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1.  Smg6/Est1 licenses embryonic stem cell differentiation via nonsense-mediated mRNA decay 
The EMBO Journal  2015;34(12):1630-1647.
Nonsense-mediated mRNA decay (NMD) is a post-transcriptional mechanism that targets aberrant transcripts and regulates the cellular RNA reservoir. Genetic modulation in vertebrates suggests that NMD is critical for cellular and tissue homeostasis, although the underlying mechanism remains elusive. Here, we generate knockout mice lacking Smg6/Est1, a key nuclease in NMD and a telomerase cofactor. While the complete loss of Smg6 causes mouse lethality at the blastocyst stage, inducible deletion of Smg6 is compatible with embryonic stem cell (ESC) proliferation despite the absence of telomere maintenance and functional NMD. Differentiation of Smg6-deficient ESCs is blocked due to sustained expression of pluripotency genes, normally repressed by NMD, and forced down-regulation of one such target, c-Myc, relieves the differentiation block. Smg6-null embryonic fibroblasts are viable as well, but are refractory to cellular reprograming into induced pluripotent stem cells (iPSCs). Finally, depletion of all major NMD factors compromises ESC differentiation, thus identifying NMD as a licensing factor for the switch of cell identity in the process of stem cell differentiation and somatic cell reprograming.
doi:10.15252/embj.201489947
PMCID: PMC4475398  PMID: 25770585
cell reprograming; ESC differentiation; NMD; Smg6/Est1; telomere
2.  ZxNHX controls Na+ and K+ homeostasis at the whole-plant level in Zygophyllum xanthoxylum through feedback regulation of the expression of genes involved in their transport 
Annals of Botany  2014;115(3):495-507.
Background and Aims In order to cope with arid environments, the xerohalophyte Zygophyllum xanthoxylum efficiently compartmentalizes Na+ into vacuoles, mediated by ZxNHX, and maintains stability of K+ in its leaves. However, the function of ZxNHX in controlling Na+ and K+ homeostasis at the whole-plant level remains unclear. In this study, the role of ZxNHX in regulating the expression of genes involved in Na+ and K+ transport and spatial distribution was investigated.
Methods The role of ZxNHX in maintaining Na+ and K+ homeostasis in Z. xanthoxylum was studied using post-transcriptional gene silencing via  Agrobacterium-mediated transformation. Transformed plants were grown with or without 50 mm NaCl, and expression levels and physiological parameters were measured.
Key Results It was found that 50 mm NaCl induced a 620 % increase in transcripts of ZxSOS1 but only an 80 % increase in transcripts of ZxHKT1;1 in roots of wild-type (WT) plants. Consequently, the ability of ZxSOS1 to transport Na+ exceeded that of ZxHKT1;1, and Na+ was loaded into the xylem by ZxSOS1 and delivered to the shoots. However, in a ZxNHX-silenced line (L7), the capacity to sequester Na+ into vacuoles of leaves was weakened, which in turn regulated long-distance Na+ transport from roots to shoots. In roots of L7, NaCl (50 mm) increased transcripts of ZxSOS1 by only 10 %, whereas transcripts of ZxHKT1;1 increased by 53 %. Thus, in L7, the transport ability of ZxHKT1;1 for Na+ outweighed that of ZxSOS1. Na+ was unloaded from the xylem stream, consequently reducing Na+ accumulation and relative distribution in leaves, but increasing the relative distribution of Na+ in roots and the net selective transport capacity for K+ over Na+ from roots to shoots compared with the WT. Silencing of ZxNHX also triggered a downregulation of  ZxAKT1 and ZxSKOR in roots, resulting in a significant decrease in K+ accumulation in all the tissues in plants grown in 50 mm NaCl. These changes led to a significant reduction in osmotic adjustment, and thus an inhibition of growth in ZxNHX-silenced lines.
Conclusions The results suggest that ZxNHX is essential for controlling Na+, K+ uptake, long-distance transport and their homeostasis at whole-plant level via feedback regulation of the expression of genes involved in Na+, K+ transport. The net result is the maintenance of the characteristic salt accumulation observed in Z. xanthoxylum and the regulation of its normal growth. A model is proposed for the role of ZxNHX in regulating the Na+ transport system in Z. xanthoxylum under saline conditions.
doi:10.1093/aob/mcu177
PMCID: PMC4332602  PMID: 25252687
Xerohalophyte; tonoplast Na+/H+ antiporter ZxNHX; Na+ and K+ homeostasis; long-distance transport; gene silencing; ZxSOS1; ZxHKT1;1; Zygophyllum xanthoxylum
3.  A Retrospective Study of Preferable Alternative Route to Right Internal Jugular Vein for Placing Tunneled Dialysis Catheters: Right External Jugular Vein versus Left Internal Jugular Vein 
PLoS ONE  2016;11(1):e0146411.
Background
Right internal jugular vein (IJV) is a preferred access route for tunneled (cuffed) dialysis catheters (TDCs), and both right external jugular vein (EJV) and left IJV are alternative routes for patients in case the right IJV isn’t available for TDC placement. This retrospective study aimed to determine if a disparity exists between the two alternative routes in hemodialysis patients in terms of outcomes of TDCs.
