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1.  Inflammation and Mechanical Stretch Promote Aortic Stiffening in Hypertension Through Activation of p38 MAP Kinase 
Circulation research  2013;114(4):616-625.
Rationale
Aortic stiffening commonly occurs in hypertension and further elevates systolic pressure. Hypertension is also associated with vascular inflammation and increased mechanical stretch. The interplay between inflammation, mechanical stretch and aortic stiffening in hypertension remains undefined.
Objective
To determine the role of inflammation and mechanical stretch in aortic stiffening.
Methods and Results
Chronic angiotensin II infusion caused marked aortic adventitial collagen deposition, as quantified by Masson’s Trichrome Blue staining and biochemically by hydroxyproline content, in wild-type (WT) but not in Recombination Activation Gene-1 deficient (RAG-1−/−) mice. Aortic compliance, defined by ex-vivo measurements of stress-strain curves, was reduced by chronic angiotensin II infusion in WT mice (p<0.01) but not in RAG-1−/− mice (p<0.05). Adoptive transfer of T cells to RAG-1−/− mice restored aortic collagen deposition and stiffness to values observed in WT mice. Mice lacking the T cell derived cytokine IL-17a were also protected against aortic stiffening. In additional studies, we found that blood pressure normalization by treatment with hydralazine and hydrochlorothiazide prevented angiotensin II-induced vascular T cell infiltration, aortic stiffening and collagen deposition. Finally, we found that mechanical stretch induces expression of collagen 1α1, 3α1 and 5a1 in cultured aortic fibroblasts in a p38 MAP kinase-dependent fashion, and that inhibition of p38 prevented angiotensin II-induced aortic stiffening in vivo. IL-17a also induced collagen 3a1 expression via activation of p38 MAP kinase.
Conclusions
Our data define a pathway in which inflammation and mechanical stretch lead to vascular inflammation that promotes collagen deposition. The resultant increase in aortic stiffness likely further worsens systolic hypertension and its attendant end-organ damage.
doi:10.1161/CIRCRESAHA.114.302157
PMCID: PMC4186716  PMID: 24347665
Inflammation; mechanical stretch; collagen deposition; aortic stiffening; vascular remodeling
2.  Purification and characterization of a novel defensin from the salivary glands of the black fly, Simulium bannaense 
Parasites & Vectors  2015;8:71.
Background
Black flies (Diptera: Simuliidae) are haematophagous insects that can cause allergic reactions and act as vectors of pathogens. Although their saliva has been thought to contain a diverse array of physiologically active molecules, little information is available on antimicrobial factors in black fly salivary glands, especially no defensins have been reported so far.
Methods
A novel cationic defensin designated SibaDef was purified using reverse phase high-performance liquid chromatography (RP-HPLC) from the salivary glands of the black fly Simulium bannaense. The amino acid sequence of SibaDef was determined by a combination method of automated Edman degradation and cDNA sequencing. The morphologic changes of Gram-positive bacteria Staphylococcus aureus or Bacillus subtilis treated with SibaDef were assessed by scanning electron microscopy (SEM). Quantitative PCR (qPCR) was performed to analyze the expression of SibaDef mRNA in whole bodies of insects after oral infection with the bacteria S. aureus or B. subtilis.
Results
Surprisingly, the phylogenetic analysis of defensin-related amino acid sequences demonstrated that SibaDef is most closely related to defensins from the human body louse Pediculus humanus corporis (Anoplura: Pediculidae), rather than to other dipteran defensins. SibaDef showed potent antimicrobial activities against Gram-positive bacteria with minimal inhibitory concentrations (MICs) ranging from 0.83 μM to 2.29 μM. SEM analysis indicated that SibaDef killed microorganisms through the disruption of cell membrane integrity. The transcript levels of SibaDef in the bacteria-immunized flies increased with the time course, reaching maximum at 36 h and then slowly decreased from that time point.
Conclusions
Our results indicate that SibaDef is involved in the innate humoral response of the black fly S. bannaense, and it might play a significant role in the defence against microorganisms in both sugar and blood meals.
doi:10.1186/s13071-015-0669-9
PMCID: PMC4324660  PMID: 25649358
Insect; Antimicrobial peptide; Defensin; Salivary gland; Black fly; Simulium bannaense
3.  Differential regulation of cytotoxicity pathway discriminating between HIV, HCV mono- and co-infection identified by transcriptome profiling of PBMCs 
Virology Journal  2015;12:4.
Background
Despite the easy accessibility and diagnostic utility of PBMCs and their potential to show distinct expression patterns associated with the accelerated disease progression in HIV/HCV co-infection, there has not been a systematic study focusing on the global dysregulations of the biological pathways in PBMCs from HIV, HCV mono- and co-infected individuals. This study aimed at identifying the transcriptome distinctions of PBMCs between these patient groups.
Methods
Genome-wide transcriptomes of PBMCs from 10 HIV/HCV co-infected patients, 7 HIV+ patients, 5 HCV+ patients, and 5 HIV/HCV sero-negative healthy controls were analyzed using Illumina microarray. Pairwise comparisons were performed to identify differentially expressed genes (DEGs), followed by gene set enrichment analysis (GSEA) to detect the global dysregulations of the biological pathways between HIV, HCV mono- and co-infection.
