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1.  Chromatin modifications and genomic contexts linked to dynamic DNA methylation patterns across human cell types 
Scientific Reports  2015;5:8410.
DNA methylation is related closely to sequence contexts and chromatin modifications; however, their potential differences in different genomic regions across cell types remain largely unexplored. We used publicly available genome-scale DNA methylation and histone modification profiles to study their relationships among different genomic regions in human embryonic stem cells (H1), H1-derived neuronal progenitor cultured cells (NPC), and foetal fibroblasts (IMR90) using the Random forests classifier. Histone modifications achieved high accuracy in modelling DNA methylation patterns on a genome scale in the three cell types. The inclusion of sequence features helped improve accuracy only in non-promoter regions of IMR90. Furthermore, the top six feature combinations obtained by mean decrease Gini were important indicators of different DNA methylation patterns, suggesting that H3K4me2 and H3K4me3 are important indicators that are independent of genomic regions and cell types. H3K9me3 was IMR90-specific and exhibited a genomic region-specific correlation with DNA methylation. Variations of essential chromatin modification signals may effectively discriminate changes of DNA methylation between H1 and IMR90. Genes with different co-variations of epigenetic marks exhibited genomic region-specific biological relevance. This study provides an integrated strategy to identify systematically essential epigenetic and genetic elements of genomic region-specific and cell type-specific DNA methylation patterns.
doi:10.1038/srep08410
PMCID: PMC4325317  PMID: 25673498
2.  Unfavorable outcome of antiviral therapy in cytomegalovirus-positive ulcerative colitis may be due to inappropriate study inclusion in meta-analysis 
Some previous articles reported that antiviral treatment was effective to reduce the colectomy rate in ulcerative colitis (UC) patients with cytomegalovirus (CMV) infection. Kopylov et al recently carried out a systematic review and meta-analysis to evaluate the impact of antiviral therapy on CMV-positive UC. The results showed that patients who received antiviral treatment had a higher risk of 30-d colectomy. We found that in this meta-analysis, some studies were inappropriately included, leading to an unfavorable outcome of anti-CMV therapy in UC patients.
doi:10.3748/wjg.v21.i5.1689
PMCID: PMC4316116  PMID: 25663793
Ulcerative colitis; Cytomegalovirus; Antiviral therapy; Colectomy; Meta-analysis
4.  A review of Solenysa spiders from Japan (Araneae, Linyphiidae), with a comment on the type species S. mellotteei Simon, 1894 
ZooKeys  2015;39-56.
The present paper gives a review of Solenysa species from Japan and provides a solution for the species bearing the generotype name Solenysa mellotteei Simon, 1894. A total of six species are recorded, including two new species Solenysa macrodonta sp. n. and Solenysa trunciformis sp. n. The species collected from Kawasaki (NSMT-Ar 11154) and Hachioji should be the generotype Solenysa mellotteei, with Solenysa akihisai Tu, 2011, syn. n. as its junior synonym. To distinguish these congeneric species from each other, their genital characters are provided in detail based on images collected by scanning electron microscopy and light microscopy.
doi:10.3897/zookeys.481.8545
PMCID: PMC4319100
Genitalia; morphology; new species; taxonomy
5.  Re-Examination of Chinese Semantic Processing and Syntactic Processing: Evidence from Conventional ERPs and Reconstructed ERPs by Residue Iteration Decomposition (RIDE) 
PLoS ONE  2015;10(1):e0117324.
A number of studies have explored the time course of Chinese semantic and syntactic processing. However, whether syntactic processing occurs earlier than semantics during Chinese sentence reading is still under debate. To further explore this issue, an event-related potentials (ERPs) experiment was conducted on 21 native Chinese speakers who read individually-presented Chinese simple sentences (NP1+VP+NP2) word-by-word for comprehension and made semantic plausibility judgments. The transitivity of the verbs was manipulated to form three types of stimuli: congruent sentences (CON), sentences with a semantically violated NP2 following a transitive verb (semantic violation, SEM), and sentences with a semantically violated NP2 following an intransitive verb (combined semantic and syntactic violation, SEM+SYN). The ERPs evoked from the target NP2 were analyzed by using the Residue Iteration Decomposition (RIDE) method to reconstruct the ERP waveform blurred by trial-to-trial variability, as well as by using the conventional ERP method based on stimulus-locked averaging. The conventional ERP analysis showed that, compared with the critical words in CON, those in SEM and SEM+SYN elicited an N400–P600 biphasic pattern. The N400 effects in both violation conditions were of similar size and distribution, but the P600 in SEM+SYN was bigger than that in SEM. Compared with the conventional ERP analysis, RIDE analysis revealed a larger N400 effect and an earlier P600 effect (in the time window of 500–800 ms instead of 570–810ms). Overall, the combination of conventional ERP analysis and the RIDE method for compensating for trial-to-trial variability confirmed the non-significant difference between SEM and SEM+SYN in the earlier N400 time window. Converging with previous findings on other Chinese structures, the current study provides further precise evidence that syntactic processing in Chinese does not occur earlier than semantic processing.
