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1.  Two Pear Glutathione S-Transferases Genes Are Regulated during Fruit Development and Involved in Response to Salicylic Acid, Auxin, and Glucose Signaling 
PLoS ONE  2014;9(2):e89926.
Two genes encoding putative glutathione S-transferase proteins were isolated from pear (Pyrus pyrifolia) and designated PpGST1 and PpGST2. The deduced PpGST1 and PpGST2 proteins contain conserved Glutathione S-transferase N-terminal domain (GST_N) and Glutathione S-transferase, C-terminal domain (GST_C). Using PCR amplification technique, the genomic clones corresponding to PpGST1 and PpGST2 were isolated and shown to contain two introns and a singal intron respectively with typical GT/AG boundaries defining the splice junctions. Phylogenetic analysis clearly demonstrated that PpGST1 belonged to Phi class of GST superfamilies and had high homology with apple MdGST, while PpGST2 was classified into the Tau class of GST superfamilies. The expression of PpGST1 and PpGST2 genes was developmentally regulated in fruit. Further study demonstrated that PpGST1 and PpGST2 expression was remarkably induced by glucose, salicylic acid (SA) and indole-3-aceticacid (IAA) treatments in pear fruit, and in diseased fruit. These data suggested that PpGST1 and PpGST2 might be involved in response to sugar, SA, and IAA signaling during fruit development of pear.
doi:10.1371/journal.pone.0089926
PMCID: PMC3934943  PMID: 24587129
2.  Mathematical models for the Notch and Wnt signaling pathways and the crosstalk between them during somitogenesis 
Background
Somitogenesis is a fundamental characteristic feature of development in various animal embryos. Molecular evidence has proved that the Notch and Wnt pathways play important roles in regulating the process of somitogenesis and there is crosstalk between these two pathways. However, it is difficult to investigate the detailed mechanism of these two pathways and their interactions in somitogenesis through biological experiments. In recent years some mathematical models have been proposed for the purpose of studying the dynamics of the Notch and Wnt pathways in somitogenesis. Unfortunately, only a few of these models have explored the interactions between them.
Results
In this study, we have proposed three mathematical models for the Notch signalling pathway alone, the Wnt signalling pathway alone, and the interactions between them. These models can simulate the dynamics of the Notch and Wnt pathways in somitogenesis, and are capable of reproducing the observations derived from wet experiments. They were used to investigate the molecular mechanisms of the Notch and Wnt pathways and their crosstalk in somitogenesis through the model simulations.
Conclusions
Three mathematical models are proposed for the Notch and Wnt pathways and their interaction during somitogenesis. The simulations demonstrate that the extracellular Notch and Wnt signals are essential for the oscillating expressions of both Notch and Wnt target genes. Moreover, the internal negative feedback loops and the three levels of crosstalk between these pathways play important but distinct roles in maintaining the system oscillation. In addition, the results of the parameter sensitivity analysis of the models indicate that the Notch pathway is more sensitive to perturbation in somitogenesis.
doi:10.1186/1742-4682-10-27
PMCID: PMC3648501  PMID: 23602012
3.  Fast Principal Component Analysis of Large-Scale Genome-Wide Data 
PLoS ONE  2014;9(4):e93766.
Principal component analysis (PCA) is routinely used to analyze genome-wide single-nucleotide polymorphism (SNP) data, for detecting population structure and potential outliers. However, the size of SNP datasets has increased immensely in recent years and PCA of large datasets has become a time consuming task. We have developed flashpca, a highly efficient PCA implementation based on randomized algorithms, which delivers identical accuracy in extracting the top principal components compared with existing tools, in substantially less time. We demonstrate the utility of flashpca on both HapMap3 and on a large Immunochip dataset. For the latter, flashpca performed PCA of 15,000 individuals up to 125 times faster than existing tools, with identical results, and PCA of 150,000 individuals using flashpca completed in 4 hours. The increasing size of SNP datasets will make tools such as flashpca essential as traditional approaches will not adequately scale. This approach will also help to scale other applications that leverage PCA or eigen-decomposition to substantially larger datasets.
doi:10.1371/journal.pone.0093766
PMCID: PMC3981753  PMID: 24718290
4.  Association between Folate Intake and the Risk of Lung Cancer: A Dose-Response Meta-Analysis of Prospective Studies 
PLoS ONE  2014;9(4):e93465.
Background
Studies have reported inconsistent results regarding the existence of an association between folate intake and the risk of lung cancer. The purpose of this study was to summarize the evidence from prospective cohort studies regarding this relationship by using a dose-response meta-analytic approach.
Methodology and Principal Findings
In September 2013, we performed electronic searches in PubMed, Embase, and the Cochrane Library to identify studies examining the effect of folate intake on the incidence of lung cancer. Only prospective cohort studies that reported the effect estimates about the incidence of lung cancer with 95% confidence intervals (CIs) for more than 2 categories of folate intake were included. Overall, we examined 9 cohort studies reporting the data of 566,921 individuals. High folate intake had little effect on the risk of lung cancer (risk ratio [RR], 0.92; 95% CI, 0.84–1.01; P = 0.076). Dose-response meta-analysis also suggested that a 100 µg/day increase in folate intake had no significant effect on the risk of lung cancer (RR, 0.99; 95% CI, 0.97–1.01; P = 0.318). Subgroup analysis suggested that the potential protective effect of low folate intake (100–299 µg/day) was more evident in women than men, while the opposite was true of high folate intake (>400 µg/day). Finally, subgroup analyses of a 100 µg/day increment in folate intake indicated that its potential protective effect was more evident in men than in women.