Methods
49 hemodialysis patients who required TDCs through right EJV (n = 21) or left IJV (n = 28) as long-term vascular access were included in this study. The primary end point was cumulative catheter patency. Secondary end points include primary catheter patency, proportion of patients that never required urokinase and incidence of catheter-related bloodstream infections (CRBSI).
Results
A total of 20,870 catheter-days were evaluated and the median was 384 (interquartile range, 262–605) catheter-days. Fewer catheters were removed in the right EJV group than in the left IJV group (P = 0.007). Mean cumulative catheter patency was higher in the right EJV group compared with the left IJV group (P = 0.031). There was no significant difference between the two groups in the incidence of CRBSI, primary catheter patency or proportion of patients that never required urokinase use. Total indwell time of antecedent catheters was identified as an independent risk factor for cumulative catheter patency by Cox regression hazards test with an HR of 2.212 (95% CI, 1.363–3.588; p = 0.001).
Conclusions
Right EJV might be superior to left IJV as an alternative insertion route for TDC placement in hemodialysis patients whose right IJVs are unavailable.
doi:10.1371/journal.pone.0146411
PMCID: PMC4709068  PMID: 26751380
4.  ING2 (inhibitor of growth protein-2) plays a crucial role in preimplantation development 
Zygote (Cambridge, England)  2015;24(1):89-97.
Summary
ING2 (inhibitor of growth protein-2) is a member of the ING-gene family and participates in diverse cellular processes involving tumor suppression, DNA repair, cell cycle regulation, and cellular senescence. As a subunit of the Sin3 histone deacetylase complex co-repressor complex, ING2 binds to H3K4me3 to regulate chromatin modification and gene expression. Additionally, ING2 recruits histone methyltransferase (HMT) activity for gene repression, which is independent of the HDAC class I or II pathway. However, the physiological function of ING2 in mouse preimplantation embryo development has not yet been characterized previously. The expression, localization and function of ING2 during preimplantation development were investigated in this study. We showed increasing expression of ING2 within the nucleus from the 4-cell embryo stage onwards; and that down-regulation of ING2 expression by endoribonuclease-prepared small interfering RNA (esiRNA) microinjection results in developmental arrest during the morula to blastocyst transition. Embryonic cells microinjected with ING2-specific esiRNA exhibited decreased blastulation rate compared to the negative control. Further investigation of the underlying mechanism indicated that down-regulation of ING2 significantly increased expression of p21, whilst decreasing expression of HDAC1. These results suggest that ING2 may play a crucial role in the process of preimplantation embryo development through chromatin regulation.
doi:10.1017/S0967199414000768
PMCID: PMC4697306  PMID: 25672483
ING2; Inhibitor of growth protein; Preimplantation development
5.  Effect of Metal Film Thickness on Tamm Plasmon-Coupled Emission 
Tamm plasmons (TPs) are the result of trapping optical energy at the interface between a metal film and a one-dimensional photonic crystal. In contrast to surface plasmons, TPs display unique properties such as the ability of direct optical excitation without the aid of prisms, or gratings, being populated using both S- and P- polarized light, and importantly, they can be created with incident light normal to the surfaces. This latter property has recently been used to obtain Tamm plasmon-coupled emission (TPCE) which beams along a path directly perpendicular to the surface. In this paper the effects of metal film thickness on TPCE are investigated using back focal plane (BFP) imaging and spectral resolutions. The observed experimental results are in agreement with the numerical simulations. The present work provides the basic understanding to design the structures for TPCE, which in turn has potential applications in the fabrication of the active material for light emitting devices, fluorescence based-sensing using microarrays and imaging.
doi:10.1039/c4cp04031g
PMCID: PMC4438750  PMID: 25349013
Fluorescence; Tamm Plasmons; Tamm Plasmon-Coupled Emission; Metal film; Back Focal Plane imaging
6.  Smg6/Est1 licenses embryonic stem cell differentiation via nonsense-mediated mRNA decay 
The EMBO Journal  2015;34(12):1630-1647.
Nonsense-mediated mRNA decay (NMD) is a post-transcriptional mechanism that targets aberrant transcripts and regulates the cellular RNA reservoir. Genetic modulation in vertebrates suggests that NMD is critical for cellular and tissue homeostasis, although the underlying mechanism remains elusive. Here, we generate knockout mice lacking Smg6/Est1, a key nuclease in NMD and a telomerase cofactor. While the complete loss of Smg6 causes mouse lethality at the blastocyst stage, inducible deletion of Smg6 is compatible with embryonic stem cell (ESC) proliferation despite the absence of telomere maintenance and functional NMD. Differentiation of Smg6-deficient ESCs is blocked due to sustained expression of pluripotency genes, normally repressed by NMD, and forced down-regulation of one such target, c-Myc, relieves the differentiation block. Smg6-null embryonic fibroblasts are viable as well, but are refractory to cellular reprograming into induced pluripotent stem cells (iPSCs). Finally, depletion of all major NMD factors compromises ESC differentiation, thus identifying NMD as a licensing factor for the switch of cell identity in the process of stem cell differentiation and somatic cell reprograming.
doi:10.15252/embj.201489947
PMCID: PMC4475398  PMID: 25770585
cell reprograming; ESC differentiation; NMD; Smg6/Est1; telomere
7.  Epidemiology of haemodialysis catheter complications: a survey of 865 dialysis patients from 14 haemodialysis centres in Henan province in China 
BMJ Open  2015;5(11):e007136.
