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1.  Interleukin-7 Produced by Intestinal Epithelial Cells in Response to Citrobacter rodentium Infection Plays a Major Role in Innate Immunity against This Pathogen 
Infection and Immunity  2015;83(8):3213-3223.
Interleukin-7 (IL-7) engages multiple mechanisms to overcome chronic viral infections, but the role of IL-7 in bacterial infections, especially enteric bacterial infections, remains unclear. Here we characterized the previously unexplored role of IL-7 in the innate immune response to the attaching and effacing bacterium Citrobacter rodentium. C. rodentium infection induced IL-7 production from intestinal epithelial cells (IECs). IL-7 production from IECs in response to C. rodentium was dependent on gamma interferon (IFN-γ)-producing NK1.1+ cells and IL-12. Treatment with anti-IL-7Rα antibody during C. rodentium infection resulted in a higher bacterial burden, enhanced intestinal damage, and greater weight loss and mortality than observed with the control IgG treatment. IEC-produced IL-7 was only essential for protective immunity against C. rodentium during the first 6 days after infection. An impaired bacterial clearance upon IL-7Rα blockade was associated with a significant decrease in macrophage accumulation and activation in the colon. Moreover, C. rodentium-induced expansion and activation of intestinal CD4+ lymphoid tissue inducer (LTi) cells was completely abrogated by IL-7Rα blockade. Collectively, these data demonstrate that IL-7 is produced by IECs in response to C. rodentium infection and plays a critical role in the protective immunity against this intestinal attaching and effacing bacterium.
PMCID: PMC4496619  PMID: 26034215
2.  Vaccines in the treatment of invasive candidiasis 
Virulence  2015;6(4):309-315.
Candida albicans is the most common cause of hematogenously disseminated candidiasis, and this disease is particularly prevalent in immunocompromised patients. The mortality of invasive candidiasis remains 40% to 50% even with the proper treatment with current antifungal drugs. Recently, with the better understanding of host-fungus interactions, notable progress has been made in antifungal vaccine research. Most antifungal vaccines exert protection by inducing either (or both) B-cell and T-cell responses. Here we summarize the current available information on C. albicans vaccines, highlight the obstacles that researchers identified, and offer several suggestions.
PMCID: PMC4601158  PMID: 25559739
Candida albicans; immune response; invasive candidiasis; vaccine; virulence
3.  Abolishing Cell Wall Glycosylphosphatidylinositol-Anchored Proteins in Candida albicans Enhances Recognition by Host Dectin-1 
Infection and Immunity  2015;83(7):2694-2704.
Fungi can shield surface pathogen-associated molecular patterns (PAMPs) for evading host immune attack. The most common and opportunistic human pathogen, Candida albicans, can shield β-(1 3)-glucan on the cell wall, one of the major PAMPs, to avoid host phagocyte Dectin-1 recognition. The way to interfere in the shielding process for more effective antifungal defense is not well established. In this study, we found that deletion of the C. albicans GPI7 gene, which was responsible for adding ethanolaminephosphate to the second mannose in glycosylphosphatidylinositol (GPI) biosynthesis, could block the attachment of most GPI-anchored cell wall proteins (GPI-CWPs) to the cell wall and subsequently unmask the concealed β-(1,3)-glucan. Neutrophils could kill the uncloaked gpi7 mutant more efficiently with an augmented respiratory burst. The gpi7 mutant also stimulated Dectin-1-dependent immune responses of macrophages, including activation of nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) pathways and secretion of specific cytokines, such as tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), and IL-12p40. Furthermore, the gpi7 null mutant could induce an enhanced inflammatory response through promoting significant recruitment of neutrophils and monocytes and could stimulate stronger Th1 and Th17 cell responses to fungal infections in vivo. These in vivo phenotypes also were Dectin-1 dependent. Thus, we assume that GPI-CWPs are involved in the immune mechanism of C. albicans escaping from host recognition by Dectin-1. Our studies also indicate that the blockage of GPI anchor synthesis is a strategy to inhibit C. albicans evading host recognition.
PMCID: PMC4468527  PMID: 25895969
4.  The Historical Speciation of Mauremys Sensu Lato: Ancestral Area Reconstruction and Interspecific Gene Flow Level Assessment Provide New Insights 
PLoS ONE  2015;10(12):e0144711.