Conclusion/Significance
Our study revealed that folate intake had little or no effect on the risk of lung cancer. Subgroup analyses indicated that an increased folate intake was associated with a reduced risk of lung cancer in men. Furthermore, low folate intake may be a protective factor for women, and high folate intake for men.
doi:10.1371/journal.pone.0093465
PMCID: PMC3979671  PMID: 24713625
5.  Regulatory Phenotype, PD-1 and TLR3 Expression in T Cells and Monocytes from HCV Patients Undergoing Antiviral Therapy: A Randomized Clinical Trial 
PLoS ONE  2014;9(4):e93620.
Background & Aims
The cellular immunity has a profound impact on the status of hepatitis C virus (HCV) infection. However, the response of cellular immunity on the virological response in patients with antiviral treatment remains largely unclear. We aimed to clarify the response of peripheral T cells and monocytes in chronic hepatitis C patients with antiviral treatment.
Methods
Patients with chronic hepatitis C were treated either with interferon alpha-2b plus ribavirin (n = 37) or with pegylated interferon alpha-2a plus ribavirin (n = 33) for up to 24 weeks. Frequencies of peripheral regulatory T-cells (Tregs), programmed death-1 (PD-1) expressing CD4+ T-cells or CD8+ T-cells and toll-like receptor (TLR) 3 expressing CD14+ monocytes were evaluated by flow cytometry in patients at baseline, 12 and 24 weeks following treatment and in 20 healthy controls.
Results
Frequencies of Tregs, PD-1 and TLR3 expressing cells were higher in patients than those in control subjects (P<0.05). Patients with complete early virological response (cEVR) showed lower Tregs, PD-1 expressing CD4+ or CD8+ T-cells than those without cEVR at 12 weeks (P<0.05). Patients with low TLR3 expressing CD14+ monocytes at baseline had a high rate of cEVR (P<0.05).
Conclusions
Low peripheral TLR3 expressing CD14+ monocytes at baseline could serve as a predictor for cEVR of antiviral therapy in chronic HCV-infected patients. The cEVR rates were significantly increased in the patients with reduced circulating Tregs, PD-1 expressing CD4+ or CD8+ T-cells.
Trial Registration
Chinese Clinical Trial Registry ChiCTR10001090.
doi:10.1371/journal.pone.0093620
PMCID: PMC3977904  PMID: 24709775
6.  Ovariectomy Results in Variable Changes in Nociception, Mood and Depression in Adult Female Rats 
PLoS ONE  2014;9(4):e94312.
Decline in the ovarian hormones with menopause may influence somatosensory, cognitive, and affective processing. The present study investigated whether hormonal depletion alters the nociceptive, depressive-like and learning behaviors in experimental rats after ovariectomy (OVX), a common method to deplete animals of their gonadal hormones. OVX rats developed thermal hyperalgesia in proximal and distal tail that was established 2 weeks after OVX and lasted the 7 weeks of the experiment. A robust mechanical allodynia was also occurred at 5 weeks after OVX. In the 5th week after OVX, dilute formalin (5%)-induced nociceptive responses (such as elevating and licking or biting) during the second phase were significantly increased as compared to intact and sham-OVX females. However, chronic constriction injury (CCI) of the sciatic nerve-induced mechanical allodynia did not differ as hormonal status (e.g. OVX and ovarian intact). Using formalin-induced conditioned place avoidance (F-CPA), which is believed to reflect the pain-related negative emotion, we further found that OVX significantly attenuated F-CPA scores but did not alter electric foot-shock-induced CPA (S-CPA). In the open field and forced swimming test, there was an increase in depressive-like behaviors in OVX rats. There was no detectable impairment of spatial performance by Morris water maze task in OVX rats up to 5 weeks after surgery. Estrogen replacement retrieved OVX-induced nociceptive hypersensitivity and depressive-like behaviors. This is the first study to investigate the impacts of ovarian removal on nociceptive perception, negative emotion, depressive-like behaviors and spatial learning in adult female rats in a uniform and standard way.
doi:10.1371/journal.pone.0094312
PMCID: PMC3978042  PMID: 24710472
7.  Effects of Fortunella margarita Fruit Extract on Metabolic Disorders in High-Fat Diet-Induced Obese C57BL/6 Mice 
PLoS ONE  2014;9(4):e93510.
Introduction
Obesity is a nutritional disorder associated with many health problems such as dyslipidemia, type 2 diabetes and cardiovascular diseases. In the present study, we investigated the anti-metabolic disorder effects of kumquat (Fortunella margarita Swingle) fruit extract (FME) on high-fat diet-induced C57BL/6 obese mice.
Methods
The kumquat fruit was extracted with ethanol and the main flavonoids of this extract were analyzed by HPLC. For the preventive experiment, female C57BL/6 mice were fed with a normal diet (Chow), high-fat diet (HF), and high-fat diet with 1% (w/w) extract of kumquat (HF+FME) for 8 weeks. For the therapeutic experiment, female C57BL/6 mice were fed with high-fat diet for 3 months to induce obesity. Then the obese mice were divided into two groups randomly, and fed with HF or HF+FME for another 2 weeks. Body weight and daily food intake amounts were recorded. Fasting blood glucose, glucose tolerance test, insulin tolerance test, serum and liver lipid levels were assayed and the white adipose tissues were imaged. The gene expression in mice liver and brown adipose tissues were analyzed with a quantitative PCR assay.
