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1.  Developing Screening Services for Colorectal Cancer on Android Smartphones 
Telemedicine Journal and e-Health  2014;20(8):687-695.
Abstract
Introduction: Colorectal cancer (CRC) is an important health problem in Western countries and also in Asia. It is the third leading cause of cancer deaths in both men and women in Taiwan. According to the well-known adenoma-to-carcinoma sequence, the majority of CRC develops from colorectal adenomatous polyps. This concept provides the rationale for screening and prevention of CRC. Removal of colorectal adenoma could reduce the mortality and incidence of CRC. Mobile phones are now playing an ever more crucial role in people's daily lives. The latest generation of smartphones is increasingly viewed as hand-held computers rather than as phones, because of their powerful on-board computing capability, capacious memories, large screens, and open operating systems that encourage development of applications (apps). Subjects and Methods: If we can detect the potential CRC patients early and offer them appropriate treatments and services, this would not only promote the quality of life, but also reduce the possible serious complications and medical costs. In this study, an intelligent CRC screening app on Android™ (Google™, Mountain View, CA) smartphones has been developed based on a data mining approach using decision tree algorithms. For comparison, the stepwise backward multivariate logistic regression model and the fecal occult blood test were also used. Results: Compared with the stepwise backward multivariate logistic regression model and the fecal occult blood test, the proposed app system not only provides an easy and efficient way to quickly detect high-risk groups of potential CRC patients, but also brings more information about CRC to customer-oriented services. Conclusions: We developed and implemented an app system on Android platforms for ubiquitous healthcare services for CRC screening. It can assist people in achieving early screening, diagnosis, and treatment purposes, prevent the occurrence of complications, and thus reach the goal of preventive medicine.
doi:10.1089/tmj.2013.0288
PMCID: PMC4106382  PMID: 24848873
colorectal cancer; mobile health telehealth; data mining; health monitoring
2.  A Conserved Domain Is Crucial for Acceptor Substrate Binding in a Family of Glucosyltransferases 
Journal of Bacteriology  2014;197(3):510-517.
Serine-rich repeat glycoproteins (SRRPs) are highly conserved in streptococci and staphylococci. Glycosylation of SRRPs is important for bacterial adhesion and pathogenesis. Streptococcus agalactiae is the leading cause of bacterial sepsis and meningitis among newborns. Srr2, an SRRP from S. agalactiae strain COH1, has been implicated in bacterial virulence. Four genes (gtfA, gtfB, gtfC, and gtfD) located downstream of srr2 share significant homology with genes involved in glycosylation of other SRRPs. We have shown previously that gtfA and gtfB encode two glycosyltransferases, GtfA and GtfB, that catalyze the transfer of GlcNAc residues to the Srr2 polypeptide. However, the function of other glycosyltransferases in glycosylation of Srr2 is unknown. In this study, we determined that GtfC catalyzed the direct transfer of glucosyl residues to Srr2-GlcNAc. The GtfC crystal structure was solved at 2.7 Å by molecular replacement. Structural analysis revealed a loop region at the N terminus as a putative acceptor substrate binding domain. Deletion of this domain rendered GtfC unable to bind to its substrate Srr2-GlcNAc, concurrently abolished the glycosyltransferase activity of GtfC, and also altered glycosylation of Srr2. Furthermore, deletion of the corresponding regions from GtfC homologs also abolished their substrate binding and enzymatic activity, indicating that this region is functionally conserved. In summary, we have determined that GtfC is important for the glycosylation of Srr2 and identified a conserved loop region that is crucial for acceptor substrate binding from GtfC homologs in streptococci. These findings shed new mechanistic insight into this family of glycosyltransferases.
doi:10.1128/JB.02267-14
PMCID: PMC4285981  PMID: 25404702
3.  IL-27 Signaling Is Crucial for Survival of Mice Infected with African Trypanosomes via Preventing Lethal Effects of CD4+ T Cells and IFN-γ 
PLoS Pathogens  2015;11(7):e1005065.
African trypanosomes are extracellular protozoan parasites causing a chronic debilitating disease associated with a persistent inflammatory response. Maintaining the balance of the inflammatory response via downregulation of activation of M1-type myeloid cells was previously shown to be crucial to allow prolonged survival. Here we demonstrate that infection with African trypanosomes of IL-27 receptor-deficient (IL-27R-/-) mice results in severe liver immunopathology and dramatically reduced survival as compared to wild-type mice. This coincides with the development of an exacerbated Th1-mediated immune response with overactivation of CD4+ T cells and strongly enhanced production of inflammatory cytokines including IFN-γ. What is important is that IL-10 production was not impaired in infected IL-27R-/- mice. Depletion of CD4+ T cells in infected IL-27R-/- mice resulted in a dramatically reduced production of IFN-γ, preventing the early mortality of infected IL-27R-/- mice. This was accompanied by a significantly reduced inflammatory response and a major amelioration of liver pathology. These results could be mimicked by treating IL-27R-/- mice with a neutralizing anti-IFN-γ antibody. Thus, our data identify IL-27 signaling as a novel pathway to prevent early mortality via inhibiting hyperactivation of CD4+ Th1 cells and their excessive secretion of IFN-γ during infection with African trypanosomes. These data are the first to demonstrate the essential role of IL-27 signaling in regulating immune responses to extracellular protozoan infections.