Mauremys sensu lato was divided into Mauremys, Chinemys, Ocadia, and Annamemys based on earlier research on morphology. Phylogenetic research on this group has been controversial because of disagreements regarding taxonomy, and the historical speciation is still poorly understood. In this study, 32 individuals of eight species that are widely distributed in Eurasia were collected. The complete mitochondrial (mt) sequences of 14 individuals of eight species were sequenced. Phylogenetic relationships, interspecific divergence times, and ancestral area reconstructions were explored using mt genome data (10,854 bp). Subsequent interspecific gene flow level assessment was performed using five unlinked polymorphic microsatellite loci. The Bayesian and maximum likelihood analyses revealed a paraphyletic relationship among four old genera (Mauremys, Annamemys, Chinemys, and Ocadia) and suggested the four old genera should be merged into the genus (Mauremys). Ancestral area reconstruction and divergence time estimation suggested Southeast Asia may be the area of origin for the common ancestral species of this genus and genetic drift may have played a decisive role in species divergence due to the isolated event of a glacial age. However, M. japonica may have been speciated due to the creation of the island of Japan. The detection of extensive gene flow suggested no vicariance occurred between Asia and Southeast Asia. Inconsistent results between gene flow assessment and phylogenetic analysis revealed the hybrid origin of M. mutica (Southeast Asian). Here ancestral area reconstruction and interspecific gene flow level assessment were first used to explore species origins and evolution of Mauremys sensu lato, which provided new insights on this genus.
PMCID: PMC4678219  PMID: 26657158
5.  Methods of the International Tobacco Control (ITC) China Survey: Waves 1, 2, and 3 
Tobacco control  2014;24(0 4):iv1-iv5.
This paper describes the methods of sampling design and data collection of Waves 1, 2, and 3 of the ITC China Survey, with major focus on longitudinal features of the study. Key measures of quality of the survey data, such as retention rates and final sample sizes, are presented. Sample replenishment procedures are outlined, including the addition of a new city, Kunming, at Wave 3. Methods for constructing the longitudinal and cross-sectional survey weights are briefly described.
PMCID: PMC4673048  PMID: 25550421
Sampling design; longitudinal survey; replenishment sample; retention rates; longitudinal survey weights; cross-sectional survey weights
6.  Individual and interpersonal triggers to quit smoking in China: a cross-sectional analysis 
Tobacco control  2015;24(0 4):iv40-iv47.
To determine the most prominent individual and interpersonal triggers to quit smoking in China and their associations with socio-demographic characteristics.
Data come from Waves 1-3 (2006-2009) of the ITC China Survey, analysed cross-sectionally as person-waves (N=14,358). Measures included socio-demographic and smoking characteristics. Those who quit between waves (4.3%) were asked about triggers that “very much” led them to stop smoking, and continuing smokers about triggers that “very much” made them think about quitting. Triggers covered individual (personal health concerns, cigarette price, smoking restrictions, advertisements, warning labels) and interpersonal factors (family/societal disapproval of smoking, setting an example to children, concerns about second-hand smoke).
Over a third of respondents (34.9%) endorsed at least one trigger strongly; quitters were more likely than smokers to mention any trigger. While similar proportions of smokers endorsed individual (24.4%) and interpersonal triggers (24.0%), quitters endorsed more individual (61.1%) than interpersonal (48.3%) triggers. However, the most common triggers (‘personal health concerns’; ‘setting an example to children’) were the same, endorsed by two-thirds of quitters and a quarter of smokers, as were the least common triggers (‘warning labels’; ‘cigarette price’), endorsed by one in ten quitters and one in twenty smokers. Lower dependence among smokers and greater education among all respondents were associated with endorsing any trigger.
Individual rather than interpersonal triggers appear more important for quitters. Major opportunities to motivate quit attempts are missed in China, particularly with regard to taxation and risk communication. Interventions need to focus on more dependent and less-educated smokers.
PMCID: PMC4644698  PMID: 25888422
triggers to stop; China; tobacco control; motivation to stop; smoking cessation
7.  Determinants of smoking-induced deprivation in China 
Tobacco control  2014;24(0 4):iv35-iv39.
Spending on cigarettes may deprive households of other items like food. The goal of this study was to examine the prevalence of and factors associated with this smoking-induced deprivation among adult smokers in China.
The data came from waves 1–3 of the International Tobacco Control (ITC) China Survey, conducted from 2006 to 2009 among urban adults aged 18 years or older in China. We focus on the samples of current smokers from six cities (N=7981). Smoking-induced deprivation was measured with the survey question, “In the last six months, have you spent money on cigarettes that you knew would be better spent on household essentials like food?” We examined whether sociodemographic factors, smoking intensity and price paid per pack of cigarettes were associated with smoking-induced deprivation using generalised estimating equations modelling.