Results
In the preventive treatment, FME controlled the body weight gain and the size of white adipocytes, lowered the fasting blood glucose, serum total cholesterol (TC), serum low density lipoprotein cholesterol (LDL-c) levels as well as liver lipid contents in high-fat diet-fed C57BL/6 mice. In the therapeutic treatment, FME decreased the serum triglyceride (TG), serum TC, serum LDL-c, fasting blood glucose levels and liver lipid contents, improved glucose tolerance and insulin tolerance. Compared with the HF group, FME significantly increased the mRNA expression of PPARα and its target genes.
Conclusion
Our study suggests that FME may be a potential dietary supplement for preventing and ameliorating the obesity and obesity-related metabolic disturbances.
doi:10.1371/journal.pone.0093510
PMCID: PMC3976270  PMID: 24705395
8.  Identification of Candidate Reference Genes in Perennial Ryegrass for Quantitative RT-PCR under Various Abiotic Stress Conditions 
PLoS ONE  2014;9(4):e93724.
Background
Quantitative real-time reverse-transcriptase PCR (qRT-PCR) is an important technique for analyzing differences in gene expression due to its sensitivity, accuracy and specificity. However, the stability of the expression of reference genes is necessary to ensure accurate qRT-PCR assessment of expression in genes of interest. Perennial ryegrass (Lolium perenne L.) is important forage and turf grass species in temperate regions, but the expression stability of its reference genes under various stresses has not been well-studied.
Methodology/Principal Findings
In this study, 11 candidate reference genes were evaluated for use as controls in qRT-PCR to quantify gene expression in perennial ryegrass under drought, high salinity, heat, waterlogging, and ABA (abscisic acid) treatments. Four approaches – Delta CT, geNorm, BestKeeper and Normfinder were used to determine the stability of expression in these reference genes. The results are consistent with the idea that the best reference genes depend on the stress treatment under investigation. Eukaryotic initiation factor 4 alpha (eIF4A), Transcription elongation factor 1 (TEF1) and Tat binding protein-1 (TBP-1) were the three most stably expressed genes under drought stress and were also the three best genes for studying salt stress. eIF4A, TBP-1, and Ubiquitin-conjugating enzyme (E2) were the most suitable reference genes to study heat stress, while eIF4A, TEF1, and E2 were the three best reference genes for studying the effects of ABA. Finally, Ubiquitin (UBQ), TEF1, and eIF4A were the three best reference genes for waterlogging treatments.
Conclusions/Significance
These results will be helpful in choosing the best reference genes for use in studies related to various abiotic stresses in perennial ryegrass. The stability of expression in these reference genes will enable better normalization and quantification of the transcript levels for studies of gene expression in such studies.
doi:10.1371/journal.pone.0093724
PMCID: PMC3974806  PMID: 24699822
9.  A dynamic Bayesian Markov model for phasing and characterizing haplotypes in next-generation sequencing 
Bioinformatics  2013;29(7):878-885.
Motivation: Next-generation sequencing (NGS) technologies have enabled whole-genome discovery and analysis of genetic variants in many species of interest. Individuals are often sequenced at low coverage for detecting novel variants, phasing haplotypes and inferring population structures. Although several tools have been developed for SNP and genotype calling in NGS data, haplotype phasing is often done separately on the called genotypes.
Results: We propose a dynamic Bayesian Markov model (DBM) for simultaneous genotype calling and haplotype phasing in low-coverage NGS data of unrelated individuals. Our method is fully probabilistic that produces consistent inference of genotypes, haplotypes and recombination probabilities. Using data from the 1000 Genomes Project, we demonstrate that DBM not only yields more accurate results than some popular methods, but also provides novel characterization of haplotype structures at the individual level for visualization, interpretation and comparison in downstream analysis. DBM is a powerful and flexible tool that can be applied to many sequencing studies. Its statistical framework can also be extended to accommodate broader scopes of data.
Availability and implementation: http://stat.psu.edu/∼yuzhang/software/dbm.tar
Contact: yuzhang@stat.psu.edu
Supplementary information: Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/btt065
PMCID: PMC3656686  PMID: 23407359
10.  hsp70-Dependent Antiviral Immunity against Cytopathic Neuronal Infection by Vesicular Stomatitis Virus 
Journal of Virology  2013;87(19):10668-10678.