doi:10.1371/journal.pone.0117324
PMCID: PMC4304814  PMID: 25615600
6.  Coordinate Development of Skin Cells and Cutaneous Sensory Axons in Zebrafish 
Peripheral sensory axons innervate the epidermis early in embryogenesis to detect touch stimuli. To characterize the time course of cutaneous innervation and the nature of interactions between sensory axons and skin cells at early developmental stages, we conducted a detailed analysis of cutaneous innervation in the head, trunk, and tail of zebrafish embryos and larvae from 18 to 78 hours postfertilization. This analysis combined live imaging of fish expressing transgenes that highlight sensory neurons and skin cells, transmission electron microscopy (TEM), and serial scanning electron microscopy (sSEM). In zebrafish, the skin initially consists of two epithelial layers, and all of the axons in the first wave of innervation are free endings. Maturation of the epithelium coincides with, but does not depend on, its innervation by peripheral sensory axons. We found that peripheral axons initially arborize between the two epithelial skin layers, but not within the basal lamina, as occurs in other organisms. Strikingly, as development proceeds, axons become tightly enveloped within basal keratinocytes, an arrangement suggesting that keratinocytes may serve structural or functional roles, akin to Schwann cells, in somatosensation mediated by these sensory neurons.
doi:10.1002/cne.22791
PMCID: PMC4299821  PMID: 22020759
zebrafish; somatosensation; skin; peripheral axon; trigeminal; Rohon-Beard neurons
7.  The Relationship Between Disability-Adjusted Life Years of Cataracts and Ambient Erythemal Ultraviolet Radiation in China 
Journal of Epidemiology  2015;25(1):57-65.
Background
Cataracts are one of the major public health problems worldwide. Ultraviolet radiation (UVR) is one of the risk factors for cataract development. We analyzed the relationship between disability-adjusted life year (DALY) rates of cataracts and UVR exposure in China.
Methods
DALY rates of cataracts and UVR exposure in 31 regions of China were calculated based on data from the Second China National Sample Survey on Disability and the United States’ National Aeronautics and Space Administration database. The relationship between the DALY rates of cataracts and UVR was estimated by Spearman rank correlation analysis and linear regression analysis.
Results
The elderly (≥65 years) had higher DALY rates of cataracts than the whole population. The DALY rate of cataracts in the agricultural population was higher than that observed in the non-agricultural population. The DALY rates of cataracts were positively associated with UVR The DALY rates of cataracts in regions with higher UVR were higher than those in regions with lower UVR. An increase in the daily ambient erythemal UVR of 1000 J/m2 was associated with an increase in the DALY rates of cataracts by 92 DALYs/100 000 (R2 = 0.676) among the whole population, 34 DALYs/100 000 among the population <65 years old (R2 = 0.423), 607 DALYs/100 000 among the population aged 65–74 years (R2 = 0.617), and by 1342 DALYs/100 000 among the population ≥75 years old (R2 = 0.758).
Conclusions
DALY rates of cataracts increased with increases in UVR exposure in 31 regions of China. Greater exposure to UVR increases the disease burden of cataracts in the whole population, especially in the elderly and among the agricultural population.
doi:10.2188/jea.JE20140017
PMCID: PMC4275439
cataract; UVR exposure; disease burden; DALYs
8.  The Thellungiella salsuginea Tonoplast Aquaporin TsTIP1;2 Functions in Protection Against Multiple Abiotic Stresses 
Plant and Cell Physiology  2013;55(1):148-161.
Examination of aquaporin (AQP) membrane channels in extremophile plants may increase our understanding of plant tolerance to high salt, drought or other conditions. Here, we cloned a tonoplast AQP gene (TsTIP1;2) from the halophyte Thellungiella salsuginea and characterized its biological functions. TsTIP1;2 transcripts accumulate to high levels in several organs, increasing in response to multiple external stimuli. Ectopic overexpression of TsTIP1;2 in Arabidopsis significantly increased plant tolerance to drought, salt and oxidative stresses. TsTIP1;2 had water channel activity when expressed in Xenopus oocytes. TsTIP1;2 was also able to conduct H2O2 molecules into yeast cells in response to oxidative stress. TsTIP1;2 was not permeable to Na+ in Xenopus oocytes, but it could facilitate the entry of Na+ ions into plant cell vacuoles by an indirect process under high-salinity conditions. Collectively, these data showed that TsTIP1;2 could mediate the conduction of both H2O and H2O2 across membranes, and may act as a multifunctional contributor to survival of T. salsuginea in highly stressful habitats.
doi:10.1093/pcp/pct166
PMCID: PMC3894706  PMID: 24214268
Aquaporin; Channeling activity; Stress tolerance; Thellungiella salsuginea
9.  Integrated prevention of mother-to-child transmission for human immunodeficiency virus, syphilis and hepatitis B virus in China 
Abstract
Problem
China continues to face challenges in eliminating mother-to-child transmission of human immunodeficiency virus (HIV), syphilis and hepatitis B virus (HBV).