Results
Forty-one, 262, and 44 DEGs with fold change > 1.5 and FDR (false discovery rate) <0.05 for the comparisons of HCV versus co-infection, HIV versus co-infection, and HIV versus HCV were identified, respectively. Significantly altered pathways (FDR < 0.05), featured by those involved in immune system, signaling transduction, and cell cycle, were detected. Notably, the differential regulation of cytotoxicity pathway discriminated between HIV, HCV mono- and co-infection (up-regulated in the former versus the latter group: co-infection versus HIV or HCV, HIV versus HCV; FDR <0.001 ~ 0.019). Conversely, the cytokine-cytokine receptor interaction pathway was down-regulated in co-infection versus either HCV (FDR = 0.003) or HIV (FDR = 0.028). For the comparison of HIV versus HCV, the cell cycle (FDR = 0.016) and WNT signaling (FDR = 0.006) pathways were up- and down-regulated in HIV, respectively.
Conclusions
Our study is the first to identify the differential regulation of cytotoxicity pathway discriminating between HIV, HCV mono- and co-infection, which may reflect the distinct patterns of virus-host cell interactions underlying disease progression. Further inspection of cytotoxicity pathway has pinned down to the expression of the KIR genes to be associated with specific patterns of particular virus-host interactions. Between HIV and HCV, the altered cell cycle and WNT signaling pathways may suggest the different impact of HIV and HCV on cell proliferation and differentiation.
Electronic supplementary material
The online version of this article (doi:10.1186/s12985-014-0236-6) contains supplementary material, which is available to authorized users.
doi:10.1186/s12985-014-0236-6
PMCID: PMC4312599  PMID: 25623235
HIV; HCV; HIV/HCV co-infection; Transcriptome; Cytotoxicity pathway
4.  HMGA2 is associated with epithelial–mesenchymal transition and can predict poor prognosis in nasopharyngeal carcinoma 
OncoTargets and therapy  2015;8:169-176.
Objective
High-mobility group protein 2 (HMGA2) and epithelial–mesenchymal transition (EMT)-associated proteins play key roles in cancer progression and metastasis. However, the clinical significance of HMGA2 and its relationship with EMT markers in nasopharyngeal carcinoma (NPC) is unclear. This study aimed to assess the clinicopathological significance and prognostic value of HMGA2, E-cadherin, and vimentin in NPC.
Methods
Using immunohistochemistry, HMGA2, E-cadherin, and vimentin expression levels were evaluated in NPC (n=124) and non-tumoral inflammatory nasopharynx (n=20) tissues. The association of HMGA2 and EMT markers with clinicopathological characteristics and relationships between the protein levels and overall survival were analyzed.
Results
Compared with non-tumorous tissues, HMGA2 and vimentin levels were markedly increased in NPC tissues, whereas decreased E-cadherin levels were observed (P<0.001). Moreover, HMGA2 expression was positively correlated with vimentin levels (r=0.431, P<0.001) and negatively correlated with E-cadherin amounts (r=−0.413, P<0.001) in NPC tissues. The expression of all three proteins correlated significantly with tumor N stage, TNM stage, and 2-year metastasis. Furthermore, significant correlations were found for T stage, N stage, TNM stage, HMGA2, E-cadherin, and vimentin (all P<0.013) with poor prognosis (univariate analysis). However, multivariate analyses showed that only HMGA2 (hazard ratio [HR]: 2.683, 95% confidence interval [CI]: 1.185–6.077, P=0.018) and N stage (HR: 7.892, 95% CI: 2.731–22.807, P<0.001) were independent predictors of poor prognosis.
Conclusion
These results demonstrated that HMGA2, an independent prognostic factor, may promote NPC progression and metastasis, and is significantly associated with EMT proteins. Therefore, HMGA2 may be considered a potential therapeutic target in NPC.
doi:10.2147/OTT.S74397
PMCID: PMC4303461  PMID: 25653540
EMT; NPC; high-mobility group protein 2
5.  Identification and Characterization of Phosphorylation Sites within the Pregnane X Receptor Protein 
Biochemical pharmacology  2013;87(2):360-370.
Pregnane X receptor (PXR) is a xenobiotic sensor regulating the expression of genes involved in xenobiotic detoxification and elimination. Phosphorylation plays an important role in modulating PXR activity and several phosphorylation sites have been predicted and characterized in in vitro experiments. Although PXR has been shown to be a phosphoprotein in vivo, the exact residues that are phosphorylated remain elusive. Using mass spectrometry, we identified for the first time S114, T133/135, S167, and S200 residues that are phosphorylated in PXR following an in vitro kinase assay using cyclin-dependent kinase 2. We further found that the phosphorylation at S114, T133, and T135 occurred in PXR isolated from cells. We tested the phosphodeficient and phosphomimetic mutants corresponding to all the sites identified and determined that phosphorylation at S114 attenuates the transcriptional activity of PXR, consistent with the observation that the S114D mutant displayed reduced association with the PXR-targeted DNA response element. Phosphomimetic mutations at either T133 or T135 did not show a significant change in transcriptional activity however, the dual phosphomimetic mutant T133D/T135D displayed reduced transcriptional activity. Subcellular localization studies showed a varied distribution of the mutants suggesting that the regulation of PXR is much more complex than what we can observe by just overexpressing the mutants. Thus, our results provide the first direct evidence that PXR is phosphorylated at specific residues and suggest that further investigation is warranted to fully understand the regulation of PXR by phosphorylation.
doi:10.1016/j.bcp.2013.10.015
PMCID: PMC3947193  PMID: 24184507
PXR; drug metabolism; phosphorylation; phosphomimetic mutations
6.  Enterocyte dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin expression in inflammatory bowel disease 
AIM: To investigate dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) expression in intestinal epithelial cells (IECs) in inflammatory bowel disease (IBD).
