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1.  Naringin administration inhibits platelet aggregation and release by reducing blood cholesterol levels and the cytosolic free calcium concentration in hyperlipidemic rabbits 
This study investigated the effects of naringin on platelet aggregation and release in hyperlipidemic rabbits, and the underlying mechanisms. The safety of naringin was also investigated. The rabbits were orally administered 60, 30 or 15 mg/kg of naringin once a day for 14 days after being fed a high fat/cholesterol diet for four weeks. Following the two weeks of drug administration, the degree of platelet aggregation induced by arachidonic acid, adenosine diphosphate and collagen was significantly reduced by naringin at certain doses compared with those in the rabbits of the model group (P<0.01). The levels of P-selectin and platelet factor 4 (PF4) also decreased following treatment with naringin compared with those of the model group. Certain doses of naringin significantly reduced the total cholesterol (TC) levels and elevated the ratio of high-density lipoprotein cholesterol to TC compared with those in the model group, and significantly decreased the cytosolic free calcium concentration ([Ca2+]i). No significant difference in the coagulation function was observed between the control and drug-treatment groups. These results indicate that naringin improved platelet aggregation and inhibited the excessive release of P-selectin and PF4 in hyperlipidemic rabbits. This study suggests that the antiplatelet effect of naringin may be due to its ability to regulate the levels of blood cholesterol and [Ca2+]i in platelets. Naringin also did not cause bleeding in the hyperlipidemic rabbits.
doi:10.3892/etm.2014.1794
PMCID: PMC4113534  PMID: 25120631
naringin; hyperlipidemic; aggregation; cytosolic free calcium concentration; P-selectin; platelet factor 4
2.  The triterpenoid pristimerin induces U87 glioma cell apoptosis through reactive oxygen species-mediated mitochondrial dysfunction 
Oncology Letters  2012;5(1):242-248.
It has become evident that some of the natural or synthetic triterpenoids are natural proteasome inhibitors that have great potential for use in cancer prevention and treatment. However, the mechanisms for the antitumor activity of triterpenoids remain to be elucidated. In the present study, we investigated the anticancer activities of a natural triterpenoid, pristimerin, and the signaling pathways affected. Pristimerin was found to possess potent cytotoxic effects, inducing apoptosis and inhibiting proliferation in U87 human glioma cells. Hoechst 33258 staining and Annexin V/PI double staining exhibited the typical nuclear features of apoptosis and increased the proportion of apoptotic Annexin V-positive cells in a dose-dependent manner, respectively. Moreover, western blotting assay revealed that this apoptotic induction was associated with activated caspase-9, caspase-3, PARP cleavage and downregulation of Bcl-xl/Bax in a concentration-dependent manner. Pristimerin also increased the generation of reactive oxygen species and induced the subsequent release of cytochrome c from the mitochondria into the cytosol. Additionally, pristimerin downregulated EGFR protein expression and inhibited downstream signaling pathways in U87 cells. Our results suggest that pristimerin may have potential as a new targeting therapeutic strategy in the treatment of EGFR-overexpressing gliomas.
doi:10.3892/ol.2012.982
PMCID: PMC3525416  PMID: 23255929
pristimerin; glioma; apoptosis; reactive oxygen species; U87 cells
3.  Bullatacin Triggered ABCB1-Overexpressing Cell Apoptosis via the Mitochondrial-Dependent Pathway 
This paper was to explore bullatacin-mediated multidrug-resistant cell apoptosis at extremely low concentration. To investigate its precise mechanisms, the pathway of cell apoptosis induced by bullatacin was examined. Bullatacin causes an upregulation of ROS and a downregulation of ΔΨm in a concentration-dependent manner in ABCB1-overexpressing KBv200 cells. In addition, cleavers of caspase-9, caspase-3, and PARP were observed following the release of cytochrome c from mitochondria after bullatacin treatment. However, neither cleavage of caspase-8 nor change of expression level of bcl-2, bax and Fas was observed by the same treatment. Pretreating KBv200 cells with N-acetylcysteine, an antioxidant modulator, resulted in a significant reduction of ROS generation and cell apoptosis induced by bullatacin. Bullatacin-induced apoptosis was antagonized by z-LEHD-fmk, a caspase-9 inhibitor, but not by z-IETD-fmk, a caspase-8 inhibitor. These implied that apoptosis of KBv200 cells induced by bullatacin was associated with the mitochondria-dependent pathway that was limited to activation of apical caspase-9.
doi:10.1155/2009/867123
PMCID: PMC2715821  PMID: 19639048
4.  Vandetanib (Zactima, ZD6474) Antagonizes ABCC1- and ABCG2-Mediated Multidrug Resistance by Inhibition of Their Transport Function 
PLoS ONE  2009;4(4):e5172.
Background
ABCC1 and ABCG2 are ubiquitous ATP-binding cassette transmembrane proteins that play an important role in multidrug resistance (MDR). In this study, we evaluated the possible interaction of vandetanib, an orally administered drug inhibiting multiple receptor tyrosine kinases, with ABCC1 and ABCG2 in vitro.