Approach
In 2010, a programme that integrated and standardized prevention of mother-to-child transmission (PMTCT) efforts for HIV, syphilis and HBV was implemented in 1156 counties. At participating antenatal care clinics, pregnant women were offered all three tests concurrently and free of charge. Further interventions such as free treatment, prophylaxis and testing for mothers and their children were provided for HIV and syphilis.
Local setting
China’s national PMTCT HIV programme started in 2003, at which time there were no national programmes for perinatal syphilis and HBV. In 2009, the rate of maternal-to-child transmission of HIV was 8.1% (57/702). Reported congenital syphilis was 60.8 per 100 000 live births. HBV infection was 7.2% of the overall population infected.
Relevant changes
Between 2010 and 2013 the number of pregnant women attending antenatal care clinics with integrated PMTCT services increased from 5.5 million to 13.1 million. In 2013, 12.7 million pregnant women were tested for HIV, 12.6 million for syphilis and 12.7 million for HBV. Mother-to-child transmission of HIV fell to 6.7% in 2013. Data on syphilis transmission are not yet available.
Lessons learnt
Integrated PMTCT services proved to be feasible and effective, and they are now part of the routine maternal and child health services provided to infected women. The services are provided through a collaboration between maternal and child health clinics, the national and local Centers for Disease Control and Prevention, and general hospitals.
doi:10.2471/BLT.14.139626
PMCID: PMC4271682  PMID: 25558108
10.  Red Cell Distribution Width Is Associated with Presence, Stage, and Grade in Patients with Renal Cell Carcinoma 
Disease Markers  2014;2014:860419.
It has been reported that red blood cell width (RDW) is a marker associated with the presence and adverse outcomes of various diseases. However, no data are available on the correlation of RDW with presence, stage, and grade in patients with renal cell carcinoma (RCC) yet. By retrospectively analyzing clinical and laboratory data at baseline of histologically confirmed RCC cases and controls, the present study demonstrated that the RDW values were significantly higher in patients with RCC than those in controls, and the baseline RDW value was independently associated with the presence of RCC. Besides, the data revealed a positive association between RCC stage and grade and the level of RDW. These findings may have important clinical implications due to future application using a RDW value in predicting RCC.
doi:10.1155/2014/860419
PMCID: PMC4280806  PMID: 25580051
11.  Intra-articular hyaluronic acid and corticosteroids in the treatment of knee osteoarthritis: A meta-analysis 
The aim of the present study was to evaluate the therapeutic effect of intra-articular hyaluronic acid (HA) in comparison to corticosteroids (CS) for knee osteoarthritis (OA). The data sources included PubMed, EMBASE, The Cochrane Central Register of Controlled Trials and hand searched reviews. Randomized controlled trials that reported the effects of intra-articular HA and CS in the treatment of knee OA were selected based on specific inclusion criteria. A meta-analysis was performed for the visual analog scale (VAS), Lequesne index, Knee Society Clinical Rating System (KSS), maximum flexion and adverse events of knee OA. Sensitivity analysis was also conducted to avoid bias. The seven eligible trials included 583 participants and the majority of the trials were of high quality. After one month, the mean difference in the VAS was 1.66 [95% confidence interval (CI); −0.90, 4.23), indicating equal efficacy for HA and CS. However, after three months, the mean difference was −12.58 (95% CI; −17.76, −7.40), while after six months, the difference was −9.01 (95% CI; −12.62, −5.40), favoring HA. For the additional indicators, including the Lequesne index, the KSS, maximum flexion and adverse events, no statistically significant differences were observed between the two treatment approaches for knee OA. Therefore, the results of the meta-analysis highlight a therapeutic trajectory for intra-articular HA in knee OA pain, as compared with CS, over six months post-intervention. After one month, the two approaches exhibited equal efficacy; however, in the long term, HA was found to have an enhanced effect. No statistically significant difference was observed in the adverse events caused by the two interventions. Further investigation and understanding into the trend observed in the present study may aid clinicians in the treatment of knee OA.