Objectives
To investigate the incidence rates and risk factors for catheter-related complications in different districts and populations in Henan Province in China.
Design
Cross-sectional.
Setting
Fourteen hospitals in Henan Province.
Participants
865 patients with renal dysfunction undergoing dialysis using catheters between October 2013 and October 2014.
Main outcome measures
The main outcome measures were complications, risk factors and patient characteristics. Catheter-related complications included catheter-related infection (catheter exit-site infection, catheter tunnel infection and catheter-related bloodstream infection), catheter dysfunction (thrombosis, catheter malposition or kinking, and fibrin shell formation) and central vein stenosis.
Results
The overall incidence rate was 7.74/1000 catheter-days, affecting 38.61% of all patients, for catheter infections, 10.58/1000 catheter-days, affecting 56.65% of all patients, for catheter dysfunction, and 0.68/1000 catheter-days, affecting 8.79% of all patients, for central vein stenosis. Multivariate analysis showed that increased age, diabetes, primary educational level or below, rural residence, lack of a nephropathy visit before dialysis and pre-established permanent vascular access, not taking oral drugs to prevent catheter thrombus, lower serum albumin levels and higher ferritin levels were independently associated with catheter infections. Rural residence, not taking oral drugs to prevent thrombus, lack of an imaging examination after catheter insertion, non-tunnel catheter type, lack of medical insurance, lack of nephropathy visit before dialysis and pre-established permanent vascular access, left-sided catheter position, access via the femoral vein and lower haemoglobin level were independently associated with catheter dysfunction. Diabetes, lack of nephropathy visit before dialysis and pre-established permanent vascular access, lack of oral drugs to prevent catheter thrombus, left-sided catheter location and higher number of catheter insertions, were independently associated with central vein stenosis.
Conclusions
The rate of catheter-related complications was high in patients with end-stage renal disease in Henan Province. Our finding suggest that strategies should be implemented to decrease complication rates.
doi:10.1136/bmjopen-2014-007136
PMCID: PMC4663418  PMID: 26589425
8.  A Useful Strategy to Evaluate the Quality Consistency of Traditional Chinese Medicines Based on Liquid Chromatography and Chemometrics 
Evaluation of the batch consistency of traditional Chinese medicines (TCMs) is essential for the promotion of the development and quality control of TCMs. The aim of the present work was to develop a useful strategy via liquid chromatography and chemometrics to evaluate the batch consistency of TCM preparations. Xin-Ke-Shu (XKS) tablet was chosen as a model for this method development. Four types of chromatographic fingerprint approaches were compared by using similarity analysis based on cosine of angel or correlation coefficient. Differences in the fingerprints of 71 batches of XKS tablet were illustrated by hierarchical cluster analysis. Then, Mahalanobis distance was employed for estimating the probability level (P < 0.05) of the differences mentioned above. Additionally, t-test was applied to find out the chromatographic peaks which had significant differences. For XKS tablet, the maximum wavelength fingerprint had the largest range and dispersion degree of similarity as compared with the other three ones. There were two clear clusters in all the batches of samples. And we clearly arrived at the conclusion that higher similarity does not exactly indicate small Mahalanobis distance, while lower similarity indicated larger Mahalanobis distance. Finally, a useful strategy was proposed for evaluation of the batch consistency of XKS tablet.
doi:10.1155/2015/589654
PMCID: PMC4649102  PMID: 26618023
9.  Buprenorphine-elicited alteration of adenylate cyclase activity in human embryonic kidney 293 cells coexpressing κ-, μ-opioid and nociceptin receptors 
Buprenorphine, a maintenance drug for heroin addicts, exerts its pharmacological function via κ- (KOP), μ-opioid (MOP) and nociceptin/opioid receptor-like 1 (NOP) receptors. Previously, we investigated its effects in an in vitro model expressing human MOP and NOP receptors individually or simultaneously (MOP, NOP, and MOP+NOP) in human embryonic kidney 293 cells. Here, we expanded this cell model by expressing human KOP, MOP and NOP receptors individually or simultaneously (KOP, KOP+MOP, KOP+NOP and KOP+MOP+NOP). Radioligand binding with tritium-labelled diprenorphine confirmed the expression of KOP receptors. Immunoblotting and immunocytochemistry indicated that the expressed KOP, MOP and NOP receptors are N-linked glycoproteins and colocalized in cytoplasmic compartments. Acute application of the opioid receptor agonists— U-69593, DAMGO and nociceptin— inhibited adenylate cyclase (AC) activity in cells expressing KOP, MOP and NOP receptors respectively. Buprenorphine, when applied acutely, inhibited AC activity to ~90% in cells expressing KOP+MOP+NOP receptors. Chronic exposure to buprenorphine induced concentration-dependent AC superactivation in cells expressing KOP+NOP receptors, and the level of this superactivation was even higher in KOP+MOP+NOP-expressing cells. Our study demonstrated that MOP receptor could enhance AC regulation in the presence of coexpressed KOP and NOP receptors, and NOP receptor is essential for concentration-dependent AC superactivation elicited by chronic buprenorphine exposure.