7.3% of smokers reported smoking-induced deprivation due to purchasing cigarettes. Low-income and middle-income smokers were more likely to have smoking-induced deprivation compared with high-income smokers (adjusted OR (AOR)=2.06, 95% CI 1.32 to 2.31; AOR=1.44, 95% CI 1.10 to 1.69); smokers living in Shenyang (AOR=1.68, 95% CI 1.25 to 2.24) and Yinchuan (AOR=2.50, 95% CI 1.89 to 3.32) were more likely to have smoking-induced deprivation compared with smokers living in Beijing. Retired smokers were less likely to have smoking-induced deprivation compared with employed smokers (AOR=0.67, 95% CI 0.52 to 0.87). There was no statistically significant relationship between smoking intensity, price paid per pack of cigarettes and smoking-induced deprivation.
Our findings indicate that certain groups of smokers in China acknowledge spending money on cigarettes that could be better spent on household essentials. Tobacco control policies that reduce smoking in China may improve household living standards by reducing smoking-induced deprivation.
PMCID: PMC4398649  PMID: 24827978
Tobacco control  2014;24(0 4):iv28-iv34.
To date there is limited published evidence on the efficacy of tobacco control mass media campaigns in China. This study aimed to evaluate the impact of a mass media campaign “Giving Cigarettes is Giving Harm” (GCGH) on Chinese smokers’ knowledge of smoking-related harms and attitudes toward cigarette gifts.
Population-based, representative data were analyzed from a longitudinal cohort of 3,709 adult smokers who participated in the International Tobacco Control China Survey conducted in six Chinese cities before and after the campaign. Logistic regression models were estimated to examine associations between campaign exposure and attitudes about cigarettes as gifts measured post-campaign. Poisson regression models were estimated to assess the effects of campaign exposure on post-campaign knowledge, adjusting for pre-campaign knowledge.
Fourteen percent (n=335) of participants recalled the campaign within the cities where the GCGH campaign was implemented. Participants in the intervention cities who recalled the campaign were more likely to disagree that cigarettes are good gifts (71% vs. 58%, p<0.01) and had greater levels of campaign-targeted knowledge than those who did not recall the campaign (Mean=1.97 vs. 1.62, p<0.01). Disagreeing that cigarettes are good gifts was higher in intervention cities than in control cities. Changes in campaign-targeted knowledge were similar in both cities, perhaps due to a secular trend, low campaign recall, or contamination issues.
These findings suggest that the GCGH campaign increased knowledge of smoking harms, which could promote downstream cessation. Findings provide evidence to support future campaign development to effectively fight the tobacco epidemic in China.
PMCID: PMC4580527  PMID: 24813427
Low/Middle income country; Media; Social marketing; Prevention; Tobacco control campaign evaluation
9.  ECG-Based Detection of Early Myocardial Ischemia in a Computational Model: Impact of Additional Electrodes, Optimal Placement, and a New Feature for ST Deviation 
BioMed Research International  2015;2015:530352.
In case of chest pain, immediate diagnosis of myocardial ischemia is required to respond with an appropriate treatment. The diagnostic capability of the electrocardiogram (ECG), however, is strongly limited for ischemic events that do not lead to ST elevation. This computational study investigates the potential of different electrode setups in detecting early ischemia at 10 minutes after onset: standard 3-channel and 12-lead ECG as well as body surface potential maps (BSPMs). Further, it was assessed if an additional ECG electrode with optimized position or the right-sided Wilson leads can improve sensitivity of the standard 12-lead ECG. To this end, a simulation study was performed for 765 different locations and sizes of ischemia in the left ventricle. Improvements by adding a single, subject specifically optimized electrode were similar to those of the BSPM: 2–11% increased detection rate depending on the desired specificity. Adding right-sided Wilson leads had negligible effect. Absence of ST deviation could not be related to specific locations of the ischemic region or its transmurality. As alternative to the ST time integral as a feature of ST deviation, the K point deviation was introduced: the baseline deviation at the minimum of the ST-segment envelope signal, which increased 12-lead detection rate by 7% for a reasonable threshold.
PMCID: PMC4637443  PMID: 26587538
10.  The Role of Mms22p in DNA Damage Response in Candida albicans 
G3: Genes|Genomes|Genetics  2015;5(12):2567-2578.