The major inducible 70-kDa heat shock protein (hsp70) protects against measles virus (MeV) neurovirulence in the mouse that is caused by a cell-associated noncytolytic neuronal infection. Protection is type I interferon (IFN) dependent, and we have established a novel axis of antiviral immunity in which hsp70 is released from virus-infected neurons to induce IFN-β in macrophages. The present work used vesicular stomatitis virus (VSV) to establish the relevance of hsp70-dependent antiviral immunity to fulminant cytopathic neuronal infections. In vitro, hsp70 that was constitutively expressed in mouse neuronal cells caused a modest increase in VSV replication. Infection induced an early extracellular release of hsp70 from viable cells, and the release was progressive, increasing with virus-induced apoptosis and cell lysis. The impact of this VSV-hsp70 interaction on neurovirulence was established in weanling male hsp70 transgenic and nontransgenic mice. Constitutive expression of hsp70 in neurons of transgenic mice enhanced viral clearance from brain and reduced mortality, and it was correlated with enhanced expression of type I IFN mRNA. Nontransgenic mice were also protected against neurovirulence and expressed increased type I IFN mRNA in brain when hsp70 was expressed by a recombinant VSV (rVSV-hsp70), indicating that hsp70 in the virus-infected cell is sufficient for host protection. In vitro data confirmed extracellular release of hsp70 from cells infected with rVSV-hsp70 and also showed that viral replication is not enhanced when hsp70 is expressed in this manner, suggesting that hsp70-mediated protection in vivo is not dependent on stimulatory effects of hsp70 on virus gene expression.
doi:10.1128/JVI.00872-13
PMCID: PMC3807379  PMID: 23885078
11.  U4 at the 3′ UTR of PB1 Segment of H5N1 Influenza Virus Promotes RNA Polymerase Activity and Contributes to Viral Pathogenicity 
PLoS ONE  2014;9(3):e93366.
The viral RNA-dependent RNA polymerase has been found to contribute to efficient replication in mammalian systems and to the high pathogenicity of H5N1 influenza A virus in humans and other mammals. The terminal untranslated regions of the viral segments perform functions such as polyadenylation and contain signals for genomic packaging and initiation of RNA synthesis. These sequences are highly conserved, apart from a U/C polymorphism at position 4 of the 3′ end, most often seen in the polymerase gene segments. However, no study has yet tested whether the untranslated regions of H5N1 make any contribution to its high pathogenicity. Herein, the association of the fourth nucleotide at the 3′ end of the untranslated region in segment 2 (PB1), of A/Vietnam/1194/2004 (H5N1), with pathogenicity was examined in mice. To this end, an RNA polymerase reporter system was constructed, and viruses with mutations at this site were rescued. Results showed the U4 in PB1 was found to contribute to greater amounts of RNA-dependent RNA polymerase activity and differentially regulate genomic transcription and replication. Although a recombinant H5N1 virus with the rarer C4 sequence in all eight segments was viable and replicated to high titers in vitro, replacing a single U4 at the 3′ termini of the PB1 gene segment enhanced viral reproduction and more pathogenesis. In this way, these data showed the importance of untranslated regions of H5N1 influenza virus to pathogenicity.
doi:10.1371/journal.pone.0093366
PMCID: PMC3968160  PMID: 24676059
12.  A Comparison Study of Gold Nanohexapods, Nanorods, and Nanocages for Photothermal Cancer Treatment 
ACS nano  2013;7(3):2068-2077.
Gold nanohexapods represent a novel class of optically tunable nanostructures consisting of an octahedral core and six arms grown on its vertices. By controlling the length of the arms, their localized surface plasmon resonance peaks could be tuned from the visible to the near-infrared region for deep penetration of light into soft tissues. Herein we compare the in vitro and in vivo capabilities of Au nanohexapods as photothermal transducers for theranostic applications by benchmarking against those of Au nanorods and nanocages. While all these Au nanostructures could absorb and convert near-infrared light into heat, Au nanohexapods exhibited the highest cellular uptake and the lowest cytotoxicity in vitro for both the as-prepared and PEGylated nanostructures. In vivo pharmacokinetic studies showed that the PEGylated Au nanohexapods had significant blood circulation and tumor accumulation in a mouse breast cancer model. Following photothermal treatment, substantial heat was produced in situ and the tumor metabolism was greatly reduced for all these Au nanostructures, as determined with 18F-flourodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT). Combined together, we can conclude that Au nanohexapods are promising candidates for cancer theranostics in terms of both photothermal destruction and contrast-enhanced diagnosis.
doi:10.1021/nn304332s
PMCID: PMC3609935  PMID: 23383982
theranostics; gold nanostructures; near-infrared; photothermal effect; tumor ablation
13.  A Novel Oncolytic Herpes Simplex Virus Type 2 Has Potent Anti-Tumor Activity 
PLoS ONE  2014;9(3):e93103.
Oncolytic viruses are promising treatments for many kinds of solid tumors. In this study, we constructed a novel oncolytic herpes simplex virus type 2: oHSV2. We investigated the cytopathic effects of oHSV2 in vitro and tested its antitumor efficacy in a 4T1 breast cancer model. We compared its effect on the cell cycle and its immunologic impact with the traditional chemotherapeutic agent doxorubicin. In vitro data showed that oHSV2 infected most of the human and murine tumor cell lines and was highly oncolytic. oHSV2 infected and killed 4T1 tumor cells independent of their cell cycle phase, whereas doxorubicin mainly blocked cells that were in S and G2/M phase. In vivo study showed that both oHSV2 and doxorubicin had an antitumor effect, though the former was less toxic. oHSV2 treatment alone not only slowed down the growth of tumors without causing weight loss but also induced an elevation of NK cells and mild decrease of Tregs in spleen. In addition, combination therapy of doxorubicin followed by oHSV2 increased survival with weight loss than oHSV2 alone. The data showed that the oncolytic activity of oHSV2 was similar to oHSV1 in cell lines examined and in vivo. Therefore, we concluded that our virus is a safe and effective therapeutic agent for 4T1 breast cancer and that the sequential use of doxorubicin followed by oHSV2 could improve antitumor activity without enhancing doxorubicin’s toxicity.