doi:10.1111/jcmm.12644
PMCID: PMC4627564  PMID: 26153065
adenylate cyclase activity; buprenorphine; opioid receptors
10.  Workplace Violence and Job Performance among Community Healthcare Workers in China: The Mediator Role of Quality of Life 
Objective: To explore the impact of workplace violence on job performance and quality of life of community healthcare workers in China, especially the relationship of these three variables. Methods: From December 2013 to April 2014, a total of 1404 healthcare workers were recruited by using the random cluster sampling method from Community Health Centers in Guangzhou and Shenzhen. The workplace violence scale, the job performance scale and the quality of life scale (SF-36) were self-administered. The structural equation model constructed by Amos 17.0 was employed to assess the relationship among these variables. Results: Our study found that 51.64% of the respondents had an experience of workplace violence. It was found that both job performance and quality of life had a negative correlation with workplace violence. A positive association was identified between job performance and quality of life. The path analysis showed the total effect (β = −0.243) of workplace violence on job performance consisted of a direct effect (β = −0.113) and an indirect effect (β = −0.130), which was mediated by quality of life. Conclusions: Workplace violence among community healthcare workers is prevalent in China. The workplace violence had negative effects on the job performance and quality of life of CHCs’ workers. The study suggests that improvement in the quality of life may lead to an effective reduction of the damages in job performance caused by workplace violence.
doi:10.3390/ijerph121114872
PMCID: PMC4661685  PMID: 26610538
community healthcare worker; workplace violence; job performance; quality of life; mediator
11.  Tamm plasmon- and surface plasmon-coupled emission from hybrid plasmonic–photonic structures 
Optica  2014;1(6):407-413.
Photonic and plasmon-coupled emissions present new opportunities for control on light emission from fluorophores, and have many applications in the physical and biological sciences. The mechanism of and the influencing factors for the coupling between the fluorescent molecules and plasmon and/or photonic modes are active areas of research. In this paper, we describe a hybrid photonic–plasmonic structure that simultaneously contains two plasmon modes: surface plasmons (SPs) and Tamm plasmons (TPs), both of which can modulate fluorescence emission. Experimental results show that both SP-coupled emission (SPCE) and TP-coupled emission (TPCE) can be observed simultaneously with this hybrid structure. Due to the different resonant angles of the TP and SP modes, the TPCE and SPCE can be beamed in different directions and can be separated easily. Back focal plane images of the fluorescence emission show that the relative intensities of the SPCE and TPCE can be changed if the probes are at different locations inside the hybrid structure, which reveals the probe location-dependent different coupling strengths of the fluorescent molecules with SPs and TPs. The different coupling strengths are ascribed to the electric field distribution of the two modes in the structure. Here, we present an understanding of these factors influencing mode coupling with probes, which is vital for structure design for suitable applications in sensing and diagnostics.
doi:10.1364/OPTICA.1.000407
PMCID: PMC4626639  PMID: 26526929
12.  Metal–Dielectric Waveguides for High Efficiency Fluorescence Imaging 
We demonstrate that Metal–Dielectric Waveguide structures (MDWs) with high efficiency of fluorescence coupling can be suitable as substrates for fluorescence imaging. This hybrid MDWs consists of a continuous metal film and a dielectric top layer. The optical modes sustaining inside this structure can be excited with a high numerical aperture (N.A) objective, and then focused into a virtual optical probe with high intensity, leading to efficient excitation of fluorophores deposited on top of the MDWs. The emitted fluorophores couple with the optical modes thus enabling the directional emission, which is verified by the back focal plane (BFP) imaging. These unique properties of MDWs have been adopted in a scanning laser confocal optical microscopy, and show the merit of high efficiency fluorescence imaging. MDWs can be easily fabricated by vapor deposition and/or spin coating, the silica surface of the MDWs is suitable for biomolecule tethering, and will offer new opportunities for cell biology and biophysics research.
doi:10.1021/acs.jpcc.5b08582
PMCID: PMC4627712  PMID: 26525494
13.  Selectable Surface and Bulk Fluorescence Imaging with Plasmon-Coupled Waveguides 
In this letter, we propose a new method for selective imaging of surface bound probes or simultaneous imaging of surface bound plus fluorescence from dye molecules in bulk water solution. The principle of this method relies on use of two optical modes with different mode distributions, filed decay lengths and polarization states that are sustaining in a plasmon waveguide. The two modes with different decay lengths couple with dye molecules of different regions, at different distances from the PCW-water interface. The emission from two different regions occur as two coupled emission rings with different polarizations and emitting angles in the back focal plane (BFP) images. By using an electric-driven liquid crystal in BFP imaging, we selectively imaged surface or surface plus bulk fluorescence. Accordingly two coupled emissions can be switched ON or OFF independently, that are for either surface or bulk fluorescence imaging. Our work provides a new method for fluorescence imaging or sensing just by using a planar multilayer film, which may be a useful for fluorescence-based techniques in chemistry, materials science, molecular biology, and medicine.
doi:10.1021/acs.jpcc.5b06912
PMCID: PMC4626206  PMID: 26523158
14.  Extracting surface wave-coupled emission with subsurface dielectric gratings 
Optics letters  2014;39(15):4341-4344.