Methodology and Principal Findings
MDR cancer cells overexpressing ABCC1 or ABCG2 and their sensitive parental cell lines were used. MTT assay showed that vandetanib had moderate and almost equal-potent anti-proliferative activity in both sensitive parental and MDR cancer cells. Concomitant treatment of MDR cells with vandetanib and specific inhibitors of ABCC1 or ABCG2 did not alter their sensitivity to the former drug. On the other hand, clinically attainable but non-toxic doses of vandetanib were found to significantly enhance the sensitivity of MDR cancer cells to ABCC1 or ABCG2 substrate antitumor drugs. Flow cytometric analysis showed that vandetanib treatment significantly increase the intracellular accumulation of doxorubicin and rhodamine 123, substrates of ABCC1 and ABCG2 respectively, in a dose-dependent manner (P<0.05). However, no significant effect was shown in sensitive parental cell lines. Reverse transcription-PCR and Western blot analysis showed that vandetanib did not change the expression of ABCC1 and ABCG2 at both mRNA and protein levels. Furthermore, total and phosphorylated forms of AKT and ERK1/2 remained unchanged after vandetanib treatment in both sensitive and MDR cancer cells.
Conclusions
Vandetanib is unlikely to be a substrate of ABCC1 or ABCG2. It overcomes ABCC1- and ABCG2-mediated drug resistance by inhibiting the transporter activity, independent of the blockade of AKT and ERK1/2 signal transduction pathways.
doi:10.1371/journal.pone.0005172
PMCID: PMC2669214  PMID: 19390592
5.  The Effect of Adverse Housing and Neighborhood Conditions on the Development of Diabetes Mellitus among Middle-aged African Americans 
American journal of epidemiology  2007;166(4):379-387.
The authors examined the associations of observed neighborhood (block face) and housing conditions with the incidence of diabetes by using data from 644 subjects in the African-American Health Study (St. Louis area, Missouri). They also investigated five mediating pathways (health behavior, psychosocial, health status, access to medical care, and sociodemographic characteristics) if significant associations were identified. The external appearance of the block the subjects lived on and housing conditions were rated as excellent, good, fair, or poor. Subjects reported about neighborhood desirability. Self-reported diabetes was obtained at baseline and 3 years later. Of 644 subjects without self-reported diabetes, 10.3% reported having diabetes at the 3-year follow-up. Every housing condition rated as fair-poor was associated with an increased risk of diabetes, with odds ratios ranging from 2.53 (95% confidence interval: 1.47, 4.34 for physical condition inside the building) to 1.78 (95% confidence interval: 1.03, 3.07 for cleanliness inside the building) in unadjusted analyses. No association was found between any of the block face conditions or perceived neighborhood conditions and incident diabetes. The odds ratios for the five housing conditions were unaffected when adjusted for the mediating pathways. Poor housing conditions appear to be an independent contributor to the risk of incident diabetes in urban, middle-aged African Americans.
doi:10.1093/aje/kwm190
PMCID: PMC4519088  PMID: 17625220
African Americans; aging; diabetes mellitus; housing; questionnaires; residence characteristics
6.  Ethanol extract of propolis protects macrophages from oxidized low density lipoprotein-induced apoptosis by inhibiting CD36 expression and endoplasmic reticulum stress-C/EBP homologous protein pathway 
Background
Ethanol extract of propolis (EEP), rich in flavones, has been known for various biological activities including antioxidant, antiinflammatory and antibiotic activities. Our previous studies have shown that EEP protects endothelial cells from oxidized low-density lipoprotein (ox-LDL)-induced apoptosis and inhibits atherosclerotic lesion development. In this present study, we explored the protective effect of EEP on ox-LDL-induced cytotoxicity in macrophages and specifically the endoplasmic reticulum (ER) stress-C/EBP homologous protein (CHOP) pathway-mediated apoptosis.
Methods
EEP was prepared and the total flavonoids content of EEP was determined by the colorimetric method of Chinese Standard (GB/T 20574-2006). The effects of EEP on lipid accumulation, cytotoxicity and apoptosis in RAW264.7 cells induced by ox-LDL or tunicamycin (TM, an ER stress inducer) were assayed using oil red O staining, MTT assay, flow cytometric analysis and so on. Immunofluorescence, Western blot and real time-PCR analysis were then used to further investigate the molecular mechanisms by which EEP protects macrophages from ox-LDL-induced apoptosis. 4-phenylbutyric acid (PBA), an ER stress inhibitor, was used as a positive control.
Results
EEP (7.5, 15 and 30 mg/L) not only attenuated ox-LDL-induced lipid accumulation in RAW264.7 macrophages in a dose-dependent manner but also inhibited the decreased cell viability and the increased lactate dehydrogenase (LDH) leakage, caspase-3 activation and apoptosis induced by ox-LDL or tunicamycin (TM, a classical ER stress inducer), which were similar to 4-phenylbutyric acid (PBA, an inhibitor of ER stress) treatment. In addition, like PBA, EEP significantly suppressed the ox-LDL- or TM-induced activation of ER stress signaling pathway including the phosphorylation of double-stranded RNA-activated protein kinase-like ER kinase (PERK) and eukaryotic translation initiation factor 2α (eIF2α) as well as upregulation of glucose regulated protein 78 (GRP78) and the pro-apoptotic protein CHOP. Furthermore, EEP significantly suppressed ox-LDL intake by macrophages and the upregulation of CD36 induced by ox-LDL.
Conclusion
These data indicate that EEP may protect macrophages from ox-LDL-induced apoptosis and the mechanism at least partially involves its ability to suppress the CD36-mediated ox-LDL intake and subsequent activation of ER stress-CHOP signalling pathway.
doi:10.1186/s12906-015-0759-4
PMCID: PMC4501110  PMID: 26169264
Ethanol extract of propolis; Endoplasmic reticulum stress; C/EBP homologous protein; Oxidized low density lipoprotein; Macrophage; Apoptosis
7.  Conjugation of toll-like receptor-7 agonist to gastric cancer antigen MG7-Ag exerts antitumor effects 
AIM: To investigate the effects of our tumor vaccines on reversing immune tolerance and generating therapeutic response.