doi:10.1371/journal.pone.0093103
PMCID: PMC3966855  PMID: 24671154
14.  Protective Effects of Long Pentraxin PTX3 on Lung Injury in a Severe Acute Respiratory Syndrome Model in Mice 
The outbreak of severe acute respiratory syndrome (SARS) in 2003 reinforces the potential of lethal pandemics of respiratory viral infection s. The underlying mechanisms of SARS are still largely undefined. Long pentraxin PTX3, a humoral mediator of innate immunity, has been reported to have anti-viral effects. We examined the role of PTX3 in Coronavirus murine hepatitis virus strain 1 (MHV-1)-induced acute lung injury, a previously reported animal model for SARS. PTX3 deficient mice (129/SvEv/C57BL6/J) and their wild type littermates were intranasally infected MHV-1. These mice were also treated with recombinant PTX3. Effects of PTX3 on viral binding and infectivity were determined in vitro. Cytokine expression, severity of lung injury, leukocyte infiltration and inflammatory responses were examined in vivo. In PTX3wild type mice, MHV -1 induced PTX3 expression in the lung and serum in a time dependent manner. MHV-1 infection led to acute lung injury with greater severity in PTX3 deficient mice than that in wild type mice. PTX3 deficiency enhanced early infiltration of neutrophils and macrophages in the lung. PTX3 bound to MHV-1 and MHV-3 and reduced MHV-1 infectivity in vitro. Administration of recombinant PTX3 significantly accelerated viral clearance in the lung; attenuated MHV-1 induced lung injury, and reduced early neutrophil influx and elevation of inflammatory mediators in the lung. Results from this study indicate a protective role of PTX3 in coronaviral infection -induced acute lung injury.
doi:10.1038/labinvest.2012.92
PMCID: PMC3955193  PMID: 22732935 CAMSID: cams4008
acute lung injury; inflammatory response; neutrophil infiltration; pulmonary viral infection; transgenic mice
15.  ALDH2 and ADH1 Genetic Polymorphisms May Contribute to the Risk of Gastric Cancer: A Meta-Analysis 
PLoS ONE  2014;9(3):e88779.
Aim
We conducted a meta-analysis of case-control studies to determine whether ALDH2, ADH1 and ADH2 genetic polymorphisms contribute to the pathogenesis of gastric cancer.
Methods
The PubMed, CISCOM, CINAHL, Web of Science, Google Scholar, EBSCO, Cochrane Library, and CBM databases were searched for relevant articles published before November 1st, 2013 without any language restrictions. Meta-analysis was conducted using the STATA 12.0 software. We calculated crude odds ratios (ORs) with their 95% confidence intervals (95%CI) to evaluate their relationships under five genetic models. Seven case-control studies with a total of 2,563 gastric cancer patients and 4,192 healthy controls met the inclusion criteria. Nine common polymorphisms were evaluated, including rs671, rs16941667 and rs886205 in the ALDH2 gene, rs1230025, rs13123099, rs698 and rs1693482 in the ADH1 gene, and rs1229984 and rs17033 in the ADH2 gene.
Results
The results of our meta-analysis suggested that ALDH2 genetic polymorphisms might be strongly correlated with an increased risk of gastric cancer (allele model: OR  = 1.21, 95%CI: 1.11∼1.32, P<0.001; dominant model: OR  = 1.23, 95%CI: 1.09∼1.39, P = 0.001; respectively), especially for rs671 polymorphism. Furthermore, we observed significant associations between ADH1 genetic polymorphisms and an increased risk of gastric cancer (allele model: OR  = 1.21, 95%CI: 1.08∼1.36, P = 0.001; dominant model: OR  = 10.52, 95%CI: 3.04∼36.41, P<0.001; respectively), especially for rs1230025 polymorphism. Nevertheless, no positive relationships were found between ADH2 genetic polymorphisms and gastric cancer risk (all P>0.05).
Conclusion
The current meta-analysis suggests that ALDH2 and ADH1 genetic polymorphisms may play crucial roles in the pathogenesis of gastric cancer. However, ADH2 genetic polymorphisms may not be important dominants of susceptibility to gastric cancer.
doi:10.1371/journal.pone.0088779
PMCID: PMC3954547  PMID: 24633362
16.  The Circular F-Actin Bundles Provide a Track for Turnaround and Bidirectional Movement of Mitochondria in Arabidopsis Root Hair 
PLoS ONE  2014;9(3):e91501.
Background
The movement of organelles in root hairs primarily occurs along the actin cytoskeleton. Circulation and “reverse fountain” cytoplasmic streaming constitute the typical forms by which most organelles (such as mitochondria and the Golgi apparatus) in plant root hair cells engage in bidirectional movement. However, there remains a lack of in-depth research regarding the relationship between the distribution of the actin cytoskeleton and turnaround organelle movement in plant root hair cells.
Results
In this paper, Arabidopsis seedlings that had been stably transformed with a GFP-ABD2-GFP (green fluorescent protein-actin-binding domain 2-green fluorescent protein) construct were utilized to study the distribution of bundles of filamentous (F)-actin and the directed motion of mitochondria along these bundles in root hairs. Observations with a confocal laser scanning microscope revealed that there were widespread circular F-actin bundles in the epidermal cells and root hairs of Arabidopsis roots. In root hairs, these circular bundles primarily start at the sub-apical region, which is the location where the turnaround movement of organelles occurs. MitoTracker probes were used to label mitochondria, and the dynamic observation of root hair cells with a confocal laser scanning microscope indicated that turnaround mitochondrial movement occurred along circular F-actin bundles.