METHODS: The expression of DC-SIGN in IECs was examined by immunohistochemistry of intestinal mucosal biopsies from 32 patients with IBD and 10 controls. Disease activity indices and histopathology scores were used to assess the tissue lesions and pathologic damage. Animal studies utilized BALB/c mice with dextran sodium sulfate (DSS)-induced colitis treated with anti-P-selectin lectin-EGF domain monoclonal antibody (PsL-EGFmAb). Controls, untreated and treated mice were sacrificed after 7 d, followed by isolation of colon tissue and IECs. Colonic expression of DC-SIGN, CD80, CD86 and MHC II was examined by immunohistochemistry or flow cytometry. The capacity of mouse enterocytes or dendritic cells to activate T cells was determined by co-culture with naïve CD4+ T cells. Culture supernatant and intracellular levels of interleukin (IL)-4 and interferon (IFN)-γ were measured by enzyme-linked immunosorbent assay and flow cytometry, respectively. The ability of IECs to promote T cell proliferation was detected by flow cytometry staining with carboxyfluorescein diacetate succinimidyl ester.
RESULTS: Compared with controls, DC-SIGN expression was significantly increased in IECs from patients with Crohn’s disease (P < 0.01) or ulcerative colitis (P < 0.05). DC-SIGN expression was strongly correlated with disease severity in IBD (r = 0.48; P < 0.05). Similarly, in the DSS-induced colitis mouse model, IECs showed upregulated expression of DC-SIGN, CD80, CD86 and MHC, and DC-SIGN expression was positively correlated with disease activity (r = 0.62: P < 0.01). IECs from mouse colitis stimulated naïve T cells to generate IL-4 (P < 0.05). Otherwise, dendritic cells promoted a T-helper-1-skewing phenotype by stimulating IFN-γ secretion. However, DC-SIGN expression and T cell differentiation were suppressed following treatment of mice with DSS-induced colitis with PsL-EGFmAb. The proliferation cycles of CD4+ T cells from mice with DSS-induced colitis appeared as five cycles, which was more than in the control and treated groups. These results suggest that IECs can promote T cell proliferation.
CONCLUSION: IECs regulate tissue-associated immune compartments under the control of DC-SIGN in IBD.
doi:10.3748/wjg.v21.i1.187
PMCID: PMC4284334  PMID: 25574091
Dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin; Dendritic cells; Immune compartmentalization; Inflammatory bowel disease; Intestinal epithelial cells
7.  Effect of Metformin on Cancer Risk and Treatment Outcome of Prostate Cancer: A Meta-Analysis of Epidemiological Observational Studies 
PLoS ONE  2014;9(12):e116327.
Background
Laboratory studies have shown the anti-tumor effect of metformin on prostate cancer. However, recent epidemiological studies have yielded inconclusive results.
Methods
We searched PubMed database from the inception to May 30 2014 for studies which assessed the effect of metformin use on cancer risk of prostate cancer, biochemical recurrence (BCR) and all-cause mortality of patients with prostate cancer. The pooled results and 95% confidence intervals (CIs) were estimated by random-effect model.
Results
Twenty-one studies were eligible according to the inclusion criteria. Based on the pooled results of available observational studies, metformin use was significantly associated with a decreased cancer risk (14 datasets, 963991 male subjects, odds ratio: 0.91, 95% CI: 0.85–0.97) and BCR (6 datasets, 2953 patients, hazard ratio: 0.81, 95% CI: 0.68–0.98) of prostate cancer. However, the association of metformin use with all-cause mortality of patients with prostate cancer was not significant (5 datasets, 9241 patients, hazard ratio: 0.86, 95% CI: 0.64–1.14).
Conclusion
Results suggest that metformin use appears to be associated with a significant reduction in the cancer risk and BCR of prostate cancer, but not in all-cause mortality of patients with prostate cancer.
doi:10.1371/journal.pone.0116327
PMCID: PMC4278883  PMID: 25545701
8.  Human Gut Microbiome and Risk for Colorectal Cancer 
We tested the hypothesis that an altered community of gut microbes is associated with risk of colorectal cancer (CRC) in a study of 47 CRC case subjects and 94 control subjects. 16S rRNA genes in fecal bacterial DNA were amplified by universal primers, sequenced by 454 FLX technology, and aligned for taxonomic classification to microbial genomes using the QIIME pipeline. Taxonomic differences were confirmed with quantitative polymerase chain reaction and adjusted for false discovery rate. All statistical tests were two-sided. From 794217 16S rRNA gene sequences, we found that CRC case subjects had decreased overall microbial community diversity (P = .02). In taxonomy-based analyses, lower relative abundance of Clostridia (68.6% vs 77.8%) and increased carriage of Fusobacterium (multivariable odds ratio [OR] = 4.11; 95% confidence interval [CI] = 1.62 to 10.47) and Porphyromonas (OR = 5.17; 95% CI = 1.75 to 15.25) were found in case subjects compared with control subjects. Because of the potentially modifiable nature of the gut bacteria, our findings may have implications for CRC prevention.