doi:10.3892/etm.2014.2131
PMCID: PMC4280939  PMID: 25574222
osteoarthritis; knee; intra-articular; hyaluronic acid; corticosteroids; meta-analysis
12.  Impact of thrombospondin-2 gene variations on the risk of thoracic aortic dissection in a Chinese Han population 
Objective: Genetic factors play an important role in thoracic aortic dissection (TAD) etiology and thrombospondin-2 gene (THBS2) polymorphisms may be involved. This study tried to examine the single-nucleotide polymorphisms (SNP) rs8089 of THBS2 for their association with TAD susceptibility in Chinese Han population. Methods: The rs8089 SNP of THBS2 was genotyped in 112 subjects who were diagnosed as TAD and in 184 age- and gender-matched matched controls. Results: The THBS2 rs8089 SNP was associated with increased TAD susceptibility for allele level comparison (P < 0.0001), and for dominant model (P = 0.0073) or extreme genotype model (P = 0.0459) in Chinese Han Population. But for the recessive model, no statistical difference was found (P = 0.099), which may be resulted from the relatively small sample size and low genotype frequency. Conclusion: In conclusion, the present study suggested that the THBS2 rs8089 variant was associated with TAD, with the G allele representing a risk factor in a Chinese Han population.
PMCID: PMC4307556  PMID: 25664109
Thrombospondin-2; gene polymorphisms; thoracic aortic dissection
13.  Epithelium-Specific ETS (ESE)-1 upregulated GP73 expression in hepatocellular carcinoma cells 
Cell & Bioscience  2014;4(1):76.
Background
Golgi protein-73 (GP73) is a Golgi transmembrane glycoprotein elevated in numerous liver diseases. Clinically, GP73 is strongly elevated in the serum of HCC patients and is thus regarded as a novel potential biomarker for HCC. However, the mechanism leading to GP73 dysregulation in liver diseases remains unknown.
Results
This study determined that epithelium-specific ETS (ESE)-1, an epithelium-specific transcription factor, and GP73 expressions were induced by IL-1β stimulation in vitro, and both were triggered during liver inflammation in vivo. In hepatocellular carcinoma cells, the overexpression of ESE-1 induced GP73 expression, whereas its knock-down did the opposite. Mechanistically, ESE-1 activated GP73 expression by directly binding to its promoter.
Conclusions
Our findings supported a novel paradigm for ESE-1 as a transcriptional mediator of GP73. This study provided a possible mechanism for GP73 upregulation in liver diseases.
Electronic supplementary material
The online version of this article (doi:10.1186/2045-3701-4-76) contains supplementary material, which is available to authorized users.
doi:10.1186/2045-3701-4-76
PMCID: PMC4271417  PMID: 25530841
GP73; GOLPH2; GOLM1; ESE-1; Liver inflammation; HCC
14.  Effect of intensive insulin therapy on first-phase insulin secretion in newly diagnosed type 2 diabetic patients with a family history of the disease 
Intensive insulin treatment is known to improve β-cell function in the majority of patients with newly diagnosed type 2 diabetes mellitus (T2DM), and family history (FH) is known to be an important independent risk factor for T2DM. Thus, the aim of the present study was to investigate the difference in first-phase insulin secretion and the effect of intensive insulin therapy on the improvement of β-cell function between T2DM patients with and without a FH of diabetes. Patients with newly diagnosed T2DM and healthy controls were divided into groups according to their FH of diabetes. Improvement in β-cell function was evaluated with an arginine stimulation test after two weeks of continuous subcutaneous insulin infusion (CSII). Compared with the control group, the level of fasting insulin and the homeostasis model assessment of insulin resistance (HOMA2-IR) were higher in the DM group, while the homeostasis model assessment of β-cell insulin secretion (HOMA2-%β) and the first-phase peak ratio were lower (P<0.05). In addition, the first-phase peak ratio in the FH- control group was higher compared with that in the FH+ control group (P=0.023). Following CSII, all the patients achieved excellent blood glucose control in 6.2±3.6 days, without severe adverse effects. In the DM groups, the fasting insulin level and HOMA2-IR were lower, while the HOMA2-%β and first-phase peak ratio were higher, when compared with the values prior to treatment, particularly in the FH- DM group. The HOMA2-%β in the FH+ DM group was lower compared with the FH- DM group (P=0.027). Therefore, T2DM patients with and without a FH of the disease were shown to have a good response to CSII in the improvement of insulin resistance and β-cell function; however, the improvements were less significant in patients with a FH compared with patients without a FH of diabetes.
doi:10.3892/etm.2014.2114
PMCID: PMC4280938  PMID: 25574243
type 2 diabetes; intensive insulin therapy; family history; β-cell function; first-phase insulin secretion; insulin resistance
15.  Probing Binding and Cellular Activity of Pyrrolidinone and Piperidinone Small Molecules Targeting the Urokinase Receptor 
ChemMedChem  2013;8(12):1963-1977.