METHODS: Vaccines were synthesized by solid phase using an Fmoc strategy, where a small molecule toll-like receptor-7 agonist (T7) was conjugated to a monoclonal gastric cancer 7 antigen mono-epitope (T7-MG1) or tri-epitope (T7-MG3). Cytokines were measured in both mouse bone marrow dendritic cells and mouse spleen lymphocytes after exposed to the vaccines. BALB/c mice were intraperitoneally immunized with the vaccines every 2 wk for a total of three times, and then subcutaneously challenged with Ehrlich ascites carcinoma (EAC) cells. Three weeks later, the mice were killed, and the tumors were surgically removed and weighed. Serum samples were collected from the mice, and antibody titers were determined by ELISA using an alkaline phosphate-conjugated detection antibody for total IgG. Antibody-dependent cell-mediated cytotoxicity was detected by the lactate dehydrogenase method using natural killer cells as effectors and antibody-labeled EAC cells as targets. Cytotoxic T lymphocyte activities were also detected by the lactate dehydrogenase method using lymphocytes as effectors and EAC cells as targets.
RESULTS: Vaccines were successfully synthesized and validated by analytical high performance liquid chromatography and electrospray mass spectrometry, including T7, T7-MG1, and T7-MG3. Rapid inductions of tumor necrosis factor-α and interleukin-12 in bone marrow dendritic cells and interferon γ and interleukin-12 in lymphocytes occurred in vitro after T7, T7-MG1, and T7-MG3 treatment. Immunization with T7-MG3 reduced the EAC tumor burden in BALB/c mice to 62.64% ± 5.55% compared with PBS control (P < 0.01). Six or nine weeks after the first immunization, the monoclonal gastric cancer 7 antigen antibody increased significantly in the T7-MG3 group compared with the PBS control (P < 0.01). As for antibody-dependent cell-mediated cytotoxicity, antisera obtained by immunization with T7-MG3 were able to markedly enhance cell lysis compared to PBS control (31.58% ± 2.94% vs 18.02% ± 2.26%; P < 0.01). As for cytotoxic T lymphocytes, T7-MG3 exhibited obviously greater cytotoxicity compared with PBS control (40.92% ± 4.38% vs 16.29% ± 1.90%; P < 0.01).
CONCLUSION: A successful method is confirmed for the design of gastric cancer vaccines by chemical conjugation of T7 and multi-repeat-epitope of monoclonal gastric cancer 7 antigen.
doi:10.3748/wjg.v21.i26.8052
PMCID: PMC4499347  PMID: 26185376
Gastric cancer; Immunotherapy; Monoclonal gastric cancer 7 antigen; Toll-like receptor-7; Vaccine
8.  Elimination of Kalrn Expression in POMC Cells Reduces Anxiety-Like Behavior and Contextual Fear Learning 
Hormones and behavior  2014;66(2):430-438.
Kalirin, a Rho GDP/GTP exchange factor for Rac1 and RhoG, is known to play an essential role in the formation and maintenance of excitatory synapses and in the secretion of neuropeptides.
Mice unable to express any of the isoforms of Kalrn in cells that produce POMC at any time during development (POMC cells) exhibited reduced anxiety-like behavior and reduced acquisition of passive avoidance behavior, along with sex-specific alteration in the corticosterone response to restraint stress. Strikingly, lack of Kalrn expression in POMC cells closely mimicked the effects of global Kalrn knockout on anxiety-like behavior and passive avoidance conditioning without causing the other deficits noted in Kalrn knockout mice. Our data suggest that deficits in excitatory inputs onto POMC neurons are responsible for the behavioral phenotypes observed.
doi:10.1016/j.yhbeh.2014.07.001
PMCID: PMC4127147  PMID: 25014196
pituitary; ACTH; corticosterone; passive-avoidance; Cre-recombinase
9.  CD14hiCD16+ monocytes phagocytose antibody-opsonised Plasmodium falciparum infected erythrocytes more efficiently than other monocyte subsets, and require CD16 and complement to do so 
BMC Medicine  2015;13:154.
Background
With more than 600,000 deaths from malaria, mainly of children under five years old and caused by infection with Plasmodium falciparum, comes an urgent need for an effective anti-malaria vaccine. Limited details on the mechanisms of protective immunity are a barrier to vaccine development. Antibodies play an important role in immunity to malaria and monocytes are key effectors in antibody-mediated protection by phagocytosing antibody-opsonised infected erythrocytes (IE). Eliciting antibodies that enhance phagocytosis of IE is therefore an important potential component of an effective vaccine, requiring robust assays to determine the ability of elicited antibodies to stimulate this in vivo. The mechanisms by which monocytes ingest IE and the nature of the monocytes which do so are unknown.
Methods
Purified trophozoite-stage P. falciparum IE were stained with ethidium bromide, opsonised with anti-erythrocyte antibodies and incubated with fresh whole blood. Phagocytosis of IE and TNF production by individual monocyte subsets was measured by flow cytometry. Ingestion of IE was confirmed by imaging flow cytometry.