Conventional surface plasmons (SPs) or Bloch surface waves (BSWs) have a wave vector exceeding that of light in vacuum, and, therefore, the surface plasmon-coupled emission (SPCE) or Bloch surface wave-coupled emission (BSWCE) cannot escape from the corresponding structures. With the aid of a high-refractive-index prism or an oil-immersion objective, the SPCE or BSWCE can be coupled into free space. But the large volumes of the prism and objective are certainly unfavorable for miniaturization of the optical systems or inconvenient for applications such as the optical displays. Here we experimentally demonstrate a new method to extract the SPCE or BSWCE with a subsurface dielectric grating. The experimental results verify that the chip-like substrate with two decorated sides can bring out the directional fluorescence emission in free space. The emitting direction and emitting patterns can be tuned by the period size and dimensionality of the gratings. Our work provides a new strategy to realize free-space directional fluorescence emission at a very low cost and compact configuration, which has potential applications in fluorescence-based sensing, imaging, light-emitting diodes, optical displays, and other near-field optical devices.
PMCID: PMC4626216  PMID: 25078172
15.  Involvement of gelsolin in TGF-beta 1 induced epithelial to mesenchymal transition in breast cancer cells 
Background
Increasing evidence suggests that transforming growth factor-beta 1 (TGF-β1) triggers epithelial to mesenchymal transition (EMT) and facilitates breast cancer stem cell differentiation. Gelsolin (GSN) is a ubiquitous actin filament-severing protein. However, the relationship between the expression level of GSN and the TGF-β signaling for EMT progression in breast cancer cells is not clear.
Results
TGF-β1 acted on MDA-MB231 breast cancer cells by decreasing cell proliferation, changing cell morphology to a fibroblast-like shape, increasing expressions for CD44 and GSN, and increasing EMT expression and cell migration/invasion. Study with GSN overexpression (GSN op) in both MDA-MB231 and MCF-7 cells demonstrated that increased GSN expression resulted in alterations of cell proliferation and cell cycle progression, modification of the actin filament assembly associated with altering cell surface elasticity and cell detachment in these breast cancer cells. In addition, increased cell migration was found in GSN op MDA-MB231 cells. Studies with GSN op and silencing by small interfering RNA verified that GSN could modulate the expression of vimentin. Sorted by flow cytometry, TGF-β1 increased subpopulation of CD44+/CD22- cells increasing their expressions for GSN, Nanog, Sox2, Oct4, N-cadherin, and vimentin but decreasing the E-cadherin expression. Methylation specific PCR analysis revealed that TGF-β1 decreased 50 % methylation but increased 3-fold unmethylation on the GSN promoter in CD44+/CD22- cells. Two DNA methyltransferases, DNMT1and DNMT3B were also inhibited by TGF-β1.
Conclusions
TGF-β1 induced epigenetic modification of GSN could alter the EMT process in breast cancer cells.
doi:10.1186/s12929-015-0197-0
PMCID: PMC4615330  PMID: 26482896
GSN; TGF-β1; EMT; Methylation specific PCR; DNA methyltransferases
16.  Reduced Gut Acidity Induces an Obese-Like Phenotype in Drosophila melanogaster and in Mice 
PLoS ONE  2015;10(10):e0139722.
In order to identify genes involved in stress and metabolic regulation, we carried out a Drosophila P-element-mediated mutagenesis screen for starvation resistance. We isolated a mutant, m2, that showed a 23% increase in survival time under starvation conditions. The P-element insertion was mapped to the region upstream of the vha16-1 gene, which encodes the c subunit of the vacuolar-type H+-ATPase. We found that vha16-1 is highly expressed in the fly midgut, and that m2 mutant flies are hypomorphic for vha16-1 and also exhibit reduced midgut acidity. This deficit is likely to induce altered metabolism and contribute to accelerated aging, since vha16-1 mutant flies are short-lived and display increases in body weight and lipid accumulation. Similar phenotypes were also induced by pharmacological treatment, through feeding normal flies and mice with a carbonic anhydrase inhibitor (acetazolamide) or proton pump inhibitor (PPI, lansoprazole) to suppress gut acid production. Our study may thus provide a useful model for investigating chronic acid suppression in patients.