The urokinase receptor (uPAR) is a cell-surface protein that is part of an intricate web of transient and tight protein interactions that promote cancer cell invasion and metastasis. Here we evaluate the binding and biological activity of a new class of pyrrolidinone (3) and piperidinone (4) compounds, along with derivatives of previously-identified pyrazole (1) and propylamine (2) compounds. Competition assays revealed that the compounds displaced a fluorescently-labeled peptide (AE147-FAM) with inhibition constant Ki ranging from 6 to 63 μM. Structure-based computational pharmacophore analysis followed by extensive explicit-solvent molecular dynamics simulations and free energy calculations suggested pyrazole-based 1a and piperidinone-based 4 adopt different binding modes, despite their similar two-dimensional structures. In cells, compounds 1b and 1f showed significant inhibition of breast MDA-MB-231 and pancreatic ductal adenocarcinoma (PDAC) cell proliferation, but 4b exhibited no cytotoxicity even at concentrations of 100 μM. 1f impaired MDA-MB-231 invasion, adhesion, and migration in a concentration-dependent manner, while 4b inhibited only invasion. 1f inhibited gelatinase (MMP-9) activity in a concentration-dependent manner, while 4b showed no effect suggesting different mechanisms for inhibition of cell invasion. Signaling studies further highlighted these differences, showing that pyrazole compounds completely inhibited ERK phosphorylation and impaired HIF1α and NF-κB signaling, while pyrrolidinone and piperidinone (3 and 4b) had no effect. Annexin V staining suggested that the effect of pyrazole-based 1f on proliferation was due to cell killing through an apoptotic mechanism.
doi:10.1002/cmdc.201300340
PMCID: PMC4058332  PMID: 24115356
16.  Afatinib circumvents multidrug resistance via dually inhibiting ATP binding cassette subfamily G member 2 in vitro and in vivo 
Oncotarget  2014;5(23):11971-11985.
Multidrug resistance (MDR) to chemotherapeutic drugs is a formidable barrier to the success of cancer chemotherapy. Expressions of ATP-binding cassette (ABC) transporters contribute to clinical MDR phenotype. In this study, we found that afatinib, a small molecule tyrosine kinase inhibitor (TKI) targeting EGFR, HER-2 and HER-4, reversed the chemoresistance mediated by ABCG2 in vitro, but had no effect on that mediated by multidrug resistance protein ABCB1 and ABCC1. In addition, afatinib, in combination with topotecan, significantly inhibited the growth of ABCG2-overexpressing cell xenograft tumors in vivo. Mechanistic investigations exhibited that afatinib significantly inhibited ATPase activity of ABCG2 and downregulated expression level of ABCG2, which resulted in the suppression of efflux activity of ABCG2 in parallel to the increase of intracellular accumulation of ABCG2 substrate anticancer agents. Taken together, our findings may provide a new and useful combinational therapeutic strategy of afatinib with chemotherapeutical drug for the patients with ABCG2 overexpressing cancer cells.
PMCID: PMC4322967  PMID: 25436978
Multidrug resistance; ABCG2; tyrosine kinase inhibitor; afatinib; combined chemotherapy
17.  Quantitative Gait Measurement With Pulse-Doppler Radar for Passive In-Home Gait Assessment 
In this paper, we propose a pulse-Doppler radar system for in-home gait assessment of older adults. A methodology has been developed to extract gait parameters including walking speed and step time using Doppler radar. The gait parameters have been validated with a Vicon motion capture system in the lab with 13 participants and 158 test runs. The study revealed that for an optimal step recognition and walking speed estimation, a dual radar set up with one radar placed at foot level and the other at torso level is necessary. An excellent absolute agreement with intraclass correlation coefficients of 0.97 was found for step time estimation with the foot level radar. For walking speed, although both radars show excellent consistency they all have a system offset compared to the ground truth due to walking direction with respect to the radar beam. The torso level radar has a better performance (9% offset on average) in the speed estimation compared to the foot level radar (13%–18% offset). Quantitative analysis has been performed to compute the angles causing the systematic error. These lab results demonstrate the capability of the system to be used as a daily gait assessment tool in home environments, useful for fall risk assessment and other health care applications. The system is currently being tested in an unstructured home environment.
doi:10.1109/TBME.2014.2319333
PMCID: PMC4238914  PMID: 24771566
Eldercare technology; gait analysis; passive monitoring; radar; step time; walking speed
18.  High Genetic Diversity and Novelty in Eukaryotic Plankton Assemblages Inhabiting Saline Lakes in the Qaidam Basin 
PLoS ONE  2014;9(11):e112812.