Conclusions
Relevant experimental results demonstrated that the circular F-actin bundles provide a track for the turnaround and bidirectional movement of mitochondria.
doi:10.1371/journal.pone.0091501
PMCID: PMC3953408  PMID: 24626218
17.  Atheroprotective Pulsatile Flow Induces Ubiquitin-Proteasome–Mediated Degradation of Programmed Cell Death 4 in Endothelial Cells 
PLoS ONE  2014;9(3):e91564.
Objectives
We recently found low level of tumor suppressor programmed cell death 4 (PDCD4) associated with reduced atherosclerotic plaque area (unpublished). We investigated whether atheroprotective unidirectional pulsatile shear stress affects the expression of PDCD4 in endothelial cells.
Methods and Results
En face co-immunostaining of the mouse aortic arch revealed a low level of PDCD4 in endothelial cells undergoing pulsatile shear stress. Application of unidirectional pulsatile shear stress to human umbilical vein endothelial cells (HUVECs) decreased PDCD4 protein but not mRNA level. Immunoprecipitation revealed that pulsatile shear stress induced the coupling of ubiquitin with PDCD4 expression. The phosphatidyl inositol 3-kinase (PI3K)/Akt pathway was involved in this ubiquitin-proteasome–mediated degradation of PDCD4. Gain of function and loss of function experiments showed that PDCD4 induced turnover (proliferation and apoptosis) of HUVECs. Low PDCD4 level was associated with reduced proliferation but not apoptosis or phosphorylation of endothelial nitric oxide synthase caused by pulsatile shear stress to help maintain the homeostasis of endothelial cells.
Conclusions
Pulsatile shear stress induces ubiquitin-proteasome–mediated degradation of PDCD4 via a PI3K/Akt pathway in HUVECs. PDCD4 induces turnover (proliferation and apoptosis) of HUVECs. Low PDCD4 level is associated with reduced proliferation for maintenance of HUVEC homeostasis under pulsatile shear stress.
doi:10.1371/journal.pone.0091564
PMCID: PMC3953479  PMID: 24626527
18.  A Topic Clustering Approach to Finding Similar Questions from Large Question and Answer Archives 
PLoS ONE  2014;9(3):e71511.
With the blooming of Web 2.0, Community Question Answering (CQA) services such as Yahoo! Answers (http://answers.yahoo.com), WikiAnswer (http://wiki.answers.com), and Baidu Zhidao (http://zhidao.baidu.com), etc., have emerged as alternatives for knowledge and information acquisition. Over time, a large number of question and answer (Q&A) pairs with high quality devoted by human intelligence have been accumulated as a comprehensive knowledge base. Unlike the search engines, which return long lists of results, searching in the CQA services can obtain the correct answers to the question queries by automatically finding similar questions that have already been answered by other users. Hence, it greatly improves the efficiency of the online information retrieval. However, given a question query, finding the similar and well-answered questions is a non-trivial task. The main challenge is the word mismatch between question query (query) and candidate question for retrieval (question). To investigate this problem, in this study, we capture the word semantic similarity between query and question by introducing the topic modeling approach. We then propose an unsupervised machine-learning approach to finding similar questions on CQA Q&A archives. The experimental results show that our proposed approach significantly outperforms the state-of-the-art methods.
doi:10.1371/journal.pone.0071511
PMCID: PMC3942313  PMID: 24595052
19.  Neuropeptide PACAP in Mouse Liver Ischemia and Reperfusion Injury: Immunomodulation via cAMP-PKA Pathway 
Hepatology (Baltimore, Md.)  2013;57(3):1225-1237.
Hepatic ischemia and reperfusion injury (IRI), an exogenous antigen-independent local inflammation response, occurs in multiple clinical settings including liver transplantation, hepatic resection, trauma, and shock. The immune system and the nervous system maintain extensive communication, and mount a variety of integrated responses to danger signals through intricate chemical messengers. This study examined the function and potential therapeutic potential of neuropeptide PACAP (pituitary adenylate cyclase-activating polypeptide) in a murine model of partial liver “warm” ischemia (90min) followed by reperfusion. Liver IR readily triggered the expression of intrinsic PACAP and its receptors, whereas the hepatocellular damage was exacerbated in PACAP-deficient mice. Conversely, PACAP27, or PACAP38 peptide monotherapy, which elevates intracellular cyclic adenosine monophosphate - protein kinase A (cAMP-PKA) signaling, protected livers from IRI, as evidenced by diminished serum alanine aminotransferase (sALT) levels and well-preserved tissue architecture. The liver protection rendered by PACAP peptides was accompanied by diminished neutrophil/macrophage infiltration and activation, reduced hepatocyte necrosis/apoptosis, and selectively augmented hepatic IL-10 expression. Strikingly, PKA inhibition readily restored liver damage in otherwise IR-resistant PACAP-conditioned mice. In vitro, PACAP treatment not only diminished macrophage TNF-α/IL-6/IL-12 levels in an PKA-dependent manner, but also prevented necrosis and apoptosis in primary mouse hepatocyte cultures.