doi:10.1371/journal.pone.0139722
PMCID: PMC4593636  PMID: 26436771
17.  Chinese Herbal Medicines Might Improve the Long-Term Clinical Outcomes in Patients with Acute Coronary Syndrome after Percutaneous Coronary Intervention: Results of a Decision-Analytic Markov Model  
Aims. The priority of Chinese herbal medicines (CHMs) plus conventional treatment over conventional treatment alone for acute coronary syndrome (ACS) after percutaneous coronary intervention (PCI) was documented in the 5C trial (chictr.org number: ChiCTR-TRC-07000021). The study was designed to evaluate the 10-year effectiveness of CHMs plus conventional treatment versus conventional treatment alone with decision-analytic model for ACS after PCI. Methods and Results. We constructed a decision-analytic Markov model to compare additional CHMs for 6 months plus conventional treatment versus conventional treatment alone for ACS patients after PCI. Sources of data came from 5C trial and published reports. Outcomes were expressed in terms of quality-adjusted life years (QALYs). Sensitivity analyses were performed to test the robustness of the model. The model predicted that over the 10-year horizon the survival probability was 77.49% in patients with CHMs plus conventional treatment versus 77.29% in patients with conventional treatment alone. In combination with conventional treatment, 6-month CHMs might be associated with a gained 0.20% survival probability and 0.111 accumulated QALYs, respectively. Conclusions. The model suggested that treatment with CHMs, as an adjunctive therapy, in combination with conventional treatment for 6 months might improve the long-term clinical outcome in ACS patients after PCI.
doi:10.1155/2015/639267
PMCID: PMC4606398  PMID: 26495019
18.  Glycolytic inhibitor 2-deoxyglucose simultaneously targets cancer and endothelial cells to suppress neuroblastoma growth in mice 
Disease Models & Mechanisms  2015;8(10):1247-1254.
ABSTRACT
Neuroblastoma is characterized by a wide range of clinical manifestations and associated with poor prognosis when there is amplification of MYCN oncogene or high expression of Myc oncoproteins. In a previous in vitro study, we found that the glycolytic inhibitor 2-deoxyglucose (2DG) could suppress the growth of neuroblastoma cells, particularly in those with MYCN amplification. In this study, we established a mouse model of neuroblastoma xenografts with SK-N-DZ and SK-N-AS cells treated with 2DG by intraperitoneal injection twice a week for 3 weeks at 100 or 500 mg/kg body weight. We found that 2DG was effective in suppressing the growth of both MYCN-amplified SK-N-DZ and MYCN-non-amplified SK-N-AS neuroblastoma xenografts, which was associated with downregulation of HIF-1α, PDK1 and c-Myc, and a reduction in the number of tumor blood vessels. In vitro study showed that 2DG can suppress proliferation, cause apoptosis and reduce migration of murine endothelial cells, with inhibition of the formation of lamellipodia and filopodia and disorganization of F-actin filaments. The results suggest that 2DG might simultaneously target cancer cells and endothelial cells in the neuroblastoma xenografts in mice regardless of the status of MYCN amplification, providing a potential therapeutic opportunity to use 2DG or other glycolytic inhibitors for the treatment of patients with refractory neuroblastoma.
Drug Discovery Collection: Neuroblastomas are sensitive to treatment with the glycolytic inhibitor 2-deoxyglucose, which can simultaneously target cancer and endothelial cells to suppress tumor growth.
doi:10.1242/dmm.021667
PMCID: PMC4610240  PMID: 26398947
Neuroblastoma; 2-deoxyglucose; Xenograft; MYCN amplification; Endothelial cell
19.  The longitudinal epineural incision and complete nerve transection method for modeling sciatic nerve injury 
Neural Regeneration Research  2015;10(10):1663-1668.
Injury severity, operative technique and nerve regeneration are important factors to consider when constructing a model of peripheral nerve injury. Here, we present a novel peripheral nerve injury model and compare it with the complete sciatic nerve transection method. In the experimental group, under a microscope, a 3-mm longitudinal incision was made in the epineurium of the sciatic nerve to reveal the nerve fibers, which were then transected. The small, longitudinal incision in the epineurium was then sutured closed, requiring no stump anastomosis. In the control group, the sciatic nerve was completely transected, and the epineurium was repaired by anastomosis. At 2 and 4 weeks after surgery, Wallerian degeneration was observed in both groups. In the experimental group, at 8 and 12 weeks after surgery, distinct medullary nerve fibers and axons were observed in the injured sciatic nerve. Regular, dense myelin sheaths were visible, as well as some scarring. By 12 weeks, the myelin sheaths were normal and intact, and a tight lamellar structure was observed. Functionally, limb movement and nerve conduction recovered in the injured region between 4 and 12 weeks. The present results demonstrate that longitudinal epineural incision with nerve transection can stably replicate a model of Sunderland grade IV peripheral nerve injury. Compared with the complete sciatic nerve transection model, our method reduced the difficulties of micromanipulation and surgery time, and resulted in good stump restoration, nerve regeneration, and functional recovery.
doi:10.4103/1673-5374.167767
PMCID: PMC4660762  PMID: 26692866
nerve regeneration; peripheral nerve; sciatic nerve injury; animal models; longitudinal epineural incision; Sunderland IV; nerve regeneration and repair; rats; neural regenerati
20.  Exosomal levels of miRNA-21 from cerebrospinal fluids associated with poor prognosis and tumor recurrence of glioma patients 
Oncotarget  2015;6(29):26971-26981.