Saline lakes are intriguing ecosystems harboring extremely productive microbial communities in spite of their extreme environmental conditions. We performed a comprehensive analysis of the genetic diversity (18S rRNA gene) of the planktonic microbial eukaryotes (nano- and picoeukaryotes) in six different inland saline lakes located in the Qaidam Basin. The novelty level are high, with about 11.23% of the whole dataset showing <90% identity to any previously reported sequence in GenBank. At least 4 operational taxonomic units (OTUs) in mesosaline lakes, while up to eighteen OTUs in hypersaline lakes show very low CCM and CEM scores, indicating that these sequences are highly distantly related to any existing sequence. Most of the 18S rRNA gene sequence reads obtained in investigated mesosaline lakes is closely related to Holozoa group (48.13%), whereas Stramenopiles (26.65%) and Alveolates (10.84%) are the next most common groups. Hypersaline lakes in the Qaidam Basin are also dominated by Holozoa group, accounting for 26.65% of the total number of sequence reads. Notably, Chlorophyta group are only found in high abundance in Lake Gasikule (28.00%), whereas less represented in other hypersaline lakes such as Gahai (0.50%) and Xiaochaidan (1.15%). Further analysis show that the compositions of planktonic eukaryotic assemblages are also most variable between different sampling sites in the same lake. Out of the parameters, four show significant correlation to this CCA: altitude, calcium, sodium and potassium concentrations. Overall, this study shows important gaps in the current knowledge about planktonic microbial eukaryotes inhabiting Qaidam Basin (hyper) saline water bodies. The identified diversity and novelty patterns among eukaryotic plankton assemblages in saline lake are of great importance for understanding and interpreting their ecology and evolution.
doi:10.1371/journal.pone.0112812
PMCID: PMC4234628  PMID: 25401703
19.  Down-regulation of hypoxia-inducible factor-1 suppresses malignant biological behavior of triple-negative breast cancer cells 
This study is to investigate the effect and mechanism of reduced hypoxia-inducible factor (HIF)-1a expression on malignant behavior of MDA-MB-231 cells. HIF-1α expression was interfered by siRNA. Western blot was used to detect protein expression of HIF-1α, active fragments of caspase 3 and vimentin. Cell count, flow cytometry and Hoechst staining were used to evaluate cell growth and apoptosis. Matrigel invasion and wound scratch assay were performed to measure the ability of cell invasion and migration. After MDA-MB-231 cells were transfected with HIF-1α-targeted siRNA, HIF-1α protein expression was successfully interrupted and cell growth was retarded. Compared with random siRNA group, reduced HIF-1α protein expression in HIF-1α-targeted siRNA group facilitated cell apoptosis but had no effect on cell cycle. In addition, cells treated with HIF-1α-targeted siRNA expressed active fragments of caspase 3 (17 and 12 kD) after serum starvation for 0 to 60 h. Caspase 3 activity assay further confirmed the above finding. Reduced HIF-1α expression impaired the migration and invasiveness with a reduction in the expression of vimentin and CK18 protein. Inhibition of HIF-1α protein synthesis or enhancement of its degradation reversed its malignant phenotypes and could probably be a potential means for the treatment of triple-negative breast cancer.
PMCID: PMC4276159  PMID: 25550901
Hypoxia-inducible factor-1; triple-negative breast cancer; small-interfering RNA; epithelial mesenchymal transition
20.  Serum Inflammatory Cytokine Levels Correlate with Hand-Foot-Mouth Disease Severity: A Nested Serial Case-Control Study 
PLoS ONE  2014;9(11):e112676.
Background
Hand-food-mouth disease (HFMD) cases can be fatal. These cases develop rapidly, and it is important to predict the severity of HFMD from mild to fatal and to identify risk factors for mild HFMD. The objective of this study was to correlate the levels of serum inflammatory cytokines with HFMD severity.
Methods
This study was designed as a nested serial case-control study. The data collected included general information, clinical symptoms and signs, laboratory findings and serum cytokine levels.
Results
The levels of IL-4, IL-6, IL-10, TNF-α and IFN-γ in patients with severe HFMD were significantly higher than in mild patients during the 2nd to 5th day after disease onset. The levels of IL-4, IL-6, IL-10 and IFN-γ increased from the 2nd day to the 4th day and later decreased. The levels of TNF-α were high on the first two days and subsequently decreased. The changes of IL-10, TNF-α and IFN-γ in the controls were similar for all cases. The levels of IL-4, IL-6 and IL-17 in the controls were not significantly different with the progression of HFMD.