Results
CD14hiCD16+ monocytes phagocytosed antibody-opsonised IE and produced TNF more efficiently than CD14hiCD16- and CD14loCD16+ monocytes. Blocking experiments showed that Fcγ receptor IIIa (CD16) but not Fcγ receptor IIa (CD32a) or Fcγ receptor I (CD64) was necessary for phagocytosis. CD14hiCD16+ monocytes ingested antibody-opsonised IE when peripheral blood mononuclear cells were reconstituted with autologous serum but not heat-inactivated autologous serum. Antibody-opsonised IE were rapidly opsonised with complement component C3 in serum (t1/2 = 2-3 minutes) and phagocytosis of antibody-opsonised IE was inhibited in a dose-dependent manner by an inhibitor of C3 activation, compstatin. Compared to other monocyte subsets, CD14hiCD16+ monocytes expressed the highest levels of complement receptor 4 (CD11c) and activated complement receptor 3 (CD11b) subunits.
Conclusions
We show a special role for CD14hiCD16+ monocytes in phagocytosing opsonised P. falciparum IE and production of TNF. While ingestion was mediated by Fcγ receptor IIIa, this receptor was not sufficient to allow phagocytosis; despite opsonisation with antibody, phagocytosis of IE also required complement opsonisation. Assays which measure the ability of vaccines to elicit a protective antibody response to P. falciparum should consider their ability to promote phagocytosis and fix complement.
Electronic supplementary material
The online version of this article (doi:10.1186/s12916-015-0391-7) contains supplementary material, which is available to authorized users.
doi:10.1186/s12916-015-0391-7
PMCID: PMC4493812  PMID: 26149666
Malaria; Phagocytosis; Monocyte subsets; Antibodies; Complement; CD16
10.  De Novo Formation of a Distinct Coronary Vascular Population in Neonatal Heart 
Science (New York, N.Y.)  2014;345(6192):90-94.
The postnatal coronary vessels have been viewed as developing through expansion of vessels formed during the fetal period. Using genetic lineage tracing, we found that a substantial portion of postnatal coronary vessels arise de novo in the neonatal mouse heart, rather than expanding from pre-existing embryonic vasculature. Our data show that lineage conversion of neonatal endocardial cells during trabecular compaction generates a distinct compartment of the coronary circulation located within the inner half of the ventricular wall. This lineage conversion occurs within a brief period after birth and provides an efficient means of rapidly augmenting the coronary vasculature. This mechanism of postnatal coronary vascular growth provides avenues for understanding and stimulating cardiovascular regeneration following injury and disease.
doi:10.1126/science.1251487
PMCID: PMC4275002  PMID: 24994653
11.  Enhancement of electroluminescence from embedded Si quantum dots/SiO2multilayers film by localized-surface-plasmon and surface roughening 
Scientific Reports  2015;5:11881.
In this paper, we prepared a novel structure to enhance the electroluminescence intensity from Si quantum dots/SiO2multilayers. An amorphous Si/SiO2 multilayer film was fabricated by plasma-enhanced chemical vapor deposition on a Pt nanoparticle (NP)-coated Si nanopillar array substrate. By thermal annealing, an embedded Si quantum dot (QDs)/SiO2 multilayer film was obtained. The result shows that electroluminescence intensity was significantly enhanced. And, the turn-on voltage of the luminescent device was reduced to 3 V. The enhancement of the light emission is due to the resonance coupling between the localized-surface-plasmon (LSP) of Pt NPs and the band-gap emission of Si QDs/SiO2 multilayers. The other factors were the improved absorption of excitation light and the increase of light extraction ratio by surface roughening structures. These excellent characteristics are promising for silicon-based light-emitting applications.
doi:10.1038/srep11881
PMCID: PMC4490393  PMID: 26138830
12.  De novo Transcriptome Assembly of Common Wild Rice (Oryza rufipogon Griff.) and Discovery of Drought-Response Genes in Root Tissue Based on Transcriptomic Data 
PLoS ONE  2015;10(7):e0131455.
Background
The perennial O. rufipogon (common wild rice), which is considered to be the ancestor of Asian cultivated rice species, contains many useful genetic resources, including drought resistance genes. However, few studies have identified the drought resistance and tissue-specific genes in common wild rice.
Results
In this study, transcriptome sequencing libraries were constructed, including drought-treated roots (DR) and control leaves (CL) and roots (CR). Using Illumina sequencing technology, we generated 16.75 million bases of high-quality sequence data for common wild rice and conducted de novo assembly and annotation of genes without prior genome information. These reads were assembled into 119,332 unigenes with an average length of 715 bp. A total of 88,813 distinct sequences (74.42% of unigenes) significantly matched known genes in the NCBI NT database. Differentially expressed gene (DEG) analysis showed that 3617 genes were up-regulated and 4171 genes were down-regulated in the CR library compared with the CL library. Among the DEGs, 535 genes were expressed in roots but not in shoots. A similar comparison between the DR and CR libraries showed that 1393 genes were up-regulated and 315 genes were down-regulated in the DR library compared with the CR library. Finally, 37 genes that were specifically expressed in roots were screened after comparing the DEGs identified in the above-described analyses.
Conclusion
This study provides a transcriptome sequence resource for common wild rice plants and establishes a digital gene expression profile of wild rice plants under drought conditions using the assembled transcriptome data as a reference. Several tissue-specific and drought-stress-related candidate genes were identified, representing a fully characterized transcriptome and providing a valuable resource for genetic and genomic studies in plants.
doi:10.1371/journal.pone.0131455
PMCID: PMC4489613  PMID: 26134138
13.  Assessing Participation in Community-Based Physical Activity Programs in Brazil 
Purpose
This study aimed to develop and validate a risk prediction model to examine the characteristics that are associated with participation in community-based physical activity programs in Brazil.