Glioma is a most common type of primary brain tumors. Extracellular vesicles, in the form of exosomes, are known to mediate cell–cell communication by transporting cell-derived proteins and nucleic acids, including various microRNAs (miRNAs). Here we examined the cerebrospinal fluid (CSF) from patients with recurrent glioma for the levels of cancer-related miRNAs, and evaluated the values for prognosis by comparing the measures of CSF-, serum-, and exosome-contained miR-21 levels. Samples from seventy glioma patients following surgery were compared with those from brain trauma patients as a non-tumor control group. Exosomal miR-21 levels in the CSF of glioma patients were found significantly higher than in the controls; whereas no difference was detected in serum-derived exosomal miR-21 expression. The CSF-derived exosomal miR-21 levels correlated with tumor spinal/ventricle metastasis and the recurrence with anatomical site preference. From additional 198 glioma tissue samples, we verified that miR-21 levels associated with tumor grade of diagnosis and negatively correlated with the median values of patient overall survival time. We further used a lentiviral inhibitor to suppress miR-21 expression in U251 cells. The results showed that the levels of miR-21 target genes of PTEN, RECK and PDCD4 were up-regulated at protein levels. Therefore, we concluded that the exosomal miR-21 levels could be demonstrated as a promising indicator for glioma diagnosis and prognosis, particularly with values to predict tumor recurrence or metastasis.
PMCID: PMC4694967  PMID: 26284486
extracellular vesicles; cerebrospinal fluid; hsa-mir-21; glioma; cancer prognosis
21.  Marital Status, Lifestyle and Dementia: A Nationwide Survey in Taiwan 
PLoS ONE  2015;10(9):e0139154.
Background
Evidence of an association between lifestyle and marital status and risk of dementia is limited in Asia.
Methods
In this nationwide population-based cross-sectional survey, participants were selected by computerized random sampling from all 19 counties in Taiwan. A total of 10432 residents were assessed by a door-to-door in-person survey, among whom 7035 were normal and 929 were diagnosed with dementia using the criteria recommended by National Institute on Aging-Alzheimer’s Association. Premorbid lifestyle habits and demographic data including marital status were compared between normal subjects and participants with dementia.
Results
After adjustment for age, gender, education, body mass index, smoking, drinking, marital status, sleep habits, exercise, social engagement and co-morbidities including hypertension, diabetes and cerebrovascular diseases, an increased risk for dementia was found in people with widow or widower status (OR 1.42, 95% CI 1.15–1.77) and people who used to take a nap in the afternoon (OR 1.33, 95% CI 1.02–1.72). Decreased risk was found in people with the habit of regular exercise (OR 0.12, 95% CI 0.09–0.16), adequate night sleep (OR 0.55, 95% CI 0.39–0.76) and regular social engagement (OR 0.53, 95% CI 0.36–0.77).
Conclusions
Our results provide preliminary evidence of possible risk-reduction effects for dementia, including regular exercise even in modest amounts, social engagement and adequate night sleep, whereas people with the widow/widower status or who used to take an afternoon nap might have increased risk of dementia.
doi:10.1371/journal.pone.0139154
PMCID: PMC4587383  PMID: 26413719
22.  Thrombin-induced microglial activation impairs hippocampal neurogenesis and spatial memory ability in mice 
Background
To investigate the effects of microglia/macrophages activation induced by intrastriatal thrombin injection on dentate gyrus neurogenesis and spatial memory ability in mice.
Methods
The male C57BL/6 mice were divided into 4 groups of 10: sham, intracerebral hemorrhage (ICH), ICH + hirudin (thrombin inhibitor), and ICH + indometacin (Indo, an anti-inflammation drug). ICH model was created by intrastriatal thrombin (1U) injection. BrdU (50 mg/kg) was administrated on the same day after surgery for 6 consecutive days. Motor functions were evaluated with rotarod and beam walking tests. The spatial memory deficit was measured with Morris water maze (MWM). Cell quantification was performed for doublecortin (DCX, immature neuron), BrdU (S-phase proliferating cell population) and CD68 (activated microglia/macrophage) immune-reactive cells.
Results
Microglia/macrophages activation induced by intrastriatal thrombin injection reduced hippocampal neurogenesis and impaired spatial memory ability, but did not affect the motor function at 3 and 5 days post-injury. Both hirudin and indometacin reduced microglia/macrophages activation, enhanced hippocampal neurogenesis, and improved spatial memory ability in mice.
Conclusions
Microglia/macrophages activation induced by intrastriatal thrombin injection might be responsible for the spatial memory deficit. Targeting both thrombin and inflammation systems in acute phase of ICH might be important in alleviating the significant spatial memory deficits.
doi:10.1186/s12993-015-0075-7
PMCID: PMC4584127  PMID: 26410080
Neurogenesis; Intrastriatal hemorrhage; Hirudin; Doublecortin; Microglia/macrophages; Spatial memory deficit
23.  Efficacy of acupuncture for chronic asthma: study protocol for a randomized controlled trial 
Trials  2015;16:424.
Background
Although asthma symptoms can be temporarily controlled, it is recommended to use effective low-risk, non-drug strategies to constitute a significant advance in asthma management. Acupuncture has been traditionally used to treat asthma; however, the evidence for the efficacy of this treatment is still lacking. Previous clinical trials of acupuncture in treating asthma were limited by methodological defects; therefore, high-quality research is required.