doi:10.1093/jnci/djt300
PMCID: PMC3866154  PMID: 24316595
9.  First Occurrence of Platycladus from the Upper Miocene of Southwest China and Its Phytogeographic Implications 
PLoS ONE  2014;9(12):e115141.
Platycladus Spach is native to Central China, but its natural occurrences are very difficult to establish. According to molecular phylogenetic data, this genus might have originated since the Oligocene, but no fossil record has been reported. Here, we describe eight foliage branches from the upper Miocene in western Yunnan, Southwest China as a new species, P. yunnanensis sp. nov., which is characterized by foliage branches spread in flattened sprays, and leaves decussate, imbricate, scale-like and dimorphic. The leaves are amphistomatic, and the stomata are elliptical or oblong, haplocheilic, and monocyclic type. Based on a detailed comparison with the extant genera of Cupressaceae sensu lato, our fossils are classified into the genus Platycladus. The occurrence of P. yunnanensis sp. nov. indicates that this genus had a more southernly natural distribution in the late Miocene than at present. Molecular phylogeny and fossil records support a pre-Oligocene common ancestor for the genera Platycladus, Microbiota and Calocedrus. The separation of the three taxa was most likely caused by the arid belt across Central China during the Oligocene. In addition, the cooling down of the global temperature and the strengthening of Asian monsoon since the Miocene will further promote the migration of these genera.
doi:10.1371/journal.pone.0115141
PMCID: PMC4269418  PMID: 25517767
10.  Resting-State Functional Connectivity of Subgenual Anterior Cingulate Cortex in Depressed Adolescents 
Biological psychiatry  2013;74(12):898-907.
Background
Very few studies have been performed to understand the underlying neural substrates of adolescent major depressive disorder (MDD). Studies in depressed adults have demonstrated that the subgenual anterior cingulate cortex (sgACC) plays a pivotal role in depression and have revealed aberrant patterns of resting-state functional connectivity (RSFC). Here, we examine the RSFC of the sgACC in medication-naïve first-episode adolescents with MDD.
Methods
Twenty-three adolescents with MDD and 36 well-matched control subjects underwent functional magnetic resonance imaging to assess the RSFC of the sgACC.
Results
We observed elevated connectivity between the sgACC and the insula and between the sgACC and the amygdala in the MDD group compared with the control subjects. Decreased connectivity between the sgACC and the precuneus was also found in the MDD group relative to the control subjects. Within the MDD group, higher levels of depression significantly correlated with decreased connectivity between the sgACC and left precuneus. Increased rumination was significantly associated with reduced connectivity between sgACC and the middle and inferior frontal gyri in the MDD group.
Conclusions
Our study is the first to examine sgACC connectivity in medication-naïve first-episode adolescents with MDD compared with well-matched control participants. Our results suggest aberrant functional connectivity among the brain networks responsible for salience attribution, executive control, and the resting-state in the MDD group compared with the control participants. Our findings raise the possibility that therapeutic interventions that can restore the functional connectivity among these networks to that typical of healthy adolescents might be a fruitful avenue for future research.
doi:10.1016/j.biopsych.2013.05.036
PMCID: PMC4103629  PMID: 23910949
Adolescent major depression; amygdala; default mode network; insula; resting-state; subgenual anterior cingulate
11.  HIV Treatment as Prevention: Contradictory Perspectives from Dynamic Mathematical Models 
The Scientific World Journal  2014;2014:760734.
The preventative effects of antiretroviral therapy for people with HIV have been debated since they were first raised. Models commenced studying the preventive effects of treatment in the 1990s, prior to initial public reports. However, the outcomes of the preventive effects of antiretroviral use were not consistent. Some outcomes of dynamic models were based on unfeasible assumptions, such as no consideration of drug resistance, behavior disinhibition, or economic inputs in poor countries, and unrealistic input variables, for example, overstated initiation time, adherence, coverage, and efficacy of treatment. This paper reviewed dynamic mathematical models to ascertain the complex effects of ART on HIV transmission. This review discusses more conservative inputs and outcomes relative to antiretroviral use in HIV infections in dynamic mathematical models. ART alone cannot eliminate HIV transmission.
doi:10.1155/2014/760734
PMCID: PMC4279253  PMID: 25580461
12.  Clinicopathological and Prognostic Significance of CD24 Overexpression in Patients with Gastric Cancer: A Meta-Analysis 
PLoS ONE  2014;9(12):e114746.
Objective
The prognostic significance of CD24 expression for survival in patients with gastric cancer remains controversial. We conducted a meta-analysis to investigate the impact of CD24 expression on clinicopathological features and survival outcomes in gastric cancer.