Author Summary
Infection with extracellular protozoan parasites, African trypanosomes, is characterized by a persistent inflammatory immune response. It has been recently shown that maintaining the balance of the inflammatory responses via dampening M1-type myeloid cell activation is critical to guarantee control of the parasites and survival of the host. In this study, we demonstrated that IL-27 receptor-deficient (IL-27R-/-) mice infected with African trypanosomes developed an excessive inflammatory response and severe liver immunopathology, resulting in dramatically reduced survival, as compared to infected wild-type mice. The early mortality of infected IL-27R-/- mice was correlated with significantly elevated secretions of inflammatory cytokines, particularly IFN-γ, and enhanced activation of CD4+ Th1 cells. Importantly, IL-10 production was not impaired in infected IL-27R-/- mice. Either depletion of CD4+ T cells, resulting in a dramatically reduced secretion of IFN-γ, or neutralization of IFN-γ, prevented the early mortality of infected IL-27R-/- mice with a significantly reduced inflammatory response and a major amelioration of the liver pathology. Thus, our data identify IL-27 signaling as a novel pathway to prevent the early mortality via inhibiting hyperactivation of CD4+ Th1 cells and their excessive secretions of IFN-γ during experimental infection with extracellular protozoan parasites African trypanosomes.
doi:10.1371/journal.ppat.1005065
PMCID: PMC4519326  PMID: 26222157
4.  Hypoxia-induced autophagy mediates cisplatin resistance in lung cancer cells 
Scientific Reports  2015;5:12291.
Hypoxia which commonly exists in solid tumors, leads to cancer cells chemoresistance via provoking adaptive responses including autophagy. Therefore, we sought to evaluate the role of autophagy and hypoxia as well as the underlying mechanism in the cisplatin resistance of lung cancer cells. Our study demonstrated that hypoxia significantly protected A549 and SPC-A1 cells from cisplatin-induced cell death in a Hif-1α- and Hif-2α- dependent manner. Moreover, compared with normoxia, cisplatin-induced apoptosis under hypoxia was markedly reduced. However, when autophagy was inhibited by 3-MA or siRNA targeted ATG5, this reduction was effectively attenuated, which means autophagy mediates cisplatin resisitance under hypoxia. In parallel, we showed that hypoxia robustly augmented cisplatin-induced autophagy activation, accompanying by suppressing cisplatin-induced BNIP3 death pathways, which was due to the more efficient autophagic process under hypoxia. Consequently, we proposed that autophagy was a protective mechanism after cisplatin incubation under both normoxia and hypoxia. However, under normoxia, autophagy activation ‘was unable to counteract the stress induced by cisplatin, therefore resulting in cell death, whereas under hypoxia, autophagy induction was augmented that solved the cisplatin-induced stress, allowing the cells to survival. In conclusion, augmented induction of autophagy by hypoxia decreased lung cancer cells susceptibility to cisplatin-induced apoptosis.
doi:10.1038/srep12291
PMCID: PMC4511870  PMID: 26201611
5.  Anti-inflammatory Effects of Perioperative Dexmedetomidine Administered as an Adjunct to General Anesthesia: A Meta-analysis 
Scientific Reports  2015;5:12342.
The aim of this meta-analysis is to examine the effects of dexmedetomidine on serum inflammatory markers when administered perioperatively. We searched multiple electronic databases for relevant research papers, and carried out meta-analyses of weighted mean differences and interpreted in the light of statistical heterogeneity (I2). Fifteen RCTs recruiting 641 patients were included. Dexmedetomidine treatment significantly decreased interleukin-6 (IL-6), IL-8 and tumor necrosis factor-alpha (TNF-α) levels with mean differences [95% CI] in the changes from baseline between dexmedetomidine treated and controls of −25.14 [−35.29, −15.00]; P < 0.00001 (for IL-6), −5.69 [−10.77, −0.60]; P < 0.04 (for IL-8), and −20.30 [−30.93, −9.67]; P < 0.0002 (for TNF-α) immediately after surgery; and −41.55 [−57.41, −25.70]; P < 0.00001 (IL-6), −6.46 [−10.83, −2.08]; P < 0.005 (IL-8), and −14.67 [−22.61, −6.73]; P < 0.0003 (TNF-α) on postoperative day 1 (random effects). IL-10 levels were found to increase significantly a day after surgery (8.33 [3.31, 13.36]; P = 0.001). Subgroup analyses did not reveal significant differences. In conclusion, perioperative adjunctive use of dexmedetomidine substantially decreases serum IL-6, IL-8 and TNF-α levels.
doi:10.1038/srep12342
PMCID: PMC4508837  PMID: 26196332
6.  Quantification of EUGR as a Measure of the Quality of Nutritional Care of Premature Infants 
PLoS ONE  2015;10(7):e0132584.
Objectives
To develop an index of the quality of nutritional care of premature infants based on the change in weight Z score from birth to discharge and to illustrate the use of this index in comparing the performance of different NICUs.