To ensure correct DNA replication, eukaryotes have signaling pathways that respond to replication-associated DNA damage and trigger repair. In both Saccharomyces cerevisiae and Schizosaccharomyces pombe, a complex of proteins, including the cullin protein Rtt101p and two adapter proteins Mms22p and Mms1p, is important for proper response to replication stress. We have investigated this system in Candida albicans. In this pathogen, Mms22p is important for recovery from DNA replication damage induced by agents including methylmethane sulfonate, camptothecin, and ionizing radiation. Although no clear ortholog of Mms1p has been identified in C. albicans, loss of either Mms22p or Rtt101p generates similar damage sensitivity, consistent with a common function. In S. cerevisiae, the Mrc1p−Csm3p−Tof1p complex stabilizes stalled replication forks and activates a replication checkpoint and interacts with Mms22p. A similar complex in S. pombe, consisting of the Tof1p and Csm3p orthologs Swi1p and Swi3p, along with the fission yeast Mrc1p, genetically also interacts with Mms22p. Intriguingly in C. albicans only Mrc1p and Csm3p appear involved in damage repair, and Mms22p is required for responding to DNA damage agents in MRC1 or CSM3 conditional mutants. In C. albicans, although the loss of RAD57 greatly impairs response in the pathogen to many DNA-damaging agents, lethality due to camptothecin damage requires concomitant loss of Rad57p and Mms22p, suggesting that Mms22p is only essential for homologous recombination induced by camptothecin. These results establish that although C. albicans uses conserved cellular modules to respond to DNA damage and replication blocks, the specific details of these modules differ significantly from the S. cerevisiae model.
PMCID: PMC4683630  PMID: 26438292
genomic stability; DNA repair; replication fork; homologous recombination; Candida albicans
11.  Identifying Genetic Variants for Addiction via Propensity Score Adjusted Generalized Kendall’s Tau 
Identifying replicable genetic variants for addiction has been extremely challenging. Besides the common difficulties with genome-wide association studies (GWAS), environmental factors are known to be critical to addiction, and comorbidity is widely observed. Despite the importance of environmental factors and comorbidity for addiction study, few GWAS analyses adequately considered them due to the limitations of the existing statistical methods. Although parametric methods have been developed to adjust for covariates in association analysis, difficulties arise when the traits are multivariate because there is no ready-to-use model for them. Recent nonparametric development includes U-statistics to measure the phenotype-genotype association weighted by a similarity score of covariates. However, it is not clear how to optimize the similarity score. Therefore, we propose a semiparametric method to measure the association adjusted by covariates. In our approach, the nonparametric U-statistic is adjusted by parametric estimates of propensity scores using the idea of inverse probability weighting. The new measurement is shown to be asymptotically unbiased under our null hypothesis while the previous non-weighted and weighted ones are not. Simulation results show that our test improves power as opposed to the non-weighted and two other weighted U-statistic methods, and it is particularly powerful for detecting gene-environment interactions. Finally, we apply our proposed test to the Study of Addiction: Genetics and Environment (SAGE) to identify genetic variants for addiction. Novel genetic variants are found from our analysis, which warrant further investigation in the future.
PMCID: PMC4219655  PMID: 25382885
Addiction; Comorbidity; Genome-wide association study; Inverse probability weighting; Substance dependence
12.  Conformational dynamics of human FXR-LBD ligand interactions studied by hydrogen/deuterium exchange mass spectrometry: Insights into the antagonism of the hypolipidemic agent Z-guggulsterone 
Biochimica et biophysica acta  2014;1844(9):1684-1693.
Farnesoid X Receptor (FXR) is a member of the nuclear receptor superfamily of transcription factors that plays a key role in the regulation of bile acids, lipid and glucose metabolisms. The regulative function of FXR is governed by conformational changes of the ligand binding domain (LBD) upon ligand binding. Although FXR is a highly researched potential therapeutic target, only a limited number of FXR-agonist complexes have been successfully crystallized and subsequently yielded high resolution structures. There is currently no structural information of any FXR-antagonist complexes publically available. We therefore explored the use of amide hydrogen/deuterium exchange (HDX) coupled with mass spectrometry for characterizing conformational changes in the FXR-LBD upon ligand binding. Ligand-specific deuterium incorporation profiles were obtained for three FXR ligand chemotypes: GW4064, a synthetic non-steroidal high affinity agonist; the bile acid chenodeoxycholic acid (CDCA), the endogenous low affinity agonist of FXR; and Z-guggulsterone (GG), an in vitro antagonist of the steroid chemotype. Comparison of the HDX profiles of their ligand-bound FXR-LBD complexes revealed a unique mode of interaction for GG. The conformational features of the FXR-LBD-antagonist interaction are discussed.
PMCID: PMC4137978  PMID: 24953769
Farnesoid X receptor; hydrogen/deuterium exchange; mass spectrometry; conformation; dynamics; ligand interaction; guggulsterone
13.  Reported exposures to anti-smoking messages and their impact on Chinese smoker’s subsequent quit attempts 
This study aimed to examine Chinese smokers’ exposure to anti-smoking messages in a range of channels and to determine if exposure was associated with subsequent quit attempts.