Methods
A comprehensive literature search of the electronic databases PubMed, Embase, Web of Science and China National Knowledge Infrastructure (CNKI; up to April 8, 2014) was performed for relevant studies using multiple search strategies. Correlations between CD24 expression and clinicopathological features and overall survival (OS) were analyzed.
Results
A total of 1,041 patients with gastric cancer from 9 studies were included. The pooled odds ratios (ORs) indicated CD24 expression was associated with tumor depth (OR = 0.45, 95% confidence interval [CI]  = 0.32–0.63; P<0.00001), status of lymph nodes (OR = 0.40, 95% CI = 0.25–0.64; P = 0.0001) and tumor node metastasis (TNM) stage (OR = 0.56, 95% CI = 0.41–0.77; P = 0.0003). The pooled hazard ratio (HR) for OS showed overexpression of CD24 reduced OS in gastric cancer (HR = 1.99, 95% CI = 1.29–3.07, P = 0.002). Whereas, combined ORs showed that CD24 expression had no correlation with tumor differentiation or Lauren classifications.
Conclusion
CD24 overexpression in patients with gastric cancer indicated worse survival outcomes and was associated with common clinicopathological poor prognostic factors.
doi:10.1371/journal.pone.0114746
PMCID: PMC4264770  PMID: 25503963
13.  Aerobic and sequential anaerobic fermentation to produce xylitol and ethanol using non-detoxified acid pretreated corncob 
Biotechnology for Biofuels  2014;7(1):166.
Background
For economical bioethanol production from lignocellulosic materials, the major technical challenges to lower the production cost are as follows: (1) The microorganism should use efficiently all glucose and xylose in the lignocellulose hydrolysate. (2) The microorganism should have high tolerance to the inhibitors present in the lignocellulose hydrolysate. The aim of the present work was to combine inhibitor degradation, xylitol fermentation, and ethanol production using a single yeast strain.
Results
A new process of integrated aerobic xylitol production and anaerobic ethanol fermentation using non-detoxified acid pretreated corncob by Candida tropicalis W103 was proposed. C. tropicalis W103 is able to degrade acetate, furfural, and 5-hydromethylfurfural and metabolite xylose to xylitol under aerobic conditions, and the aerobic fermentation residue was used as the substrate for ethanol production by anaerobic simultaneous saccharification and fermentation. With 20% substrate loading, furfural and 5-hydroxymethylfurfural were degraded totally after 60 h aerobic incubation. A maximal xylitol concentration of 17.1 g l-1 was obtained with a yield of 0.32 g g-1 xylose. Then under anaerobic conditions with the addition of cellulase, 25.3 g l-1 ethanol was produced after 72 h anaerobic fermentation, corresponding to 82% of the theoretical yield.
Conclusions
Xylitol and ethanol were produced in Candida tropicalis W103 using dual-phase fermentations, which comprise a changing from aerobic conditions (inhibitor degradation and xylitol production) to anaerobic simultaneous saccharification and ethanol fermentation. This is the first report of integrated xylitol and ethanol production from non-detoxified acid pretreated corncob using a single microorganism.
doi:10.1186/s13068-014-0166-y
PMCID: PMC4245779  PMID: 25431622
Bioconversion; Corncob; Fermentation; Microbial Growth; Inhibitor
14.  Changes of TCR repertoire diversity in colorectal cancer after Erbitux (cetuximab) in combination with chemotherapy 
We have previous found a positive correlation between post-therapy TCR repertoire normalization and remission of colorectal cancer (CRC) patients following fluorouracil, leucovorin, and irinotecan (FOLFIRI) plus bevacizumab or Rh-endostatin therapy. To further define the TCR repertoire diversity changes following treatment in CRC patients, and confirm its potential prognostic value, the present study extended the sample size of follow-up and used an alternative therapy regime to investigate changes of TCR repertoires following Erbitux plus FOLFIRI therapy. Inclusion and exclusion criteria have been established to screen out 26 patients to receive Erbitux plus FOLFIRI therapy. Efficacy and toxicity assessment have been made for them after 3 months’ treatment as well as the TCR repertoire diversity has been determined. A CDR3 complex scoring system was used to quantify the diversity of TCR repertoire. The results showing that the diversity of CD4+ T cells in PR group was significantly higher than that of SD and PD groups, and the difference was enlargement after treatment. The diversity of CD8+ T cells in PR group has no difference before and after treatment, but significant decrease in SD and PD group after treatment. In conclusion, analysis the diversity of T cell repertoire has an important prognosis value for CRC patients.
PMCID: PMC4266724  PMID: 25520880
Colorectal cancer (CRC); T cell receptor (TCR); TCR repertoire; complementarity determining region 3 (CDR3); Erbitux
15.  Matrix Metalloproteinase 1, 3, and 9 Polymorphisms and Esophageal Squamous Cell Carcinoma Risk 
Background
Matrix metalloproteinases (MMPs) are multifunctional zinc-dependent proteinases that play a fundamental role in the pathogenesis of tumors. We have analyzed the association between 3 single-nucleotide polymorphisms (SNPs; MMP1 −1607 1G/2G, MMP3 −1612 5A/6A, and MMP9 −1562 C/T) and the risk of esophageal squamous cell carcinoma (ESCC).