Methods/Design
This trial is designed as a multi-center, randomized, double-blind, parallel-group controlled trial. Patients with mild to moderate asthma will be randomly allocated to either a verum acupuncture plus as-needed salbutamol aerosol and/or prednisone tablets group or a sham acupuncture plus as-needed salbutamol aerosol and/or prednisone tablets group. Acupoints used in the verum acupuncture group are GV14 (Da Zhui), BL12 (Feng Men), BL13 (Fei Shu) and acupoints used in the sham acupuncture group are DU08 (Jin Suo), BL18 (Gan Shu), BL19 (Dan Shu). After a baseline period of 1 week, the patients in both groups will receive verum/sham acupuncture once every other day with a total of 20 treatment sessions in 6 weeks and a 3-month follow-up. The primary outcome will be measured by using the asthma control test and the secondary outcomes will be measured by using the percentage of symptom-free days, the average dosage of salbutamol aerosol and/or prednisone tablets, lung functions, daily asthma symptom scores, asthma quality of life questionnaire, and so on.
Discussion
This trial will assess the effect of acupuncture on asthma and aims to provide reliable clinical evidence for the efficacy of acupuncture in treating asthma.
Trial registration
ClinicalTrials.gov Identifier: NCT01931696, registered on 26 August 2013
doi:10.1186/s13063-015-0947-z
PMCID: PMC4581041  PMID: 26399399
Acupuncture; Chronic asthma; Efficacy; RCT; Study protocol
24.  Urban-Rural Differences in Cardiovascular Disease Risk Factors: A Cross-Sectional Study of Schoolchildren in Wuhan, China 
PLoS ONE  2015;10(9):e0137615.
Background
China’s rapid population growth and urban migration has developed healthcare inequity across the urban-rural divide. Past studies comparing cardiovascular disease (CVD) risk factor prevalence amongst urban-rural Chinese children are sparse and conflicting. We examined the association between urban-rural residence and risk of offspring CVD in Chinese children.
Methods
A cross-sectional study was conducted in Wuhan, China, during May and June 2010. CVD risk factors include; waist circumference (WC), systolic blood pressure (SBP), diastolic blood pressure (DBP), fasting blood glucose (FBG), triglycerides (TG), high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, body mass index (BMI), cardiorespiratory fitness (CRF), metabolic syndrome (MetS), and metabolic risk score (MRS). Analysis of covariance and multivariable logistic regression were used to estimate associations between urban-rural residence and offspring CVD risks.
Findings
A total of 579 Chinese children (338 boys and 241 girls) aged 9.6 (0.7) years participated in this study. Rural boys had significantly lower CRF and higher FBG, TG, and MRS, while urban boys had significantly higher LDL and DBP. Rural girls had significantly higher BMI, FBG, and TG, as well as lower CRF. Rural children were at increased risks for decreased CRF, elevated MRS, and TG, (OR:2.04, 95%CI:1.29–3.25), (OR:2.33, 95%CI:1.50–3.62), and (OR:2.40, 95%CI:1.62–3.57), respectively. Rural girls and mothers were at increased risks for overweight(OR:7.19, 95%CI:1.64–31.6)/obesity (OR:1.683, 95%CI:1.01–2.82). However, rural boys and fathers were less likely to have overweight(OR:0.62, 95%CI:0.34–1.12)/obesity (OR:0.68, 95%CI:0.48–0.97).
Conclusions
Rural residence was significantly associated with increased CVD risks amongst Chinese children. It is important to provide interventions aiming at China’s urban-rural healthcare inequity and community-based approaches that reduce familial CVD risk.
doi:10.1371/journal.pone.0137615
PMCID: PMC4564102  PMID: 26352586
25.  Development of a Efficient and Sensitive Dispersive Liquid–Liquid Microextraction Technique for Extraction and Preconcentration of 10 β2-Agonists in Animal Urine 
PLoS ONE  2015;10(9):e0137194.
Dispersive liquid–liquid microextraction (DLLME) coupled with ultra-performance liquid chromatography with tandem mass spectrometry (UPLC-MS/MS) was developed for the extraction and determination of 10 β2-agonists in animal urine. Some experimental parameters, such as the type and volume of the extraction solvent, the concentration of the dispersant, the salt concentration, the pH value of the sample solution, the extraction time and the speed of centrifugation, were investigated and optimized. Under the optimized conditions, a good enrichment factors (4.8 to 32.3) were obtained for the extraction. The enrichment factor show that the concentration rate of DLLME is significantly higher than other pretreatment methods, and the detection sensitivity has been greatly improved. The calibration curves were linear, the correlation coefficient ranged from 0.9928 to 0.9999 for the concentration range of 0.05 to 50 ngmL-1 and 0.1 to 50 ngmL-1, and the relative standard deviations (RSDs, n = 15, intra and inter-day precision) at a concentration of 5 ngmL-1 were in the range of 1.8 to 14.6%. The limits of detection (LODs) for the 10 β2-agonists, based on a signal-to-noise ratio (S/N) of 3, were in the range of 0.01 to 0.03 ngmL-1. The proposed method was used to identify β2-agonists in three types of animal urine (swine, cattle, sheep), and the relative recoveries from each matrix were in the range of 89.2 to 106.8%, 90.0 to 109.8% and 89.2 to 107.2%, respectively.
doi:10.1371/journal.pone.0137194
PMCID: PMC4562641  PMID: 26348922

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