Methods
We used pooled data from three surveys conducted from 2007 to 2009 in state capitals of Brazil with 6166 adults. A risk prediction model was built considering program participation as an outcome. The predictive accuracy of the model was quantified through discrimination (C statistic) and calibration (Brier score) properties. Bootstrapping methods were used to validate the predictive accuracy of the final model.
Results
The final model showed sex (women: odds ratio [OR] = 3.18, 95% confidence interval [CI] = 2.14–4.71), having less than high school degree (OR = 1.71, 95% CI = 1.16–2.53), reporting a good health (OR = 1.58, 95% CI = 1.02–2.24) or very good/excellent health (OR = 1.62, 95% CI = 1.05–2.51), having any comorbidity (OR = 1.74, 95% CI = 1.26–2.39), and perceiving the environment as safe to walk at night (OR = 1.59, 95% CI = 1.18–2.15) as predictors of participation in physical activity programs. Accuracy indices were adequate (C index = 0.778, Brier score = 0.031) and similar to those obtained from bootstrapping (C index = 0.792, Brier score = 0.030).
Conclusions
Sociodemographic and health characteristics as well as perceptions of the environment are strong predictors of participation in community-based programs in selected cities of Brazil.
doi:10.1249/MSS.0b013e3182a365ae
PMCID: PMC4476502  PMID: 23846162
EVIDENCE-BASED PUBLIC HEALTH; ADULTS; RISK MODELING; HEALTH PROMOTION
14.  Is grazing exclusion effective in restoring vegetation in degraded alpine grasslands in Tibet, China? 
PeerJ  2015;3:e1020.
Overgrazing is considered one of the key disturbance factors that results in alpine grassland degradation in Tibet. Grazing exclusion by fencing has been widely used as an approach to restore degraded grasslands in Tibet since 2004. Is the grazing exclusion management strategy effective for the vegetation restoration of degraded alpine grasslands? Three alpine grassland types were selected in Tibet to investigate the effect of grazing exclusion on plant community structure and biomass. Our results showed that species biodiversity indicators, including the Pielou evenness index, the Shannon–Wiener diversity index, and the Simpson dominance index, did not significantly change under grazing exclusion conditions. In contrast, the total vegetation cover, the mean vegetation height of the community, and the aboveground biomass were significantly higher in the grazing exclusion grasslands than in the free grazed grasslands. These results indicated that grazing exclusion is an effective measure for maintaining community stability and improving aboveground vegetation growth in alpine grasslands. However, the statistical analysis showed that the growing season precipitation (GSP) plays a more important role than grazing exclusion in which influence on vegetation in alpine grasslands. In addition, because the results of the present study come from short term (6–8 years) grazing exclusion, it is still uncertain whether these improvements will be continuable if grazing exclusion is continuously implemented. Therefore, the assessments of the ecological effects of the grazing exclusion management strategy on degraded alpine grasslands in Tibet still need long term continued research.
doi:10.7717/peerj.1020
PMCID: PMC4476103  PMID: 26157607
Grazing exclusion; Alpine grassland; Grassland degradation; Community characteristics; Biomass; Tibet
15.  TaPP2C1, a Group F2 Protein Phosphatase 2C Gene, Confers Resistance to Salt Stress in Transgenic Tobacco 
PLoS ONE  2015;10(6):e0129589.
Group A protein phosphatases 2Cs (PP2Cs) are essential components of abscisic acid (ABA) signaling in Arabidopsis; however, the function of group F2 subfamily PP2Cs is currently less known. In this study, TaPP2C1 which belongs to group F2 was isolated and characterized from wheat. Expression of the TaPP2C1-GFP fusion protein suggested its ubiquitous localization within a cell. TaPP2C1 expression was downregulated by abscisic acid (ABA) and NaCl treatments, but upregulated by H2O2 treatment. Overexpression of TaPP2C1 in tobacco resulted in reduced ABA sensitivity and increased salt resistance of transgenic seedlings. Additionally, physiological analyses showed that improved resistance to salt stress conferred by TaPP2C1 is due to the reduced reactive oxygen species (ROS) accumulation, the improved antioxidant system, and the increased transcription of genes in the ABA-independent pathway. Finally, transgenic tobacco showed increased resistance to oxidative stress by maintaining a more effective antioxidant system. Taken together, these results demonstrated that TaPP2C1 negatively regulates ABA signaling, but positively regulates salt resistance. TaPP2C1 confers salt resistance through activating the antioxidant system and ABA-independent gene transcription process.
doi:10.1371/journal.pone.0129589
PMCID: PMC4461296  PMID: 26057628
16.  Using segmented regression analysis of interrupted time series data to assess colonoscopy quality outcomes of a web-enhanced implementation toolkit to support evidence-based practices for bowel preparation: a study protocol 
Background
While there is convincing evidence on interventions to improve bowel preparation for patients, the evidence on how to implement these evidence-based practices (EBPs) in outpatient colonoscopy settings is less certain. The Strategies to Improve Colonoscopy (STIC) study compares the effect of two implementation strategies, physician education alone versus physician education plus an implementation toolkit for staff, on adoption of three EBPs (split-dosing of bowel preparation, low-literacy education, teach-back) to improve pre-procedure and intra-procedure quality measures. The implementation toolkit contains a staff education module, website containing tools to support staff in delivering EBPs, tailored patient education materials, and brief consultation with staff to determine how the EBPs can be integrated into the existing workflow. Given adaptations to the implementation plan and intentional flexibility in the delivery of the EBPs, we utilize a pragmatic study to balance external validity with demonstrating effectiveness of the implementation strategies.