Material/Methods
We investigated these 3 SNPs in 132 patients and 132 controls using polymerase chain reaction-restriction fragment length polymorphism methods. The MMP1 and MMP3 genes are located on the same chromosome. Haplotype analysis was performed to study the combined effect of the linked MMP polymorphisms on ESCC risk.
Results
The MMP1 and MMP9 promoter polymorphisms were not associated with ESCC risk, while the MMP3 −1612 5A/6A polymorphism was significantly associated with susceptibility to ESCC. Patients carrying the 5A allele had a significantly higher risk for developing ESCC compared with individuals carrying the 6A allele (OR=1.93; 95% CI 1.34–2.77; p<0.01). The 2G-5A and 1G-5A haplotypes were associated with a significantly increased risk of ESCC as compared with the 2G-6A haplotype (OR=2.04, 95% CI 1.37–3.04 and OR=3.65, 95% CI 1.26–10.55, respectively).
Conclusions
These findings implicate this MMP3 polymorphism as a contributor to ESCC susceptibility.
doi:10.12659/MSM.892413
PMCID: PMC4242704  PMID: 25391977
Esophageal Neoplasms; Genetic Association Studies; Matrix Metalloproteinase 1
16.  CYLD Negatively Regulates Nontypeable Haemophilus influenzae-Induced IL-8 Expression via Phosphatase MKP-1-Dependent Inhibition of ERK 
PLoS ONE  2014;9(11):e112516.
Nontypeable Haemophilus influenzae (NTHi), a Gram-negative bacterium, is the primary cause of otitis media in children and the exacerbation of chronic obstructive pulmonary disease in adults. A hallmark of both diseases is an overactive inflammatory response, including the upregulation of chemokines, such as interleukin-8 (IL-8). An appropriate inflammatory response is essential for eradicating pathogens. However, excessive inflammation can cause host tissue damage. Therefore, expression of IL-8 must be tightly regulated. We previously reported that NTHi induces IL-8 expression in an ERK-dependent manner. We also have shown that the deubiquitinase cylindromatosis (CYLD) suppresses NTHi-induced inflammation. However, the underlying molecular mechanism of how CYLD negatively regulates ERK-mediated IL-8 production is largely unknown. Here, we examine both human lung epithelial A549 cells and lung of Cyld−/− mice to show that CYLD specifically targets the activation of ERK. Interestingly, CYLD enhances NTHi-induced upregulation of another negative regulator, MAP Kinase Phosphatase-1 (MKP-1), which, in turn, leads to reduced ERK activation and subsequent suppression of IL-8. Taken together, the CYLD suppression of ERK-dependent IL-8 via MKP-1 may bring novel insights into the tight regulation of inflammatory responses and also lead to innovative therapeutic strategies for controlling these responses by targeting key negative regulators of inflammation.
doi:10.1371/journal.pone.0112516
PMCID: PMC4229244  PMID: 25389768
17.  Predicting Nucleosome Positioning Based on Geometrically Transformed Tsallis Entropy 
PLoS ONE  2014;9(11):e109395.
As the fundamental unit of eukaryotic chromatin structure, nucleosome plays critical roles in gene expression and regulation by controlling physical access to transcription factors. In this paper, based on the geometrically transformed Tsallis entropy and two index-vectors, a valid nucleosome positioning information model is developed to describe the distribution of A/T-riched and G/C-riched dimeric and trimeric motifs along the DNA duplex. When applied to train the support vector machine, the model achieves high AUCs across five organisms, which have significantly outperformed the previous studies. Besides, we adopt the concept of relative distance to describe the probability of arbitrary DNA sequence covered by nucleosome. Thus, the average nucleosome occupancy profile over the S.cerevisiae genome is calculated. With our peak detection model, the isolated nucleosomes along genome sequence are located. When compared with some published results, it shows that our model is effective for nucleosome positioning. The index-vector component is identified to be an important influencing factor of nucleosome organizations.
doi:10.1371/journal.pone.0109395
PMCID: PMC4224380  PMID: 25380134
18.  The Positive Regulatory Roles of the TIFY10 Proteins in Plant Responses to Alkaline Stress 
PLoS ONE  2014;9(11):e111984.
The TIFY family is a novel plant-specific protein family, and is characterized by a conserved TIFY motif (TIFF/YXG). Our previous studies indicated the potential roles of TIFY10/11 proteins in plant responses to alkaline stress. In the current study, we focused on the regulatory roles and possible physiological and molecular basis of the TIFY10 proteins in plant responses to alkaline stress. We demonstrated the positive function of TIFY10s in alkaline responses by using the AtTIFY10a and AtTIFY10b knockout Arabidopsis, as evidenced by the relatively lower germination rates of attify10a and attify10b mutant seeds under alkaline stress. We also revealed that ectopic expression of GsTIFY10a in Medicago sativa promoted plant growth, and increased the NADP-ME activity, citric acid content and free proline content but decreased the MDA content of transgenic plants under alkaline stress. Furthermore, expression levels of the stress responsive genes including NADP-ME, CS, H+-ppase and P5CS were also up-regulated in GsTIFY10a transgenic plants under alkaline stress. Interestingly, GsTIFY10a overexpression increased the jasmonate content of the transgenic alfalfa. In addition, we showed that neither GsTIFY10a nor GsTIFY10e exhibited transcriptional activity in yeast cells. However, through Y2H and BiFc assays, we demonstrated that GsTIFY10a, not GsTIFY10e, could form homodimers in yeast cells and in living plant cells. As expected, we also demonstrated that GsTIFY10a and GsTIFY10e could heterodimerize with each other in both yeast and plant cells. Taken together, our results provided direct evidence supporting the positive regulatory roles of the TIFY10 proteins in plant responses to alkaline stress.