Methods
Retrospective data analysis was performed to compare the growth of premature infants born in three perinatal centers. Infants with gestational age ≤ 32 weeks who survived to discharge from 2006 to 2010 were included. Weight Z scores at birth and discharge were calculated by the method of Fenton. Using data from one NICU as the reference, a multivariable linear regression model of change in weight Z score from birth to discharge was developed. Employing this model, a benchmark value of change in weight Z score was calculated for each baby. The difference between this calculated benchmark value and the baby’s observed change in weight Z score was defined as the performance gap for that infant. The average value of the performance gaps in a NICU serves as its quality care index.
Results
1,714 infants were included for analysis. Change in weight Z score is influenced by birth weight Z score and completed weeks of gestation; thus the model for calculating the benchmark change in weight Z score was adjusted for these two variables. We found statistically significant differences in the average performance gaps for the three units.
Conclusions
A quality care index was developed based on change in weight Z score from birth to discharge adjusted for two initial risk factors. This objective, easily calculated index may be used as a measurement of the quality of nutritional care to rank the performance of different NICUs.
doi:10.1371/journal.pone.0132584
PMCID: PMC4508031  PMID: 26193640
7.  Transcriptome analysis of mRNA and miRNA in skeletal muscle indicates an important network for differential Residual Feed Intake in pigs 
Scientific Reports  2015;5:11953.
Feed efficiency (FE) can be measured by feed conversion ratio (FCR) or residual feed intake (RFI). In this study, we measured the FE related phenotypes of 236 castrated purebred Yorkshire boars, and selected 10 extreme individuals with high and low RFI for transcriptome analysis. We used RNA-seq analyses to determine the differential expression of genes and miRNAs in skeletal muscle. There were 99 differentially expressed genes identified (q ≤ 0.05). The down-regulated genes were mainly involved in mitochondrial energy metabolism, including FABP3, RCAN, PPARGC1 (PGC-1A), HK2 and PRKAG2. The up-regulated genes were mainly involved in skeletal muscle differentiation and proliferation, including IGF2, PDE7A, CEBPD, PIK3R1 and MYH6. Moreover, 15 differentially expressed miRNAs (|log2FC| ≥ 1, total reads count ≥ 20, p ≤ 0.05) were identified. Among them, miR-136, miR-30e-5p, miR-1, miR-208b, miR-199a, miR-101 and miR-29c were up-regulated, while miR-215, miR-365-5p, miR-486, miR-1271, miR-145, miR-99b, miR-191 and miR-10b were down-regulated in low RFI pigs. We conclude that decreasing mitochondrial energy metabolism, possibly through AMPK - PGC-1A pathways, and increasing muscle growth, through IGF-1/2 and TGF-β signaling pathways, are potential strategies for the improvement of FE in pigs (and possibly other livestock). This study provides new insights into the molecular mechanisms that determine RFI and FE in pigs.
doi:10.1038/srep11953
PMCID: PMC4493709  PMID: 26150313
8.  Correlation of DNA methylation levels in blood and saliva DNA in young girls of the LEGACY Girls study 
Epigenetics  2014;9(7):929-933.
Many epidemiologic studies of environmental exposures and disease susceptibility measure DNA methylation in white blood cells (WBC). Some studies are also starting to use saliva DNA as it is usually more readily available in large epidemiologic studies. However, little is known about the correlation of methylation between WBC and saliva DNA. We examined DNA methylation in three repetitive elements, Sat2, Alu, and LINE-1, and in four CpG sites, including AHRR (cg23576855, cg05575921), cg05951221 at 2q37.1, and cg11924019 at CYP1A1, in 57 girls aged 6–15 years with blood and saliva collected on the same day. We measured all DNA methylation markers by bisulfite-pyrosequencing, except for Sat2 and Alu, which were measured by the MethyLight assay. Methylation levels measured in saliva DNA were lower than those in WBC DNA, with differences ranging from 2.8% for Alu to 14.1% for cg05575921. Methylation levels for the three repetitive elements measured in saliva DNA were all positively correlated with those in WBC DNA. However, there was a wide range in the Spearman correlations, with the smallest correlation found for Alu (0.24) and the strongest correlation found for LINE-1 (0.73). Spearman correlations for cg05575921, cg05951221, and cg11924019 were 0.33, 0.42, and 0.79, respectively. If these findings are replicated in larger studies, they suggest that, for selected methylation markers (e.g., LINE-1), methylation levels may be highly correlated between blood and saliva, while for others methylation markers, the levels may be more tissue specific. Thus, in studies that differ by DNA source, each interrogated site should be separately examined in order to evaluate the correlation in DNA methylation levels across DNA sources.
doi:10.4161/epi.28902
PMCID: PMC4143407  PMID: 24756002
buccal cells; DNA genomic methylation; LINE-1; pyrosequencing; saliva; white blood cells
9.  Oral Streptococci and Nitrite-Mediated Interference of Pseudomonas aeruginosa 
Infection and Immunity  2014;83(1):101-107.