Methods/Design
Participants will include all outpatient colonoscopy physicians, staff, and patients from a convenience sample of six endoscopy settings. Aim #1 will explore the relative effect of two strategies to implement patient-level EBPs on adoption and clinical quality outcomes. We will assess the change in level and trends of clinical quality outcomes (i.e., adequacy of bowel preparation, adenoma detection) using segmented regression analysis of interrupted time series data with two groups (intervention and delayed start). Aim #2 will examine the influence of organizational readiness to change on EBP implementation. We use a PRECIS diagram to reflect the extent to which each indicator of the study was pragmatic versus explanatory, revealing a largely pragmatic study.
Discussion
Implementation challenges have already motivated several adaptations to the original plan, reflecting the nature of implementation in real-world healthcare settings. The pragmatic study responds to the evolving needs of its healthcare partners and allows for flexibility in intervention delivery, thereby informing clinical decision-making in real-world settings. The current study will provide information about what works (intervention effectiveness), for whom it works (influence of Medicaid versus other insurance), in which contexts it works (setting characteristics that influence implementation), and how it works best (comparison of implementation strategies).
Electronic supplementary material
The online version of this article (doi:10.1186/s13012-015-0276-3) contains supplementary material, which is available to authorized users.
doi:10.1186/s13012-015-0276-3
PMCID: PMC4465008  PMID: 26050105
Colonoscopy care; Evidence-based practice; Implementation strategies; Web-based; Toolkits; Pragmatic trial; PRECIS
17.  Fasting Plasma Insulin at 5 Years of Age Predicted Subsequent Weight Increase in Early Childhood over a 5-Year Period—The Da Qing Children Cohort Study 
PLoS ONE  2015;10(6):e0127389.
Background
The association between hyperinsulinemia and obesity is well known. However, it is uncertain especially in childhood obesity, if initial fasting hyperinsulinemia predicts obesity, or obesity leads to hyperinsulinemia through insulin resistance.
Objective
To investigate the predictive effect of fasting plasma insulin on subsequent weight change after a 5-year interval in childhood.
Methods
424 Children from Da Qing city, China, were recruited at 5 years of age and followed up for 5 years. Blood pressure, anthropometric measurements, fasting plasma insulin, glucose and triglycerides were measured at baseline and 5 years later.
Results
Fasting plasma insulin at 5 years of age was significantly correlated with change of weight from 5 to 10 years (ΔWeight). Children in the lowest insulin quartile had ΔWeight of 13.08±0.73 kg compare to 18.39±0.86 in the highest insulin quartile (P<0.0001) in boys, and similarly 12.03±0.71 vs 15.80±0.60 kg (P<0.0001) in girls. Multivariate analysis showed that the predictive effect of insulin at 5 years of age on subsequent weight gain over 5 years remained statistically significant even after the adjustment for age, sex, birth weight, TV-viewing time and weight (or body mass index) at baseline. By contrast, the initial weight at 5 years of age did not predict subsequent changes in insulin level 5 years later. Children who had both higher fasting insulin and weight at 5 years of age showed much higher levels of systolic blood pressures, fasting plasma glucose, the homeostasis model assessment for insulin resistance (HOMA-IR) and triglycerides at 10 years of age.
Conclusions
Fasting plasma insulin at 5 years of age predicts weight gain and cardiovascular risk factors 5 year later in Chinese children of early childhood, but the absolute weight at 5 years of age did not predict subsequent change in fasting insulin.
doi:10.1371/journal.pone.0127389
PMCID: PMC4457927  PMID: 26047327
18.  Ultra-flexible nonvolatile memory based on donor-acceptor diketopyrrolopyrrole polymer blends 
Scientific Reports  2015;5:10683.
Flexible memory cell array based on high mobility donor-acceptor diketopyrrolopyrrole polymer has been demonstrated. The memory cell exhibits low read voltage, high cell-to-cell uniformity and good mechanical flexibility, and has reliable retention and endurance memory performance. The electrical properties of the memory devices are systematically investigated and modeled. Our results suggest that the polymer blends provide an important step towards high-density flexible nonvolatile memory devices.
doi:10.1038/srep10683
PMCID: PMC4450595  PMID: 26029856
19.  Effects of alfalfa saponin extract on mRNA expression of Ldlr, LXRα, and FXR in BRL cells*  
We studied the effects of alfalfa saponin extract (ASE) on low density lipoprotein receptor (Ldlr), liver X receptor α (LXRα), and farnesoid X receptor (FXR) in normal and hyperlipidemic Buffalo rat liver (BRL) cells. Normal and hyperlipidemic BRL cells were divided into eight groups: normal, or normal cells treated with 50, 100, and 150 mg/L ASE, hyperlipidemic, or hyperlipidemic cells treated with 50, 100, and 150 mg/L ASE. After treatment for 24 h, Ldlr, LXRα, and FXR mRNA expression levels were measured by quantitative real-time polymerase chain reaction (qRT-PCR). Data showed that mRNA expression of Ldlr in normal BRL cells was significantly up-regulated by ASE treatment and mRNA expressions of LXRα and FXR were significantly down-regulated both in normal and hyperlipidemic BRL cells after ASE treatment. Thus, ASE might ameliorate hepatic steatosis by regulating genes involved in cholesterol metabolism, including up-regulation of Ldlr as well as down-regulation of LXRα and FXR.
doi:10.1631/jzus.B1400343
PMCID: PMC4471599  PMID: 26055909
Alfalfa saponin extract; Hyperlipidemic BRL cells; Cholesterol metabolism; mRNA expression
20.  Curcumin improves synaptic plasticity impairment induced by HIV-1gp120 V3 loop 
Neural Regeneration Research  2015;10(6):925-931.