doi:10.1371/journal.pone.0111984
PMCID: PMC4222965  PMID: 25375909
19.  Effectiveness of ART and Condom Use for Prevention of Sexual HIV Transmission in Serodiscordant Couples: A Systematic Review and Meta-Analysis 
PLoS ONE  2014;9(11):e111175.
Background
Consistent and correct condom use and suppressive antiretroviral therapy for the infected partner are two of the primary strategies recommended for prevention of heterosexual HIV transmission in serodiscordant couples today. The applied effectiveness of treatment as a prevention strategy in China is still under investigation, and much less is known about its effects in the presence of other prevention strategies such as consistent condom use.
Methods
We conducted a systematic search in PubMed and three Chinese language databases to identify relevant articles for the estimation of relative effectiveness of a) consistent condom use and b) ART use by index partners for preventing HIV transmission in serodiscordant couples. We also estimated the prevention effectiveness of ART stratified by condom use level and the prevention effectiveness of consistent condom use stratified by ART use level.
Results
Pooled results from the eleven eligible studies found a pooled HIV seroconversion incidence of 0.92 cases per 100 person years (PY) among HIV-negative spouses whose index partners were taking ART versus 2.45 cases per 100 PY in untreated couples. The IRR comparing seroconversion in couples where the index-partner was on ART versus not on ART was 0.47 (95%CI: 0.43, 0.52), while stratified by condom use, the IRR was 0.33(0.17,0.64). The IRR comparing incidence in couples reporting “consistent condom use” versus those reporting otherwise was 0.02(95%CI:0.01,0.04), after stratified by ART use level, the IRR was 0.01(95%CI: 0.00, 0.06).
Conclusions
ART use by index partners could reduce HIV transmission in serodiscordant couples, and the effectiveness of this prevention strategy could be further increased with consistent condom use.
doi:10.1371/journal.pone.0111175
PMCID: PMC4219707  PMID: 25369471
20.  Human Influenza A(H7N9) Virus Infection Associated with Poultry Farm, Northeastern China 
Emerging Infectious Diseases  2014;20(11):1902-1905.
We report on a case of human infection with influenza A(H7N9) virus in Jilin Province in northeastern China. This case was associated with a poultry farm rather than a live bird market, which may point to a new focus for public health surveillance and interventions in this evolving outbreak.
doi:10.3201/eid2011.140608
PMCID: PMC4214311  PMID: 25340624
H7N9; avian influenza; China; poultry farm; influenza; flu; avian flu; human; Suggested citation for this article: Fan M; Huang B; Wang A; Deng L; Wu D; Lu X; et al. Human influenza A(H7N9) virus infection associated with poultry farm; northeastern China. Emerg Infect Dis [Internet]. 2014 Nov [date cited]. http://dx.doi.org/10.3201/eid2011.140608
22.  Type 3 muscarinic acetylcholine receptor stimulation is a determinant of endothelial barrier function and adherens junctions integrity: role of protein-tyrosine phosphatase 1B 
BMB Reports  2014;47(10):552-557.
The main purpose of this study was to investigate whether type 3 muscarinic acetylcholine receptor (M3R) dysfunction induced vascular hyperpermeability. Transwell system analysis showed that M3R inhibition by selective antagonist 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP) and small interfering RNA both increased endothelial permeability. Using coimmunoprecipitation and Western blot assay, we found that M3R inhibition increased VE-cadherin and β-catenin tyrosine phosphorylation without affecting their expression. Using PTP1B siRNA, we found that PTP1B was required for maintaining VE-cadherin and β-catenin protein dephosphorylation. In addition, 4-DAMP suppressed PTP1B activity by reducing cyclic adenosine monophosphate (cAMP), but not protein kinase Cα (PKCα). These data indicate that M3R preserves the endothelial barrier function through a mechanism potentially maintaining PTP1B activity, keeping the adherens junction proteins (AJPs) dephosphorylation. [BMB Reports 2014; 47(10): 552-557]
doi:10.5483/BMBRep.2014.47.10.216
PMCID: PMC4261512  PMID: 24393526
β-catenin; M3R; PTP1B; VE-cadherin
23.  Ten-year trends in major lifestyle risk factors using an ongoing population surveillance system in Australia 
Population Health Metrics  2014;12(1):31.
Background
Understanding how risk factors (tobacco, alcohol, physical inactivity, unhealthy diet, high blood pressure, and high cholesterol) change over time is a critical aim of public health. The associations across the social gradient over time are important considerations. Risk factor surveillance systems have a part to play in understanding the epidemiological distribution of the risk factors so as to improve preventive measures and design public health interventions for reducing the burden of disease.