The oral cavity harbors a diverse community of microbes that are physiologically unique. Oral microbes that exist in this polymicrobial environment can be pathogenic or beneficial to the host. Numerous oral microbes contribute to the formation of dental caries and periodontitis; however, there is little understanding of the role these microbes play in systemic infections. There is mounting evidence that suggests that oral commensal streptococci are cocolonized with Pseudomonas aeruginosa during cystic fibrosis pulmonary infections and that the presence of these oral streptococci contributes to improved lung function. The goal of this study was to examine the underlying mechanism by which Streptococcus parasanguinis antagonizes pathogenic P. aeruginosa. In this study, we discovered that oral commensal streptococci, including Streptococcus parasanguinis, Streptococcus sanguinis, and Streptococcus gordonii, inhibit the growth of P. aeruginosa and that this inhibition is mediated by the presence of nitrite and the production of hydrogen peroxide (H2O2) by oral streptococci. The requirement of both H2O2 and nitrite for the inhibition of P. aeruginosa is due to the generation of reactive nitrogenous intermediates (RNI), including peroxynitrite. Transposon mutagenesis showed that a P. aeruginosa mutant defective in a putative ABC transporter permease is resistant to both streptococcus/nitrite- and peroxynitrite-mediated killing. Furthermore, S. parasanguinis protects Drosophila melanogaster from killing by P. aeruginosa in a nitrite-dependent manner. Our findings suggest that the combination of nitrite and H2O2 may represent a unique anti-infection strategy by oral streptococci during polymicrobial infections.
doi:10.1128/IAI.02396-14
PMCID: PMC4288860  PMID: 25312949
10.  Microporous metal–organic framework with dual functionalities for highly efficient removal of acetylene from ethylene/acetylene mixtures 
Nature Communications  2015;6:7328.
The removal of acetylene from ethylene/acetylene mixtures containing 1% acetylene is a technologically very important, but highly challenging task. Current removal approaches include the partial hydrogenation over a noble metal catalyst and the solvent extraction of cracked olefins, both of which are cost and energy consumptive. Here we report a microporous metal–organic framework in which the suitable pore/cage spaces preferentially take up much more acetylene than ethylene while the functional amine groups on the pore/cage surfaces further enforce their interactions with acetylene molecules, leading to its superior performance for this separation. The single X-ray diffraction studies, temperature dependent gas sorption isotherms, simulated and experimental column breakthrough curves and molecular simulation studies collaboratively support the claim, underlying the potential of this material for the industrial usage of the removal of acetylene from ethylene/acetylene mixtures containing 1% acetylene at room temperature through the cost- and energy-efficient adsorption separation process.
The removal of acetylene from ethylene/acetylene mixtures is an industrially important but challenging task. Here the authors report a microporous metal–organic framework with optimized pore/cage space design and chemical functionalization, capable of removing acetylene from low concentration mixtures.
doi:10.1038/ncomms8328
PMCID: PMC4468854  PMID: 26041691
11.  Association between Work-Family Conflict and Depressive Symptoms among Chinese Female Nurses: The Mediating and Moderating Role of Psychological Capital 
Depressive symptoms have been in the limelight for many kinds of people, but few studies have explored positive resources for combating depressive symptoms among Chinese nurses. The purpose of this study is to explore the association between work-family conflict (WFC) and depressive symptoms among Chinese female nurses, along with the mediating and moderating role of psychological capital (PsyCap) in this relationship. This cross-sectional study was completed during the period of September and October 2013. A questionnaire that consisted of the Center for Epidemiologic Studies Depression Scale, the Work-Family Conflict scale and the Psychological Capital Questionnair scale was distributed to nurses in Shenyang, China. A total of 824 individuals (effective response rate: 74.9%) participated. Asymptotic and resampling strategies explored the mediating role of PsyCap in the relationship between WFC and depressive symptoms. Hierarchical linear regression analyses were performed to explore the moderating role of PsyCap. Both WFC and family-work conflict (FWC) were positively related with depressive symptoms. PsyCap positively moderated the relationship of WFC with depressive symptoms. Self-efficacy and hope positively moderated the relationship of WFC with depressive symptoms. PsyCap partially mediated the relationship of FWC with depressive symptoms. Hope and optimism partially mediated the relationship of FWC with depressive symptoms. Work-family conflict, as the risk factor of depressive symptoms, can increase nurses’ depressive symptoms, and PsyCap is a positive resource to combat nurses’ depressive symptoms. PsyCap can aggravate the effects of WFC on depressive symptoms and FWC can impact PsyCap to increase nurses’ depressive symptoms.
doi:10.3390/ijerph120606682
PMCID: PMC4483724  PMID: 26075725
depressive symptoms; work-family conflict; psychological capital
12.  Illumina human exome genotyping array clustering and quality control 
Nature protocols  2014;9(11):2643-2662.
With the rise of high-throughput sequencing technology, traditional genotyping arrays are gradually being replaced by sequencing technology. Against this trend, Illumina has introduced an exome genotyping array that provides an alternative approach to sequencing, especially suited to large-scale genome-wide association studies (GWASs). the exome genotyping array targets the exome plus rare single-nucleotide polymorphisms (SNPs), a feature that makes it substantially more challenging to process than previous genotyping arrays that targeted common SNPs. Researchers have struggled to generate a reliable protocol for processing exome genotyping array data. The Vanderbilt epidemiology center, in cooperation with Vanderbilt Technologies for Advanced Genomics Analysis and Research Design (VANGARD), has developed a thorough exome chip–processing protocol. The protocol was developed during the processing of several large exome genotyping array-based studies, which included over 60,000 participants combined. The protocol described herein contains detailed clustering techniques and robust quality control procedures, and it can benefit future exome genotyping array–based GWASs.
doi:10.1038/nprot.2014.174
PMCID: PMC4441213  PMID: 25321409
13.  Novel immunological and nutritional-based prognostic index for gastric cancer 
AIM: To assess the prognostic significance of immunological and nutritional-based indices, including the prognostic nutritional index (PNI), neutrophil-lymphocyte ratio (NLR), and platelet-lymphocyte ratio in gastric cancer.