A prospective cohort design was employed. Participants were 6,509 adult smokers who completed at least one of the first three waves (2006–2009) of the International Tobacco Control (ITC) China Survey, sampled from six Chinese cities. The main measures were reported exposure to anti-smoking messages in a range of channels and smokers’ subsequent quit attempts. Generalized Estimating Equations (GEE) modelling was used to combine respondents from all three waves while accounting for inherent within-person correlation.
The overall exposure levels to anti-smoking messages were low and varied between cities and from one channel to another. Television was the medium with the greatest overall exposure (over 50% in almost all the cities across all the waves). After controlling for a range of covariates, higher level of combined exposure were positively related to higher subsequent quit attempts (adjusted odd ratio=1.03, 95% CI 1.02~1.05, p<.001); among the individual channels exposures in newspapers and on posters were significant in their own right.
The findings suggest that anti-smoking warning messages have the potential to stimulate Chinese smokers to make quit attempts, but they also indicate that the levels and strength of warning messages in China needs to be increased. China should consider adopting proven international practices, including mandating pictorial health warnings on cigarette packages, adopting prominent point-of-sale warnings, and carrying out strong and ongoing mass media campaigns.
PMCID: PMC4546845  PMID: 24078490
health warnings; smoking cessation; longitudinal research; China
14.  Smoking-related thoughts and microbehaviours and their predictive power for quitting: Findings from the International Tobacco Control (ITC) China Survey 
Tobacco control  2014;24(4):354-361.
Negative attitudes to smoking are well-established predictors of intentions to quit and quit behaviours, but less attention has been given to whether quitting is influenced by smoking-related thoughts and microbehaviours that reflect a concern about smoking.
This paper aimed to describe the occurrence of smoking-related thoughts and microbehaviours among Chinese smokers and to examine their predictive power for making quit attempts and sustained abstinence.
The data came from the first three waves of the International Tobacco Control China Survey. Four measures of recent thoughts about smoking and two microbehaviour measures (collectively referred to as micro indicators) were examined.
Most smokers (around three quarters) reported thinking about harms of smoking to themselves or to others at least occasionally, and an increasing minority reported the two microbehaviours of prematurely butting out cigarettes and forgoing them. All micro indicators were positively related to subsequent quit attempts in individual predictor analyses, but only serious thoughts about quitting and -butting out cigarettes had independent relationships. Overall, there was no clear relationship between these micro indicators and sustained abstinence.
There was a moderately high level of occurrence of recent smoking-related thoughts and microbehaviours among the Chinese adult smokers in the six cities studied. Like in the west, micro indicators of concern about smoking were positively associated with subsequent quit attempts, but unlike in the west, they were largely unrelated to sustained abstinence.
PMCID: PMC4532545  PMID: 24570098
health concern about smoking; micro-behaviour; smoking cessation; longitudinal research; China
16.  AB114. Analyses of 77 multilocular cystic renal cell carcinoma cases from a single center 
Translational Andrology and Urology  2015;4(Suppl 1):AB114.
Multilocular cystic renal cell carcinoma (MCRCC) is a distinct subtype of clear cell renal cell carcinoma. Different from other types of renal cancers, MCRCC has a favorable outcome. The real incidence of MCRCC using the new diagnostic criteria is yet unclear. Large scale study is therefore needed to further identify the characteristics of MCRCC.
A total of 77 MCRCC cases were identified following the 2004 WHO diagnostic criteria in our institute. Their clinical and radiographical characteristics, surgical management, pathological features, and outcomes were retrospectively reviewed.
The incidence of MCRCC in our renal cell carcinoma (RCC) patients was 1.8% (77/4,189). After a median follow-up period of 51 months, no tumor recurrence or metastasis was found.
The incidence of MCRCC in RCC patients is low. Most cases showed no symptoms, and accurate diagnosis is difficult before surgery. MCRCC carries an excellent prognosis after surgical treatment, regardless of the tumor size. Partial nephrectomy should be considered as the preferable surgical approach for the management of MCRCC. The follow-up interval after surgery can be longer.
PMCID: PMC4708736
Renal cancer; pathological features; prognosis
17.  cJun and CREB2 in the Postsynaptic Neuron Contribute to Persistent Long-Term Facilitation at a Behaviorally Relevant Synapse 
The Journal of Neuroscience  2015;35(1):386-395.
