracted from the SCOP 1.73 version. When the PPA and PSPA descriptors were introduced, the new DescFold boosts the performance of fold recognition substantially. Using the SCOP_1.73_40% dataset as the fold library, the DescFold web server based on the trained SVM models was further constructed. To provide a large-scale test for the new DescFold, a stringent test set of 1,866 proteins were selected from the SCOP 1.75 version. At a less than 5% false positive rate control, the new DescFold is able to correctly recognize structural homologs at the fold level for nearly 46% test proteins. Additionally, we also benchmarked the DescFold method against several well-established fold recognition algorithms through the LiveBench targets and Lindahl dataset.
The new DescFold method was intensively benchmarked to have very competitive performance compared with some well-established fold recognition methods, suggesting that it can serve as a useful tool to assist in template-based protein structure prediction. The DescFold server is freely accessible at
PMCID: PMC2803855  PMID: 20003426
25.  Hepatitis B virus infection contributes to oxidative stress in a population exposed to aflatoxin B1 and high-risk for hepatocellular carcinoma 
Cancer letters  2008;263(2):212-222.
Biomarkers of Hepatitis B Virus (HBV) infection, aflatoxin B1 (AFB1) exposure and oxidative stress were detected in 71 hepatocellular carcinoma (HCC) patients and 694 controls from southern China. Plasma level of AFB1-Albumin-Adducts (AAA) and protein carbonyl content (PCC) were significantly higher in the 71 HCC cases than in any age/gender matched HBV sero-status groups (P<0.001). HCC patients positive for the p53-249 G-T mutation had a marginally higher level of PCC than those negative for the mutation (p=0.077). HBV infection had a prominent influence on the association between AFB1 exposure and oxidative stress biomarkers in the controls. Our study indicates a significant contribution from HBV infection to oxidative stress in a population with AFB1 exposure which might substantially increase risk for HCC in this region.
PMCID: PMC2676441  PMID: 18280645
HBV; Aflatoxin; oxidative stress; hepatocellular carcinoma

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