METHODS: We retrospectively reviewed 632 gastric cancer patients who underwent gastrectomy between 1998 and 2008. Areas under the receiver operating characteristic curve were calculated to compare the predictive ability of the indices, together with estimating the sensitivity, specificity and agreement rate. Univariate and multivariate analyses were performed to identify risk factors for overall survival (OS). Propensity score analysis was performed to adjust variables to control for selection bias.
RESULTS: Each index could predict OS in gastric cancer patients in univariate analysis, but only PNI had independent prognostic significance in multivariate analysis before and after adjustment with propensity scoring (hazard ratio, 1.668; 95% confidence interval: 1.368-2.035). In subgroup analysis, a low PNI predicted a significantly shorter OS in patients with stage II-III disease (P = 0.019, P < 0.001), T3-T4 tumors (P < 0.001), or lymph node metastasis (P < 0.001). Canton score, a combination of PNI, NLR, and platelet, was a better indicator for OS than PNI, with the largest area under the curve for 12-, 36-, 60-mo OS and overall OS (P = 0.022, P = 0.030, P < 0.001, and P = 0.024, respectively). The maximum sensitivity, specificity, and agreement rate of Canton score for predicting prognosis were 84.6%, 34.9%, and 70.1%, respectively.
CONCLUSION: PNI is an independent prognostic factor for OS in gastric cancer. Canton score can be a novel preoperative prognostic index in gastric cancer.
doi:10.3748/wjg.v21.i19.5961
PMCID: PMC4438031  PMID: 26019461
Gastric cancer; Prognostic nutritional index; Canton score; Prognosis; Neutrophil-lymphocyte ratio; Platelet-lymphocyte ratio
14.  Two Novel Motifs of Watermelon Silver Mottle Virus NSs Protein Are Responsible for RNA Silencing Suppression and Pathogenicity 
PLoS ONE  2015;10(5):e0126161.
The NSs protein of Watermelon silver mottle virus (WSMoV) is the RNA silencing suppressor and pathogenicity determinant. In this study, serial deletion and point-mutation mutagenesis of conserved regions (CR) of NSs protein were performed, and the silencing suppression function was analyzed through agroinfiltration in Nicotiana benthamiana plants. We found two amino acid (aa) residues, H113 and Y398, are novel functional residues for RNA silencing suppression. Our further analyses demonstrated that H113 at the common epitope (CE) (109KFTMHNQ117), which is highly conserved in Asia type tospoviruses, and the benzene ring of Y398 at the C-terminal β-sheet motif (397IYFL400) affect NSs mRNA stability and protein stability, respectively, and are thus critical for NSs RNA silencing suppression. Additionally, protein expression of other six deleted (ΔCR1-ΔCR6) and five point-mutated (Y15A, Y27A, G180A, R181A and R212A) mutants were hampered and their silencing suppression ability was abolished. The accumulation of the mutant mRNAs and proteins, except Y398A, could be rescued or enhanced by co-infiltration with potyviral suppressor HC-Pro. When assayed with the attenuated Zucchini yellow mosaic virus vector in squash plants, the recombinants carrying individual seven point-mutated NSs proteins displayed symptoms much milder than the recombinant carrying the wild type NSs protein, suggesting that these aa residues also affect viral pathogenicity by suppressing the host silencing mechanism.
doi:10.1371/journal.pone.0126161
PMCID: PMC4439075  PMID: 25993336
15.  Glycosylation of KSHV Encoded vGPCR Functions in Its Signaling and Tumorigenicity 
Viruses  2015;7(4):1627-1641.
Kaposi’s sarcoma-associated herpesvirus (KSHV) is a tumor virus and the etiologic agent of Kaposi’s Sarcoma (KS). KSHV G protein-coupled receptor (vGPCR) is an oncogene that is implicated in malignancies associated with KHSV infection. In this study, we show that vGPCR undergoes extensive N-linked glycosylation within the extracellular domains, specifically asparagines 18, 22, 31 and 202. An immunofluorescence assay demonstrates that N-linked glycosylation are necessary for vGPCR trafficking to the cellular membrane. Employing vGPCR mutants whose glycosylation sites were ablated, we show that these vGPCR mutants failed to activate downstream signaling in cultured cells and were severely impaired to induce tumor formation in the xenograph nude mouse model. These findings support the conclusion that glycosylation is critical for vGPCR tumorigenesis and imply that chemokine regulation at the plasma membrane is crucial for vGPCR mediated signaling.