Methods
Representative, cross-sectional data were collected in South Australia using telephone interviews, conducted on a minimum of 600 randomly selected people (of all ages) each month. Data were collected from January 2004 to December 2013. Unadjusted prevalence over time, the relative percentage change over the 10 years, and the absolute change of the risk factors with sex, age group, and socio-economic status (SES) estimates are presented.
Results
In total 55,548 adults (≥18 years) were interviewed (mean age = 47.8 years, 48.8% male). Decreases were apparent for insufficient physical activity, inadequate fruit and vegetables, smoking, and soft drink consumption of ≥500 ml/day. Increases were found over the 10 years for obesity, high cholesterol, diabetes, and for those with no risk factors. Apparent differences were noticeable by different sex, age, and SES categories. While increases in physical activity and fruit and vegetable consumption and decreases in smoking prevalence and multiple risk factors are to be expected in 2020–2021, the prevalence of obesity, high blood pressure, high cholesterol, and diabetes are expected to increase.
Conclusions
Public health efforts in increasing the proportion of the population undertaking appropriate risk factor behavior are showing signs of success, with data from 2004 to 2013 showing encouraging trends. Deriving comparable trends over time by key demographics and SES variables provides evidence for policymakers and health planners to encourage interventions aimed at preventing chronic disease.
Electronic supplementary material
The online version of this article (doi:10.1186/s12963-014-0031-z) contains supplementary material, which is available to authorized users.
doi:10.1186/s12963-014-0031-z
PMCID: PMC4222399  PMID: 25379026
Risk factors; Surveillance; Australia; Trends
24.  CT features of retroperitoneal solitary fibrous tumor: report of three cases and review of the literature 
CT findings in three cases with solitary fibrous tumors (SFTs) confirmed by histopathology and immunohistochemistry were reviewed retrospectively, and compared with pathological results. The three tumors were large, well-defined, and smooth contour masses and SFT consisted of solid components of two different densities. On enhanced CT scans, tumors were strongly enhancing, the multiple vascular shadows were seen within the tumor in the arterial phase. There is progressive enhancement from the arterial to the venous phase, and the tumor capsule can be observed. Histologically, the tumors are composed of spindle cells within a background of collagen stroma, and showed a wide range of growth patterns, alternating hypercellular (tumor cell-rich) and hypocellular (collagen-rich) areas. The diagnosis is confirmed by characteristic positive immunohistochemical staining for CD34.
doi:10.1186/1477-7819-12-324
PMCID: PMC4282173  PMID: 25351104
Retroperitoneum; Solitary fibrous tumors; Tomography; X-ray computed
25.  Validation and comparison of EuroQoL-5 dimension (EQ-5D) and Short Form-6 dimension (SF-6D) among stable angina patients 
Objectives
Several preference-based health-related quality of life (HRQoL) instruments have been published and widely used in different populations. However no consensus has emerged regarding the most appropriate instrument in therapeutic area of stable angina. This study compared and validated the psychometric properties of two generic preference-based instruments, the EQ-5D and SF-6D, among Chinese stable angina patients.
Methods
Convergent validity of the EQ-5D and SF-6D was examined with eight a priori hypotheses from stable angina patients in conjunction with Seattle Angina Questionnaire (SAQ). Responsiveness was compared using the effect size (ES), relative efficiency (RE) and receiver operating characteristic (ROC) curves. Agreement between the EQ-5D and SF-6D was tested using intra-class correlation coefficient (ICC) and Bland-Altman plot. Factors affecting utility difference were explored with multiple linear regression analysis.
Results
In 411 patients (mean age 68.08 ± 11.35), mean utility scores (SD) were 0.78 (0.15) for the EQ-5D and 0.68 (0.12) for the SF-6D. Validity was demonstrated by the moderate to strong correlation coefficients (Range: 0.368-0.594, P< 0.001) for five of the eight hypotheses in both the EQ-5D and SF-6D. There were no serious floor effects for the EQ-5D and SF-6D, but ceiling effects for the EQ-5D were large. The areas under ROC of them all exceeded 0.5 (0.660-0.814, P< 0.001). The SF-6D showed a better discriminative capacity (ES: 0.573 to 1.179) between groups with different stable-angina-specific health status than the EQ-5D (ES: 0.426 to 1.126). RE suggested that the SF-6D (RE: 44.8 to 177.8%) was more efficient than the EQ-5D except for physical function. Poor agreement between them was observed with ICC (0.448, P< 0.001) and Bland-Altman plot analysis. Multiple liner regression showed that clinical variables significantly (P< 0.05) influenced differences in utility scores between the EQ-5D and SF-6D.
Conclusions
Both EQ-5D and SF-6D are valid and sensitive preference-based HRQoL instruments in Chinese stable angina patients. The SF-6D may be a more effective tool with lower ceiling effect and greater sensitivity. Further study is needed to compare other properties, such as reliability and longitudinal response.
doi:10.1186/s12955-014-0156-6
PMCID: PMC4213514  PMID: 25343944
Quality of life; Stable angina; EQ-5D; SF-6D; Utility; China

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