Conclusions
Our findings indicate that the IL-4, IL-6, IL-10, TNF-α and IFN-γ levels correlate with HFMD severity.
doi:10.1371/journal.pone.0112676
PMCID: PMC4229228  PMID: 25391156
21.  Irisin Promotes Human Umbilical Vein Endothelial Cell Proliferation through the ERK Signaling Pathway and Partly Suppresses High Glucose-Induced Apoptosis 
PLoS ONE  2014;9(10):e110273.
Irisin is a newly discovered myokine that links exercise with metabolic homeostasis. It is involved in modest weight loss and improves glucose intolerance. However, the direct effects and mechanisms of irisin on vascular endothelial cells (ECs) are not fully understood. In the current study, we demonstrated that irisin promoted Human Umbilical Vein Endothelial Cell (HUVEC) proliferation. It was further demonstrated that this pro-proliferation effect was mediated by irisin-induced activation of extracellular signal–related kinase (ERK) signaling pathways. Inhibition of ERK signaling with U0126 decreased the pro-proliferation effect of irisin on HUVECs. It was also demonstrated that irisin reduced high glucose-induced apoptosis by up-regulating Bcl-2 expression and down-regulating Bax, Caspase-9 and Caspase-3 expression. In summary, these results suggested that irisin plays a novel role in sustaining endothelial homeostasis by promoting HUVEC proliferation via the ERK signaling pathway and protects the cell from high glucose-induced apoptosis by regulating Bcl-2,Bax and Caspase expression.
doi:10.1371/journal.pone.0110273
PMCID: PMC4206299  PMID: 25338001
22.  Ampelopsin induces apoptosis by regulating multiple c-Myc/S-phase kinase-associated protein 2/F-box and WD repeat-containing protein 7/histone deacetylase 2 pathways in human lung adenocarcinoma cells 
Molecular Medicine Reports  2014;11(1):105-112.
Ampelopsin (AMP), a plant flavonoid, has been reported to inhibit cell growth and/or induce apoptosis in various types of tumor. The aim of the present study was to assess the apoptosis-inducing activity of AMP in A549 human lung adenocarcinoma epithelial cells and the associated underlying mechanism. A549 cells were incubated with different concentrations of AMP in culture medium. Cell growth and apoptosis were evaluated by MTT assay and Annexin V/propidium iodide double staining and flow cytometry, respectively. In addition, western blotting and reverse transcription quantitative polymerase chain reaction analysis were used to examine the time-dependent changes in protein expression. Certain changes in apoptotic protein expression were detected following exposure to AMP, including X-linked inhibitor of apoptosis protein release, reduced B-cell lymphoma 2, myeloid cell leukemia 1 and survivin expression levels, increased Bcl-2-associated X protein expression levels and cleaved-poly ADP ribose polymerase expression. The results revealed that AMP was a potent inhibitor of A549 cell proliferation. The c-Myc/S-phase kinase-associated protein 2 (Skp2) and histone deacetylase (HDAC)1/2 pathways were found to exert an important role in AMP-induced A549 cell apoptosis, as increased levels of c-Myc mRNA and reduced levels of c-Myc/Skp2 and HDAC1 and 2 proteins following AMP treatment were observed. The levels of F-box and WD repeat-containing protein 7α (Fbw7α), Fbw7β, Fbw7γ, phosphorylated-(p−)c-Myc (Thr58) and glycogen synthase kinase 3β (GSK3β) proteins involved in c-Myc ubiquitin-dependent degradation were also analyzed. Following exposure to AMP, the expression levels of Fbw7α, Fbw7γ and GSK3β were reduced and p-c-Myc (Thr58) expression levels were increased. The results suggest that AMP exerts an anticancer effect, which is associated with the degradation of c-Myc, Skp2 and HDAC1 and 2. The ability of AMP to induce apoptosis independently of Fbwα and Fbw7γ suggests a possible use in drug-resistant cancer associated with Fbw7 deficiency. Understanding the exact underlying mechanism requires further investigation of the association between c-Myc and Fbw7α/γ reversal, and analysis of whether Thr58 phosphorylation of c-Myc is dependent on GSK3β.
doi:10.3892/mmr.2014.2733
PMCID: PMC4237074  PMID: 25333250
lung cancer; ampelopsin; c-Myc; S-phase kinase-associated protein 2; F-box/WD repeat-containing protein 7
23.  Integrated microRNA and mRNA Transcriptome Sequencing Reveals the Potential Roles of miRNAs in Stage I Endometrioid Endometrial Carcinoma 
PLoS ONE  2014;9(10):e110163.