doi:10.3390/v7041627
PMCID: PMC4411669  PMID: 25835533
KSHV; vGPCR; Glycosylation
16.  Epithelioid inflammatory myofibroblastic sarcoma in abdominal cavity: a case report and review of literature 
In this study, we present a rare and difficult case of epithelioid inflammatory myofibroblastic sarcoma (EIMS) in abdominal cavity. A 47-year-old female presented as left upper abdominal pain for 6 months and abdominal distention for 1 month. CT examination showed a solid mass in the left upper intra-abdomen. Grossly, the tumor was found in the mesenterium of colon with the size of 7.5 × 6.5 × 3.5 cm, and was solid and gray-yellowish in the cut surface. Focal myxomatous appearance was observed. Microscopically, stromal myxoid change together with prominant infiltrated lymphocytes, neutrophils and eosinophils were found in the tumor, and the tumor cells were round, epithelioid with vesicular nuclei, large prominant nucleoli and high mitotic rate. Immunohistochemically, strong diffused positive for vimentin, desmin, ALK (nuclear membrane staining pattern) and AAT, focally positive for CD99 and CD30, were showed, Ki67 index was about 20%; Especially, WT-1 and D240 were focally expressed in this tumor. FISH analysis showed rearrangement of ALK, and reverse-transcription polymerase chain reaction (RT-PCR) analysis was used to detect the fusion location of the RANBP2 and ALK gene. The diagnosis of EMIS was made based on its location, typical morphology, the immunohistochemical features especially the nuclear membranous immunostaining of ALK and rearrangement of RANBP2-ALK. The tumor showed higher aggressive behaviors and a poor prognosis. The differential diagnosis and other treatments of EMIS are also discussed in the present study. This finding may increase the case information of EMIS.
PMCID: PMC4467001  PMID: 26097614
Epithelioid inflammatory myofibroblastic sarcoma; ALK; retroperitoneal
17.  Activation of AKT by O-GlcNAcylation Induces Vascular Calcification in Diabetes 
Circulation research  2014;114(7):1094-1102.
Rationale
Vascular calcification is a serious cardiovascular complication that contributes to the increased morbidity and mortality of patients with diabetes. Hyperglycemia, a hallmark of diabetes, is associated with increased vascular calcification as well as increased modification of proteins by O-linked N-acetylglucosamine (O-GlcNAcylation).
Objective
We sought to determine the role of protein O-GlcNAcylation in regulating vascular calcification and the underlying mechanisms.
Methods and Results
Low-dose streptozotocin-induced diabetic mice exhibited increased aortic O-GlcNAcylation and vascular calcification, which also was associated with impaired aortic compliance in mice. Elevation of O-GlcNAcylation by administration of Thiamet-G, a potent inhibitor for O-GlcNAcase (OGA) that removes O-GlcNAcylation, further accelerated vascular calcification and worsened aortic compliance of diabetic mice in vivo. Increased O-GlcNAcylation, either by Thiamet-G or OGA knockdown, promoted calcification of primary mouse vascular smooth muscle cells (VSMC). Increased O-GlcNAcylation in diabetic arteries or in the OGA knockdown VSMC upregulated expression of the osteogenic transcription factor Runx2 and enhanced activation of AKT. O-GlcNAcylation of AKT at two new O-sites, T430 and T479, promoted AKT phosphorylation, which in turn enhanced VSMC calcification. Site-directed mutation of AKT at T430 and T479 decreased O-GlcNAcylation, inhibited phosphorylation of AKT at S473 and binding of mTOR complex 2 to AKT, and subsequently blocked Runx2 transactivity and VSMC calcification.
Conclusions
O-GlcNAcylation of AKT at two new sites enhanced AKT phosphorylation and activation, thus promoting vascular calcification. Our studies have identified a novel causative effect of O-GlcNAcylation in regulating vascular calcification in diabetes and uncovered a key molecular mechanism underlying O-GlcNAcylation-mediated activation of AKT.
doi:10.1161/CIRCRESAHA.114.302968
PMCID: PMC4030422  PMID: 24526702
Diabetes mellitus; O-GlcNAcylation; vascular calcification; smooth muscle cells; AKT activation
18.  5′-Adenosine Monophosphate-Induced Hypothermia Attenuates Brain Ischemia/Reperfusion Injury in a Rat Model by Inhibiting the Inflammatory Response 
Mediators of Inflammation  2015;2015:520745.
Hypothermia treatment is a promising therapeutic strategy for brain injury. We previously demonstrated that 5′-adenosine monophosphate (5′-AMP), a ribonucleic acid nucleotide, produces reversible deep hypothermia in rats when the ambient temperature is appropriately controlled. Thus, we hypothesized that 5′-AMP-induced hypothermia (AIH) may attenuate brain ischemia/reperfusion injury. Transient cerebral ischemia was induced by using the middle cerebral artery occlusion (MCAO) model in rats. Rats that underwent AIH treatment exhibited a significant reduction in neutrophil elastase infiltration into neuronal cells and matrix metalloproteinase 9 (MMP-9), interleukin-1 receptor (IL-1R), tumor necrosis factor receptor (TNFR), and Toll-like receptor (TLR) protein expression in the infarcted area compared to euthermic controls. AIH treatment also decreased the number of terminal deoxynucleotidyl transferase dUTP nick end labeling- (TUNEL-) positive neuronal cells. The overall infarct volume was significantly smaller in AIH-treated rats, and neurological function was improved. By contrast, rats with ischemic brain injury that were administered 5′-AMP without inducing hypothermia had ischemia/reperfusion injuries similar to those in euthermic controls. Thus, the neuroprotective effects of AIH were primarily related to hypothermia.