Basic region leucine zipper (bZIP) transcription factors regulate gene expression critical for long-term synaptic plasticity or neuronal excitability contributing to learning and memory. At sensorimotor synapses of Aplysia, changes in activation or expression of CREB1 and CREB2 in sensory neurons are required for long-term synaptic plasticity. However, it is unknown whether concomitant stimulus-induced changes in expression and activation of bZIP transcription factors in the postsynaptic motor neuron also contribute to persistent long-term facilitation (P-LTF). We overexpressed various forms of CREB1, CREB2, or cJun in the postsynaptic motor neuron L7 in cell culture to examine whether these factors contribute to P-LTF. P-LTF is evoked by 2 consecutive days of 5-HT applications (2 5-HT), while a transient form of LTF is produced by 1 day of 5-HT applications (1 5-HT). Significant increases in the expression of both cJun and CREB2 mRNA in L7 accompany P-LTF. Overexpressing each bZIP factor in L7 did not alter basal synapse strength, while coexpressing cJun and CREB2 in L7 evoked persistent increases in basal synapse strength. In contrast, overexpressing cJun and CREB2 in sensory neurons evoked persistent decreases in basal synapse strength. Overexpressing wild-type cJun or CREB2, but not CREB1, in L7 can replace the second day of 5-HT applications in producing P-LTF. Reducing cJun activity in L7 blocked P-LTF evoked by 2 5-HT. These results suggest that expression and activation of different bZIP factors in both presynaptic and postsynaptic neurons contribute to persistent change in synapse strength including stimulus-dependent long-term synaptic plasticity.
PMCID: PMC4287154  PMID: 25568130
Aplysia; cell culture; persistent synaptic plasticity; postsynaptic neuron; sensorimotor synapse; transcription factors
18.  miR-23a impairs bone differentiation in osteosarcoma via down-regulation of GJA1 
Frontiers in Genetics  2015;6:233.
Osteosarcoma is the most common type of bone cancer in children and adolescents. Impaired differentiation of osteoblast cells is a distinguishing feature of this aggressive disease. As improvements in survival outcomes have largely plateaued, better understanding of the bone differentiation program may provide new treatment approaches. The miRNA cluster miR-23a~27a~24-2, particularly miR-23a, has been shown to interact with genes important for bone development. However, global changes in gene expression associated with functional gain of this cluster have not been fully explored. To better understand the relationship between miR-23a expression and bone cell differentiation, we carried out a large-scale gene expression analysis in HOS cells. Experimental results demonstrate that over-expression of miR-23a delays differentiation in this system. Downstream bioinformatic analysis identified miR-23a target gene connexin-43 (Cx43/GJA1), a mediator of intercellular signaling critical to osteoblast development, as acutely affected by miR-23a levels. Connexin-43 is up-regulated in the course of HOS cell differentiation and is down-regulated in cells transfected with miR-23a. Analysis of gene expression data, housed at Gene Expression Omnibus, reveals that Cx43 is consistently up-regulated during osteoblast differentiation. Suppression of Cx43 mRNA by miR-23a was confirmed in vitro using a luciferase reporter assay. This work demonstrates novel interactions between microRNA expression, intercellular signaling and bone differentiation in osteosarcoma.
PMCID: PMC4488756  PMID: 26191074
miR-23a; GJA1; bone; differentiation; osteosarcoma
19.  The Heterogeneous Effects of Cigarette Prices on Brand Choice in China: Implications for Tobacco Control Policy 
Tobacco control  2015;24(0 3):iii25-iii32.
China has long kept its tobacco taxes below international standards. The Chinese government has cited as two rationales against raising tobacco tax, namely the unfair burden it places on low-income smokers and the ability of consumers to switch to cheaper brands.
This study examines how different socioeconomic subgroups of Chinese smokers switch brands in response to cigarette price changes.
We model smokers’ choice of cigarette tier as a function of tier-specific prices. We examine heterogeneous responses to prices by estimating mixed logit models for different income and education subgroups that allow for random variation in smokers’ preferences. We use data from three waves of the longitudinal ITC China Survey, collected in six large Chinese cities between 2006 and 2009.
Low-income and less educated smokers are considerably more likely to switch tiers (including both up-trading and down-trading) than are their high-socioeconomic status (SES) counterparts. For those in the second-to-lowest tier, a ¥1 ($0.16, or roughly 25%) rise in prices increases the likelihood of switching tiers by 5.6% points for low-income smokers and 7.2% points for less educated smokers, compared to 1.6% and 3.0% points for the corresponding high-SES groups. Low-income and less educated groups are also more likely to trade down compared to their high-SES counterparts.
Only a small percentage of low-income and less educated Chinese smokers switched to cheaper brands in response to price increases. Hence, the concern of the Chinese government that a cigarette tax increase will lead to large-scale brand switching is not supported by this study.