Curcumin has been shown to significantly improve spatial memory impairment induced by HIV-1 gp120 V3 in rats, but the electrophysiological mechanism remains unknown. Using extracellular microelectrode recording techniques, this study confirmed that the gp120 V3 loop could suppress long-term potentiation in the rat hippocampal CA1 region and synaptic plasticity, and that curcumin could antagonize these inhibitory effects. Using a Fura-2/AM calcium ion probe, we found that curcumin resisted the effects of the gp120 V3 loop on hippocampal synaptosomes and decreased Ca2+ concentration in synaptosomes. This effect of curcumin was identical to nimodipine, suggesting that curcumin improved the inhibitory effects of gp120 on synaptic plasticity, ameliorated damage caused to the central nervous system, and might be a potential neuroprotective drug.
doi:10.4103/1673-5374.158358
PMCID: PMC4498354  PMID: 26199609
nerve regeneration; curcumin; neurons; HIV-1 gp120 V3 loop; plasticity; HIV-associated neurocognitive disorders; output/input curve; long-term potentiation; excitatory postsynaptic potential; paired-pulse facilitation; Ca2+; synaptosome; NSFC grants; neural regeneration
21.  Toll-like receptor 2 promotes T helper 17 cells response in hepatitis B virus infection 
Purpose: Innate and adaptive immune responses play vital roles in initiating and maintaining the immunological homeostasis in both physiological and pathological processes. However, the expression and function of the important cells and molecules as well as their interaction in hepatitis B virus (HBV) infection has not been well elucidated. The aim of the current study was to determine the pattern of Toll-like receptor 2 (TLR2) in T cells in HBV infection and the function of TLR2 in regulation of T helper 17 (Th17) cells response. Methods: Thirty-four patients with HBV infection (ten acute and twenty-four chronic) were enrolled. HBV-specific and -nonspecific Th17 cells and TLR2 expression in T cells were analyzed by flow cytometry. The function of TLR2 agonist for induction of IL-17 production was also determined. Results: HBV-specific and -nonspecific IL-17 secretion in CD4+ (Th17 cells) and CD8+ T cells was significantly elevated in chronic HBV infection. Viral-specific TLR2 expression in CD4+, CD8+, and Th17 cells was also remarkably increased in patients with chronic hepatitis B. Moreover, TLR2 agonist Pam3Csk4 directly activated Th17 cells response without antigen stimulation in HBV infection. Conclusion: TLR2, which traditionally associated with innate immunity, might also promote Th17 cells response in HBV infection. The function of TLRs in regulation of adaptive immune response in HBV infection, which might play an important role in persistent HBV infection.
PMCID: PMC4509216  PMID: 26221271
Hepatitis B virus; Toll-like receptor; T helper 17 cells; immunoregulation
22.  Significance of platelet count and platelet-based models for hepatocellular carcinoma recurrence 
AIM: To explore the effects of platelet count (PLT) and 11 platelet-based indices on postoperative recurrence of hepatocellular carcinoma (HCC).
METHODS: We retrospectively analyzed 172 HCC patients who were treated by partial hepatectomy. Preoperative data, including laboratory biochemical results, were used to calculate the 11 indices included in the analysis. We performed receiver operating characteristic curve analysis to determine the optimal cut-off values for predicting recurrence. Cumulative rates of HCC recurrence were calculated using Kaplan-Meier survival curves and differences were analyzed by log-rank tests. Multivariate analyses were performed to identify independent predictors of recurrence, early recurrence (within one year after surgery), and late recurrence in HCC. To obtain better prognostic models, PLT-based indices were analyzed separately after being expressed as binary and continuous variables. Two platelet-unrelated, validated HCC prognostic models were included in the analyses as reference indices. Additional analyses were performed after patients were stratified based on hepatitis B virus infection status, cirrhosis, and tumor size to investigate the significance of platelets in different subgroups.
RESULTS: In the study cohort, 44.2% (76/172) of patients experienced HCC recurrence, and 50.6% (87/172) died during a median follow-up time of 46 mo. PLT and five of the 11 platelet-related models were significant predisposing factors for recurrence (P < 0.05). Multivariate analysis indicated that, among the clinical parameters, presence of ascites, PLT ≥ 148 × 109/L, alkaline phosphatase ≥ 116 U/L, and tumor size ≥ 5 cm were independently associated with a higher risk of HCC recurrence (P < 0.05). Independent and significant models included the aspartate aminotransferase/PLT index, fibrosis index based on the four factors, fibro-quotient, aspartate aminotransferase/PLT/γ-glutamyl transpeptidase/alpha-fetoprotein index, and the PLT/age/alkaline phosphatase/alpha-fetoprotein/aspartate aminotransferase index. There were different risk factors between early and late recurrences, and PLT and these indices were more inclined to influence late recurrence. PLT was only predictive of recurrence in non-cirrhotic HCC patients, and was not influenced by tumor size, which was a critical confounder in our study.