Conclusion
Our novel findings document the importance of PACAP mediated cAMP-PKA signaling in hepatic homeostasis and cytoprotection in vivo. As the enhancement of neural modulation differentially regulates local inflammation and prevents hepatocyte death, these results provide the rationale for novel approaches to manage liver inflammation and IRI in transplant patients.
doi:10.1002/hep.25802
PMCID: PMC3479352  PMID: 22532103
Cyclic Adenosine Monophosphate; Ischemia/Reperfusion Injury; Pituitary Adenylate Cyclase-Activating Polypeptides; Protein kinase A; Toll-like Receptor 4
20.  Investigation of Neovascularization in Three-Dimensional Porous Scaffolds In Vivo by a Combination of Multiscale Photoacoustic Microscopy and Optical Coherence Tomography 
It is a grand challenge to visualize and assess in vivo neovascularization in a three-dimensional (3D) scaffold noninvasively, together with high spatial resolution and deep penetration depth. Here we used multiscale photoacoustic microscopy (PAM), including acoustic-resolution PAM (AR-PAM) and optical-resolution PAM (OR-PAM), to chronically monitor neovascularization in an inverse opal scaffold implanted in a mouse model up to 6 weeks by taking advantage of the optical absorption contrast intrinsic to hemoglobin molecules in red blood cells. By combining with optical coherence tomography (OCT) based on optical scattering contrast, we also demonstrated the capability to simultaneously image and analyze the vasculature and the scaffold in the same mouse. The hybrid system containing OR-PAM and OCT offered a fine lateral resolution of ∼5 μm and a penetration depth of ∼1 mm into the scaffold/tissue construct. AR-PAM further extended the penetration depth up to ∼3 mm at a lateral resolution of ∼45 μm. By quantifying the 3D PAM data, we further examined the effect of pore size (200 vs. 80 μm) of a scaffold on neovascularization. The data collected from PAM were consistent with those obtained from traditional invasive, labor-intensive histologic analyses.
doi:10.1089/ten.tec.2012.0326
PMCID: PMC3557912  PMID: 22838500
21.  Expression of Human CAR Splicing Variants in BAC-Transgenic Mice 
Toxicological Sciences  2012;132(1):142-150.
The nuclear receptor constitutive androstane receptor (CAR) is a key regulator for drug metabolism in liver. Human CAR (hCAR) transcripts are subjected to alternative splicing. Some hCAR splicing variants (SVs) have been shown to encode functional proteins by reporter assays. However, in vivo research on the activity of these hCAR SVs has been impeded by the absence of a valid model. This study engineered an hCAR-BAC-transgenic (hCAR-TG) mouse model by integrating the 8.5-kbp hCAR gene as well as 73-kbp upstream and 91-kbp downstream human genomic DNA into the genome of CAR-null mice. A series of experiments demonstrate that (1) the expression of major hCAR mRNA SVs, SV0-4, in livers of hCAR-TG mice is comparable to that in human livers; (2) the hCAR SVs are predominantly expressed in liver, which resembles the tissue distribution of CAR in humans, but diverges from that in mice; and (3) major hCAR mRNA SVs increase markedly in postnatal livers of hCAR-TG mice, which mimics the ontogeny of CAR mRNA in humans. Thus, the transgene likely contains all the functional regulatory elements controlling proper spatial and temporal expression of the hCAR gene. Moreover, hCAR-TG mice respond to the hCAR-specific agonist 6-(4-chlorophenyl)imidazo[2,1-b] [1,3]thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl)oxime instead of the mouse CAR agonist 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene, as well as the common CAR activator, phenobarbital, suggesting that hCAR is fully functional in livers of transgenic mice. In summary, the hCAR-TG mice developed by this study represent a valid model for studying in vivo function and regulation of hCAR and its splicing variants.
doi:10.1093/toxsci/kfs321
PMCID: PMC3576005  PMID: 23152187
CAR; splicing variant; in vivo; BAC; transgenic mice.
22.  Effect of omega-3 fatty acid supplementation on cancer incidence, non-vascular death, and total mortality: a meta-analysis of randomized controlled trials 
BMC Public Health  2014;14:204.
Background
Omega-3 fatty acids are known to prevent cardiac death. However, previous observational studies have suggested that omega-3 fatty acids are associated with cancer risk in adults. We conducted a meta-analysis based on randomized controlled trials to evaluate the effect of omega-3 fatty acids on the risk of cancer incidence, nonvascular death, and total mortality.
Methods
In February 2013, we performed electronic searches in PubMed, EmBase, and the Cochrane Library to identify randomized controlled trials on cancer incidence, nonvascular death, and total mortality. Relative risk (RR) was used to measure the effect of omega-3 fatty acid supplementation on the risk of cancer incidence, nonvascular death, and total mortality using a random-effect model. The analysis was further stratified by factors that could affect the treatment effects.
Results
Of the 8,746 identified articles, we included 19 trials reporting data on 68,954 individuals. These studies reported 1,039 events of cancer, 2,439 events of nonvascular death, and 7,025 events of total mortality. Omega-3 fatty acid supplementation had no effect on cancer incidence (RR, 1.10; 95% CI: 0.97–1.24; P = 0.12), nonvascular death (RR, 1.00; 95% CI: 0.93–1.08; P = 1.00), or total mortality (RR, 0.95; 95% CI: 0.88–1.03; P = 0.24) when compared to a placebo. Subgroup analysis indicated that omega-3 fatty acid supplementation was associated with a reduction in total mortality risk if the proportion of men in the study population was more than 80%, or participants received alpha-linolenic acid.