Endometrioid endometrial carcinoma (EEC) is the most dominant subtype of endometrial cancer. Aberrant transcriptional regulation has been implicated in EEC. Herein, we characterized mRNA and miRNA transcriptomes by RNA sequencing in EEC to investigate potential molecular mechanisms underlying the pathogenesis. Total mRNA and small RNA were simultaneously sequenced by next generation sequencing technology for 3 pairs of stage I EEC and adjacent non-tumorous tissues. On average, 52,716,765 pair-end 100 bp mRNA reads and 1,669,602 single-end 50 bp miRNA reads were generated. Further analysis indicated that 7 miRNAs and 320 corresponding target genes were differentially expressed in the three stage I EEC patients. Six of all the seven differentially expressed miRNAs were targeting on eleven differentially expressed genes in the cell cycle pathway. Real-time quantitative PCR in sequencing samples and other independent 21 pairs of samples validated the miRNA-mRNA differential co-expression, which were involved in cell cycle pathway, in the stage I EEC. Thus, we confirmed the involvement of hsa-let-7c-5p and hsa-miR-99a-3p in EEC and firstly found dysregulation of hsa-miR-196a-5p, hsa-miR-328-3p, hsa-miR-337-3p, and hsa-miR-181c-3p in EEC. Moreover, synergistic regulations among these miRNAs were detected. Transcript sequence variants such as single nucleotide variant (SNV) and short insertions and deletions (Indels) were also characterized. Our results provide insights on dysregulated miRNA-mRNA co-expression and valuable resources on transcript variation in stage I EEC, which implies the new molecular mechanisms that underlying pathogenesis of stage I EEC and supplies opportunity for further in depth investigations.
doi:10.1371/journal.pone.0110163
PMCID: PMC4201519  PMID: 25329664
24.  Environmental Acoustic Enrichment Promotes Recovery from Developmentally Degraded Auditory Cortical Processing 
The Journal of Neuroscience  2014;34(16):5406-5415.
It has previously been shown that environmental enrichment can enhance structural plasticity in the brain and thereby improve cognitive and behavioral function. In this study, we reared developmentally noise-exposed rats in an acoustic-enriched environment for ∼4 weeks to investigate whether or not enrichment could restore developmentally degraded behavioral and neuronal processing of sound frequency. We found that noise-exposed rats had significantly elevated sound frequency discrimination thresholds compared with age-matched naive rats. Environmental acoustic enrichment nearly restored to normal the behavioral deficit resulting from early disrupted acoustic inputs. Signs of both degraded frequency selectivity of neurons as measured by the bandwidth of frequency tuning curves and decreased long-term potentiation of field potentials recorded in the primary auditory cortex of these noise-exposed rats also were reversed partially. The observed behavioral and physiological effects induced by enrichment were accompanied by recovery of cortical expressions of certain NMDA and GABAA receptor subunits and brain-derived neurotrophic factor. These studies in a rodent model show that environmental acoustic enrichment promotes recovery from early noise-induced auditory cortical dysfunction and indicate a therapeutic potential of this noninvasive approach for normalizing neurological function from pathologies that cause hearing and associated language impairments in older children and adults.
doi:10.1523/JNEUROSCI.5310-13.2014
PMCID: PMC4104291  PMID: 24741032
BDNF; environmental acoustic enrichment; frequency discrimination performance; frequency selectivity; primary auditory cortex
25.  Specific recruitment of γδ regulatory T cells in human breast cancer 
Cancer research  2013;73(20):6137-6148.
Understanding the role of different subtypes of tumor-infiltrating lymphocytes (TILs) in the immunosuppressive tumor microenvironment is essential to improving cancer treatment. Enriched γδ1 T cell populations in tumor-infiltrating lymphocytes (TILs) suppress T cell responses and dendritic cell maturation in breast cancer, where their presence is correlated negatively with clinical outcomes. However, mechanism(s) that explain the increase in this class of T regulatory cells (γδ Treg) in breast cancer patients have yet to be elucidated. In this study, we showed that IP-10 secreted by breast cancer cells attracted γδ Treg cells. Using neutralizing antibodies against chemokines secreted by breast cancer cells, we found that IP-10 was the only functional chemokine that causes γδ Treg cells to migrate toward breast cancer cells. In a humanized NSG mouse model, human breast cancer cells attracted γδ Treg cells as revealed by a live cell imaging system. IP-10 neutralization in vivo inhibited migration and trafficking of γδ Treg cells into breast tumor sites, enhancing tumor immunity mediated by tumor-specific T cells. Together, our studies show how γδ Treg accumulate in breast tumors, providing a rationale for their immunological targeting to relieve immunosuppression in the tumor microenvironment.
doi:10.1158/0008-5472.CAN-13-0348
PMCID: PMC3800256  PMID: 23959855
γδ T cells; IP-10; Regulatory T cells; Breast cancer

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