PMCID: PMC4480158  PMID: 25855642
brand choice; socioeconomic status; cigarette price; China; discrete choice analysis
20.  Inhibition of MiR-155 suppresses cell migration in nasopharyngeal carcinoma through targeting ZDHHC2 
Overexpression of miR-155 in nasopharygeal carcinoma (NPC) is partly driven by Epstein-Bar virus infection. However the role of miR-155 in NPC oncogenesis is unclear. This study showed that miR-155 inhibitor could inhibit the cell migration in NPC cell lines. ZDHHC2 was identified as a direct target of miR-155 and downregulation of ZDHHC2 prompted cell migration in NPC. Furthermore, reduced ZDHHC2 expression was associated significantly with metastasis and poor survival of NPC patients. Collectively, inhibition of miR-155 suppresses cell migration in NPC through targeting ZDHHC2. The potential of miR-155 and ZDHHC2 as therapeutic targets in NPC should be further investigated.
PMCID: PMC4538107  PMID: 26309499
Nasopharyngeal carcinoma; miR-155; ZDHHC2; cell migration
21.  Probiotic BIFICO cocktail ameliorates Helicobacter pylori induced gastritis 
AIM: To determine the protective effect of triple viable probiotics on gastritis induced by Helicobacter pylori (H. pylori) and elucidate the possible mechanisms of protection.
METHODS: Colonization of BIFICO strains in the mouse stomach was determined by counting colony-forming units per gram of stomach tissue. After treatment with or without BIFICO, inflammation and H. pylori colonization in the mouse stomach were analyzed by hematoxylin and eosin and Giemsa staining, respectively. Cytokine levels were determined by enzyme-linked immunosorbent assay and Milliplex. The activation of nuclear factor (NF)-κB and MAPK signaling in human gastric epithelial cells was evaluated by Western blot analysis. Quantitative reverse transcription-polymerase chain reaction was used to quantify TLR2, TLR4 and MyD88 mRNA expression in the mouse stomach.
RESULTS: We demonstrated that BIFICO, which contains a mixture of Enterococcus faecalis, Bifidobacterium longum and Lactobacillus acidophilus, was tolerant to the mouse stomach environment and was able to survive both the 8-h and 3-d courses of administration. Although BIFICO treatment had no effect on the colonization of H. pylori in the mouse stomach, it ameliorated H. pylori-induced gastritis by significantly inhibiting the expression of cytokines and chemokines such as TNF-α, IL-1β, IL-10, IL-6, G-CSF and MIP-2 (P < 0.05). These results led us to hypothesize that BIFICO treatment would diminish the H. pylori-induced inflammatory response in gastric mucosal epithelial cells in vitro via the NF-κB and MAPK signaling pathways. Indeed, we observed a decrease in the expression of the NF-κB subunit p65 and in the phosphorylation of IκB-α, ERK and p38. Moreover, there was a significant decrease in the production of IL-8, TNF-α, G-CSF and GM-CSF (P < 0.05), and the increased expression of TLR2, TLR4 and MyD88 induced by H. pylori in the stomach was also significantly reduced following BIFICO treatment (P < 0.05).
CONCLUSION: Our results suggest that the probiotic cocktail BIFICO can ameliorate H. pylori-induced gastritis by inhibiting the inflammatory response in gastric epithelial cells.
PMCID: PMC4458766  PMID: 26074694
BIFICO; Gastritis; Helicobacter pylori; Nuclear factor-κB; Inflammation; Toll-like receptors; Bifidobacterium longum; MAPK
22.  Synergistic Antifungal Activity of Berberine Derivative B-7b and Fluconazole 
PLoS ONE  2015;10(5):e0126393.
Our previous study demonstrated berberine (BBR) and fluconazole (FLC) used concomitantly exhibited a synergism against FLC-resistant Candida albicans in vitro. We also suggested BBR played a major antifungal role in the synergism of FLC and BBR, while FLC increased intracellular BBR concentrations. Our following systematic structural modification and reconstruction of BBR core identified the novel scaffold of N-(2-(benzo[d][1,3]dioxol-5-yl)ethyl)-2-(substituted phenyl)acet-amide derivatives 7a-i, including B-7b and B-7d exhibiting remarkable synergistic antifungal activity and low cytotoxicity. Here, the study mainly investigated the synergistic activity of FLC and B-7b and the underlying mechanism. In vitro interaction of FLC and B-7b was investigated against 30 FLC-resistant clinical isolates of C. albicans and non-C. albicans species, including Candida tropicalis, Candida parapsilosis, Candida glabrata, Candida krusei and Cryptococcus neoformans. The potent synergistic activity of B-7b in combination with FLC against FLC-resistant C. albicans was found through the checkerboard microdilution assay. The findings of agar diffusion tests and time-kill curves confirmed its better synergism with FLC. And as expected, B-7b exhibited much lower cytotoxicity than BBR to human umbilical vein endothelial cells. In contrast to BBR, we found that endogenous ROS augmentation was not involved in the synergism of FLC and B-7b. According to the results from our present comparative proteomic study, it seemed that the disruption of protein folding and processing and the weakening of cells’ self-defensive ability contributed to the synergism of FLC and B-7b. Together, these results suggested novel scaffold BBR derivative B-7b could be a promising synergist in combination with FLC for the treatment of invasive fungal infections.