CONCLUSION: PLT and PLT-based noninvasive models are effective tools for predicting postoperative recurrence, especially late recurrence. Larger cohorts are needed to validate our findings.
doi:10.3748/wjg.v21.i18.5607
PMCID: PMC4427685  PMID: 25987786
Alkaline phosphatase; Alpha-fetoprotein; Aspartate aminotransferase; Blood platelets; Hepatocellular carcinoma; Recurrence
23.  Sodium Salicylate Suppresses GABAergic Inhibitory Activity in Neurons of Rodent Dorsal Raphe Nucleus 
PLoS ONE  2015;10(5):e0126956.
Sodium salicylate (NaSal), a tinnitus inducing agent, can activate serotonergic (5-HTergic) neurons in the dorsal raphe nucleus (DRN) and can increase serotonin (5-HT) level in the inferior colliculus and the auditory cortex in rodents. To explore the underlying neural mechanisms, we first examined effects of NaSal on neuronal intrinsic properties and the inhibitory synaptic transmissions in DRN slices of rats by using whole-cell patch-clamp technique. We found that NaSal hyperpolarized the resting membrane potential, decreased the input resistance, and suppressed spontaneous and current-evoked firing in GABAergic neurons, but not in 5-HTergic neurons. In addition, NaSal reduced GABAergic spontaneous and miniature inhibitory postsynaptic currents in 5-HTergic neurons. We next examined whether the observed depression of GABAergic activity would cause an increase in the excitability of 5-HTergic neurons using optogenetic technique in DRN slices of the transgenic mouse with channelrhodopsin-2 expressed in GABAergic neurons. When the GABAergic inhibition was enhanced by optical stimulation to GABAergic neurons in mouse DRN, NaSal significantly depolarized the resting membrane potential, increased the input resistance and increased current-evoked firing of 5-HTergic neurons. However, NaSal would fail to increase the excitability of 5-HTergic neurons when the GABAergic synaptic transmission was blocked by picrotoxin, a GABA receptor antagonist. Our results indicate that NaSal suppresses the GABAergic activities to raise the excitability of local 5-HTergic neural circuits in the DRN, which may contribute to the elevated 5-HT level by NaSal in the brain.
doi:10.1371/journal.pone.0126956
PMCID: PMC4427486  PMID: 25962147
24.  Kawasaki disease in children: Epidemiology, clinical symptoms and diagnostics of 231 cases in 10 years 
The present study was a retrospective analysis of the dynamic changes and clinical characteristics of 231 cases of Kawasaki disease (KD) in pediatric patients admitted to the People's Hospital of Inner Mongolia between January 2003 and December 2012. A total of 37.23% of the cases occurred in the first 5 years, compared with 62.77% in the latter 5 years. The age distribution ranged from 3 months to 10 years, with a peak age of <1 year. The male-to-female ratio was 2.12:1, and the reoccurrence rate was 1.3%. Among the patient cohort, 7.8% were Mongolian children. The most common clinical symptom was fever (87.6%), while perianal skin peeling was the most rare (14.1%). With regard to the analyzed biomarkers, 90.4% of patients had abnormal platelet (PLT) counts; the next highest abnormality rates were associated with erythrocyte sedimentation rate (ESR) (74.46%) and white blood cell (WBC) counts (59.74%), followed by levels of C-reactive protein (CRP) (57.58%), creatinine kinase-MB (40.26%) and hemoglobin (Hb) (38.53%). In conclusion, the present study has found that approximately two-thirds of cases of KD over a 10-year period occurred in the latter 5 years. Changes in a number of experimental indicators, including PLT, ESR and WBC, could be used in the diagnosis of the condition and to reflect the success of the clinical treatment.
doi:10.3892/etm.2015.2487
PMCID: PMC4486877  PMID: 26170962
clinical characteristics; diagnostic analysis; Kawasaki disease
25.  A genome-wide association study of body mass index across early life and childhood 
Background: Several studies have investigated the effect of known adult body mass index (BMI) associated single nucleotide polymorphisms (SNPs) on BMI in childhood. There has been no genome-wide association study (GWAS) of BMI trajectories over childhood.
Methods: We conducted a GWAS meta-analysis of BMI trajectories from 1 to 17 years of age in 9377 children (77 967 measurements) from the Avon Longitudinal Study of Parents and Children (ALSPAC) and the Western Australian Pregnancy Cohort (Raine) Study. Genome-wide significant loci were examined in a further 3918 individuals (48 530 measurements) from Northern Finland. Linear mixed effects models with smoothing splines were used in each cohort for longitudinal modelling of BMI.
Results: A novel SNP, downstream from the FAM120AOS gene on chromosome 9, was detected in the meta-analysis of ALSPAC and Raine. This association was driven by a difference in BMI at 8 years (T allele of rs944990 increased BMI; PSNP = 1.52 × 10−8), with a modest association with change in BMI over time (PWald(Change) = 0.006). Three known adult BMI-associated loci (FTO, MC4R and ADCY3) and one childhood obesity locus (OLFM4) reached genome-wide significance (PWald < 1.13 × 10−8) with BMI at 8 years and/or change over time.
Conclusions: This GWAS of BMI trajectories over childhood identified a novel locus that warrants further investigation. We also observed genome-wide significance with previously established obesity loci, making the novel observation that these loci affected both the level and the rate of change in BMI. We have demonstrated that the use of repeated measures data can increase power to allow detection of genetic loci with smaller sample sizes.
doi:10.1093/ije/dyv077
PMCID: PMC4469798  PMID: 25953783
Body mass index; genome-wide association study; trajectory; childhood; ALSPAC; Raine

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