doi:10.1155/2015/520745
PMCID: PMC4385688  PMID: 25873763
19.  Antiviral Activity of a Zymolytic Grain Based Extract on Human Immunodeficiency Virus Type 1 In Vitro 
Increasing evidence shows that grains may play a role in disease prevention beyond the simple provision of energy and nutrients. It has been reported that some components contained in grains exert their functional effects on viral and bacterial infections and protect against various cancers. However, until now, hardly any intervention studies have investigated the effects of grains or grain based extracts on the inhibition of HIV-1 infection. In this study, the antiviral function of a zymolytic grain based extract (ZGE) was detected in vitro and in rats, and the antiviral mechanism was investigated. Results showed that ZGE had an inhibition effect on HIV-1 infection in vitro with low cytotoxic effects. The study of the mechanism demonstrated that this functional food possibly acted on the viral surface structure protein gp120 which is responsible for cell binding, as well as on the postattachment stage of the virus. The sera of model rats administrated with this food by gavage presented anti-infection abilities against HIV-1 in vitro during a serum concentration associated period of time. These findings provide valuable insights into the application of ZGE on the control of viral load, which may contribute to future anti-HIV treatment with less adverse effects.
doi:10.1155/2015/642327
PMCID: PMC4370203  PMID: 25838832
20.  Antibacterial and Antibiofilm Activities of Makaluvamine Analogs 
Microorganisms  2014;2(3):128-139.
Streptococcus mutans is a key etiological agent in the formation of dental caries. The major virulence factor is its ability to form biofilms. Inhibition of S. mutans biofilms offers therapeutic prospects for the treatment and the prevention of dental caries. In this study, 14 analogs of makaluvamine, a marine alkaloid, were evaluated for their antibacterial activity against S. mutans and for their ability to inhibit S. mutans biofilm formation. All analogs contained the tricyclic pyrroloiminoquinone core of makaluvamines. The structural variations of the analogs are on the amino substituents at the 7-position of the ring and the inclusion of a tosyl group on the pyrrole ring N of the makaluvamine core. The makaluvamine analogs displayed biofilm inhibition with IC50 values ranging from 0.4 μM to 88 μM. Further, the observed bactericidal activity of the majority of the analogs was found to be consistent with the anti-biofilm activity, leading to the conclusion that the anti-biofilm activity of these analogs stems from their ability to kill S. mutans. However, three of the most potent N-tosyl analogs showed biofilm IC50 values at least an order of magnitude lower than that of bactericidal activity, indicating that the biofilm activity of these analogs is more selective and perhaps independent of bactericidal activity.
doi:10.3390/microorganisms2030128
PMCID: PMC4354892  PMID: 25767719
makaluvamine; pyrroloiminoquinone; marine alkaloid; Streptococcus mutans; biofilm; antibacterial; dental caries
21.  The highly conserved domain of unknown function 1792 has a distinct glycosyltransferase fold 
Nature communications  2014;5:4339.
More than 33,000 glycosyltransferases have been identified. Structural studies, however, have only revealed two distinct glycosyltransferase (GT) folds, GT-A and GT-B. Here we report a 1.34 Å resolution X-ray crystallographic structure of a previously uncharacterized “domain of unknown function” 1792 (DUF1792) and show that the domain adopts a new fold and is required for glycosylation of a family of serine-rich repeat streptococcal adhesins. Biochemical studies reveal that the domain is a glucosyltransferase, and it catalyzes the transfer of glucose to the branch point of the hexasaccharide O-linked to the serine-rich repeat of the bacterial adhesin, Fap1 of Streptococcus parasanguinis. DUF1792 homologs from both Gram-positive and Gram-negative bacteria also exhibit the activity. Thus DUF1792 represents a new family of glycosyltransferases, so we designate it as a GT-D glycosyltransferase fold. As the domain is highly conserved in bacteria and not found in eukaryotes, it can be explored as a new antibacterial target.
doi:10.1038/ncomms5339
PMCID: PMC4352575  PMID: 25023666
streptococcal adhesin; glycosyltransferase; DUF1792
22.  Targeting Kynurenine Aminotransferase II in Psychiatric Diseases: Promising Effects of an Orally Active Enzyme Inhibitor 
Schizophrenia Bulletin  2014;40(Suppl 2):S152-S158.
Increased brain levels of the tryptophan metabolite kynurenic acid (KYNA) have been linked to cognitive dysfunctions in schizophrenia and other psychiatric diseases. In the rat, local inhibition of kynurenine aminotransferase II (KAT II), the enzyme responsible for the neosynthesis of readily mobilizable KYNA in the brain, leads to a prompt reduction in extracellular KYNA levels, and secondarily induces an increase in extracellular glutamate, dopamine, and acetylcholine levels in several brain areas. Using microdialysis in unanesthetized, adult rats, we now show that the novel, systemically active KAT II inhibitor BFF-816, applied orally at 30mg/kg in all experiments, mimics the effects of local enzyme inhibition. No tolerance was seen when animals were treated daily for 5 consecutive days. Behaviorally, daily injections of BFF-816 significantly decreased escape latency in the Morris water maze, indicating improved performance in spatial and contextual memory. Thus, systemically applied BFF-816 constitutes an excellent tool for studying the neurobiology of KYNA and, in particular, for investigating the mechanisms linking KAT II inhibition to changes in glutamatergic, dopaminergic, and cholinergic function in brain physiology and pathology.
doi:10.1093/schbul/sbt157
PMCID: PMC3934402  PMID: 24562494
kynurenic acid; microdialysis; Morris water maze; schizophrenia; spatial memory
23.  Shaping ability of ProTaper Universal, WaveOne and ProTaper Next in simulated L-shaped and S-shaped root canals 
BMC Oral Health  2015;15:27.