PMCID: PMC4438075  PMID: 25992630
23.  Molecular genetic techniques for gene manipulation in Candida albicans 
Virulence  2014;5(4):507-520.
Candida albicans is one of the most common fungal pathogen in humans due to its high frequency as an opportunistic and pathogenic fungus causing superficial as well as invasive infections in immunocompromised patients. An understanding of gene function in C. albicans is necessary to study the molecular basis of its pathogenesis, virulence and drug resistance. Several manipulation techniques have been used for investigation of gene function in C. albicans, including gene disruption, controlled gene expression, protein tagging, gene reintegration, and overexpression. In this review, the main cassettes containing selectable markers used for gene manipulation in C. albicans are summarized; the advantages and limitations of these cassettes are discussed concerning the influences on the target gene expression and the virulence of the mutant strains.
PMCID: PMC4063812  PMID: 24759671
Candida albicans; gene manipulation; selectable markers; homologous recombination; virulence
24.  Quantitative assessment of the association between AXIN2 rs2240308 polymorphism and cancer risk 
Scientific Reports  2015;5:10111.
Axin2 is involved in the regulation of Wnt/β-catenin pathway and implicated in cancer development and progression. The association between AXIN2 rs2240308 polymorphism and cancer risk has been examined in several case-control studies, but the conclusions were conflicting. Here we performed a meta-analysis to evaluate the role of rs2240308 in cancer risk. A total of 8 studies were included in this meta-analysis (1559 cancer cases and 1503 controls). The pooled odds ratios (OR) and the 95% confidence intervals (CIs) were assessed to evaluate the association of the AXIN2 rs2240308 polymorphism with a susceptibility to cancer. A significantly decreased overall cancer risk was observed in the homozygous (TT vs. CC), heterozygous (CT vs. CC), dominant (CT+TT vs. CC) and allelic (T vs. C) models (P < 0.005), rather than that in the recessive (TT vs. CT+CC) model (P = 0.092). AXIN2 polymorphism rs2240308 was also associated with decreased cancer risk under all five models in lung cancer. However, AXIN2 rs2240308 polymorphism was not associated with cancer risk under any above model in Turkish population and under homozygous, heterozygous, recessive models in Japanese population. These findings indicate that AXIN2 rs2240308 polymorphism significantly and race-specifically correlates with decreased cancer risk.
PMCID: PMC4431355  PMID: 25974148
25.  BDCA1-Positive Dendritic Cells (DCs) Represent a Unique Human Myeloid DC Subset That Induces Innate and Adaptive Immune Responses to Staphylococcus aureus Infection 
Infection and Immunity  2014;82(11):4466-4476.
Staphylococcus aureus bloodstream infection (bacteremia) is a major cause of morbidity and mortality and places substantial cost burdens on health care systems. The role of peripheral blood dendritic cells (PBDCs) in the immune responses against S. aureus infection has not been well characterized. In this study, we demonstrated that BDCA1+ myeloid DCs (mDCs) represent a unique PBDC subset that can induce immune responses against S. aureus infection. BDCA1+ mDCs could engulf S. aureus and strongly upregulated the expression of costimulatory molecules and production of proinflammatory cytokines. Furthermore, BDCA1+ mDCs expressed high levels of major histocompatibility complex (MHC) class I and II molecules in response to S. aureus and greatly promoted proliferation and gamma interferon (IFN-γ) production in CD4 and CD8 T cells. Moreover, BDCA1+ mDCs expressed higher levels of Toll-like receptor 2 (TLR-2) and scavenger receptor A (SR-A) than those on CD16+ and BDCA3+ mDCs, and these two receptors were both required for the recognition of S. aureus and the subsequent activation of BDCA1+ mDCs. Finally, BDCA1+ mDC-mediated immune responses against S. aureus were dependent on MyD88 signaling pathways. These results demonstrate that human BDCA1+ mDCs represent a unique subset of mDCs that can respond to S. aureus to undergo maturation and activation and to induce Th1 and Tc1 immune responses.
PMCID: PMC4249336  PMID: 25114114

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