Conclusions
Omega-3 fatty acid supplementation does not have an effect on cancer incidence, nonvascular death, or total mortality.
doi:10.1186/1471-2458-14-204
PMCID: PMC3938028  PMID: 24568238
Omega-3 fatty acid; Cancer; Mortality; Meta-analysis
23.  Mesenteric Lymph Drainage Alleviates Acute Kidney Injury Induced by Hemorrhagic Shock without Resuscitation 
The Scientific World Journal  2014;2014:720836.
This study aimed to investigate the effect of mesenteric lymph drainage on the acute kidney injury induced by hemorrhagic shock without resuscitation. Eighteen male Wistar rats were randomly divided into sham, shock, and drainage groups. The hemorrhagic shock model (40 mmHg, 3 h) was established in shock and drainage groups; mesenteric lymph drainage was performed from 1 h to 3 h of hypotension in the drainage group. The results showed that renal tissue damage occurred; the levels of urea, creatinine, and trypsin in the plasma as well as intercellular adhesion molecule-1 (ICAM-1), receptor of advanced glycation end-products (RAGE), tumor necrosis factor-α (TNF-α), malondialdehyde (MDA), lactic acid (LA), and 2,3-DPG in the renal tissue were increased in the shock group after 3 h of hypotension. Mesenteric lymph drainage lessened the following: renal tissue damage; urea and trypsin concentrations in the plasma; ICAM-1, RAGE, TNF-α, MDA, and LA levels in the renal tissue. By contrast, mesenteric lymph drainage increased the 2,3-DPG level in the renal tissue. These findings indicated that mesenteric lymph drainage could relieve kidney injury caused by sustained hypotension, and its mechanisms involve the decrease in trypsin activity, suppression of inflammation, alleviation of free radical injury, and improvement of energy metabolism.
doi:10.1155/2014/720836
PMCID: PMC3956641  PMID: 24723822
24.  Evaluating the immune responses of mice to subcutaneous immunization with Helicobacter pylori urease B subunit 
Background
Helicobacter pylori, a gram-negative bacterial pathogen that expresses a strong urease activity, is associated with the development of gastroduodenal disease. Urease B subunit, one of the two structural subunits of urease, was expressed in E. coli BL21 (DE3) strain. The objective of this study was to evaluate the effects of Helicobacter pylori urease B subunit on the immune responses in mice by subcutaneous immunization.
Methods
The mice were immunized and boosted with Helicobacter pylori urease B subunit antigen subcutaneously three times with 2-wk intervals between the immunizations and boosters. The mice in the control group were immunized with PBS. The adjuvant group received PBS containing complete/incomplete freund’s adjuvant identical to antigen group without Helicobacter pylori urease B subunit antigen. Four weeks after the final booster, all the mice were sacrificed. Blood was collected on d 0, 14, 28 and 56 before immunization, booster and sacrifice, respectively. Immediately after sacrifice, gastric liquid and spleen were collected for antibody and cytokine analyses.
Results
Urease B subunit increased the concentrations of serum and gastric anti-urease B antigen specific IgG, and the levels of interleukin-4 and interferon-γ in splenocytes of the mice (P < 0.05).
Conclusions
This study demonstrated that recombinant urease B subunit can induce systemic and local immune responses in mice by subcutaneous immunization, which might be used as the effective component of vaccine against Helicobacter pylori.
doi:10.1186/2049-1891-5-14
PMCID: PMC3976096  PMID: 24558967
Antibody; Cytokines; Helicobacter pylori urease B subunit; Mice
25.  A facile solid-state heating method for preparation of poly(3,4-ethelenedioxythiophene)/ZnO nanocomposite and photocatalytic activity 
Poly(3,4-ethylenedioxythiophene)/zinc oxide (PEDOT/ZnO) nanocomposites were prepared by a simple solid-state heating method, in which the content of ZnO was varied from 10 to 20 wt%. The structure and morphology of the composites were characterized by Fourier transform infrared (FTIR) spectroscopy, ultraviolet-visible (UV-vis) absorption spectroscopy, X-ray diffraction (XRD), and transmission electron microscopy (TEM). The photocatalytic activities of the composites were investigated by the degradation of methylene blue (MB) dye in aqueous medium under UV light and natural sunlight irradiation. The FTIR, UV-vis, and XRD results showed that the composites were successfully synthesized, and there was a strong interaction between PEDOT and nano-ZnO. The TEM results suggested that the composites were a mixture of shale-like PEDOT and less aggregated nano-ZnO. The photocatalytic activity results indicated that the incorporation of ZnO nanoparticles in composites can enhance the photocatalytic efficiency of the composites under both UV light and natural sunlight irradiation, and the highest photocatalytic efficiency under UV light (98.7%) and natural sunlight (96.6%) after 5 h occurred in the PEDOT/15wt%ZnO nanocomposite.
doi:10.1186/1556-276X-9-89
PMCID: PMC3948018  PMID: 24555419
Solid-state heating method; Poly(3,4-ethylenedioxythiophene); Nano-ZnO; Composite; Photocatalyst

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