Background
The purpose of this study was to compare the shaping ability of the ProTaper Universal (PTU; Dentsply Maillefer, Ballaigues, Switzerland), WaveOne (WO; Dentsply Maillefer) and ProTaper Next (PTN; Dentsply Maillefer) in simulated L-shaped and S-shaped root canals respectively.
Methods
30 simulated L-shaped and 30 simulated S-shaped root canals in resin blocks were employed and randomly divided into 3 groups (n = 10), respectively. The canals were prepared to a tip size 25 using PTU, WO or PTN: PTU F2 (taper 0.08 over the first 3 mm from apical tip), WO Primary (taper 0.08 over the first 3 mm from apical tip), and PTN X2 (taper 0.06 over the first 3 mm from apical tip). Photos of the simulated root canals were taken pre- and postinstrumentation. The 2 layers were superimposed after a series of image processing and 10 points were selected from apical constriction with 1 mm interval. And then the central axis transportation and straightened curvature were measured with software of image analysis.
Results
In simulated L-shaped root canals, PTU and PTN caused less transportation than WO at curved section (P < 0.05), and PTN caused the least transportation at apical constriction (P < 0.05). Moreover, PTN maintained the canal curvature best among the 3 groups (P < 0.05). But PTN produced more transportation at straight section compared with PTU and WO (P < 0.05). In simulated S-shaped root canals, PTN preserved the coronal curvature best (P < 0.05), but there was no significant difference in apical curvature since all the files straightened the curvature obviously.
Conclusions
PTN showed a better shaping ability than PTU and WO at the curved section of root canals, and PTN maintained the best apical constriction. But all the files had a tendency to straighten the apical curvature in multi-curved canals.
doi:10.1186/s12903-015-0012-z
PMCID: PMC4350914  PMID: 25886847
Central axis transportation; Curvature straightening; ProTaper Universal; WaveOne; ProTaper Next
24.  The Mediating Role of Psychological Capital on the Association between Occupational Stress and Job Burnout among Bank Employees in China 
Although job burnout is common among bank employees, few studies have explored positive resources for combating burnout in this population. This study aims to explore the relationship between occupational stress and job burnout among Chinese bank employees, and particularly the mediating role of psychological capital. A cross-sectional study was conducted in Liaoning, China, during June to August of 2013. A questionnaire that included the effort-reward imbalance scale, the Psychological Capital Questionnaire and the Maslach Burnout Inventory-General Survey, as well as demographic and working factors, was distributed to 1739 employees of state-owned banks. This yielded 1239 effective respondents (467 men, 772 women). Asymptotic and resampling strategies explored the mediating role of psychological capital in the relationship between occupational stress and job burnout. Both extrinsic effort and overcommitment were positively associated with emotional exhaustion and depersonalisation. Meanwhile, reward was negatively associated with emotional exhaustion and depersonalisation, but positively associated with personal accomplishment. There was a gender difference in the mediating role of Psychological capital on the occupational stress-job burnout. In male bank employees, Psychological capital mediated the relationships of extrinsic effort and reward with emotional exhaustion and depersonalization; in female bank employees, it partially mediated the relationships of extrinsic effort, reward and overcommitment with emotional exhaustion and depersonalisation, as well as the relationship between reward and personal accomplishment. Psychological capital was generally a mediator between occupational stress and job burnout among Chinese bank employees. Psychological capital may be a potential positive resource in reducing the negative effects of occupational stress on job burnout and relieving job burnout among bank employees, especially female bank employees.
doi:10.3390/ijerph120302984
PMCID: PMC4377947  PMID: 25764060
job burnout; occupational stress; psychological capital; bank employees
25.  Secretion of One Adipokine Nampt/Visfatin Suppresses the Inflammatory Stress-Induced NF-κB Activity and Affects Nampt-Dependent Cell Viability in Huh-7 Cells 
Mediators of Inflammation  2015;2015:392471.
Nampt/visfatin acts in both intracellular and extracellular compartments to regulate multiple biological roles, including NAD metabolism, cancer, inflammation, and senescence. However, its function in chronic inflammation and carcinogenesis in hepatocellular carcinoma (HCC) has not been well-defined. Here we use Huh-7 hepatoma cells as a model to determine how Nampt/visfatin affects cellular survival under oxidative stress. We found that the transition of Nampt/visfatin from intracellular into extracellular form was induced by H2O2 treatment in 293T cells and confirmed that this phenomenon was not due to cell death but through the secretion of Nampt/visfatin. In addition, Nampt/visfatin suppressed cell viability in oxidative treatment in Huh-7 cells and acted on the inhibition of hepatoma cell growth. Oxidative stress also reduced the Nampt-mediated activation of NF-κB gene expression. In this study, we identify a novel feature of Nampt/visfatin which functions as an adipokine that can be secreted upon cellular stress. Our results provide an example to understand how adipokine interacts with chemotherapeutic treatment by oxidative stress in HCC.
doi:10.1155/2015/392471
PMCID: PMC4357042  PMID: 25814788

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