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2.  Coxsackie and adenovirus receptor (CAR) is a modifier of cardiac conduction and arrhythmia vulnerability in the setting of myocardial ischemia 
Objectives
To investigate the modulatory effect of the Coxsackie and adenovirus receptor (CAR) on ventricular conduction and arrhythmia vulnerability in the setting of myocardial ischemia.
Background
A heritable component in risk for ventricular fibrillation (VF) during myocardial infarction (MI) has been well established. A recent genome-wide association study (GWAS) for VF during acute MI has led to the identification of a locus on chromosome 21q21 (rs2824292) in the vicinity of the CXADR gene. CXADR encodes the coxsackie and adenovirus receptor (CAR), a cell adhesion molecule predominantly located at intercalated discs of the cardiomyocyte.
Methods
The correlation between CAR transcript levels and rs2824292 genotype was investigated in human left ventricular samples. Electrophysiological studies and molecular analyses were performed CAR haploinsufficient mice (CAR+/−).
Results
In human left ventricular samples, the risk allele at the chr21q21 GWAS locus was associated with lower CXADR mRNA levels, suggesting that decreased cardiac levels of CAR predispose to ischemia-induced VF. Hearts from CAR+/− mice displayed ventricular conduction slowing in addition to an earlier onset of ventricular arrhythmias during the early phase of acute myocardial ischemia following LAD ligation. Connexin43 expression and distribution was unaffected, but CAR+/− hearts displayed increased arrhythmia susceptibility upon pharmacological electrical uncoupling. Patch-clamp analysis of isolated CAR+/− myocytes showed reduced sodium current magnitude specifically at the intercalated disc. Moreover, CAR co-precipitated with NaV1.5 in vitro, suggesting that CAR affects sodium channel function through a physical interaction with NaV1.5.
Conclusion
We identify CAR as a novel modifier of ventricular conduction and arrhythmia vulnerability in the setting of myocardial ischemia. Genetic determinants of arrhythmia susceptibility (such as CAR) may constitute future targets for risk stratification of potentially lethal ventricular arrhythmias in patients with coronary artery disease
doi:10.1016/j.jacc.2013.10.062
PMCID: PMC3926969  PMID: 24291282
arrhythmia; ventricular fibrillation; ischemia; single nucleotide polymorphism genetics; ion channels
3.  Repeatability and Reproducibility of a Double-Pass Optical Quality Analysis Device 
PLoS ONE  2015;10(2):e0117587.
Purpose
To evaluate the repeatability and reproducibility of a double-pass instrument (OQASII, Visiomereics SL, Spain), which objectively measures overall optical quality of the human eyes.
Methods
The right eye of 119 healthy subjects with best corrected visual acuity of 20/25 or better was included in this prospective, comparative, observational study. Two separate tests with OQASII were conducted sequentially on the same day by two different examiners. A week later, the first examiner conducted the third measurement. All subjects underwent three consecutive tests during each session. The repeatability and reproducibility of the modulation transfer function cut off frequency (MTF cutoff), the Strehl ratio, the OQAS values (OVs) at contrasts of 100%, 20% and 9%, and the objective scatter index (OSI) were analyzed.
Results
For MTF cutoff, Strehl ratio, OV100%, OV20%, OV9%, and OSI, the mean values were 39.32±9.75cpd, 0.22±0.06, 1.31±0.33, 1.33±0.39, 1.33±0.41, 0.60±0.42, respectively. Repeatability and reproducibility were good with a very low coefficient of variation and high interclass correlation coefficients (>0.88) for all parameters. Bland-Altman plots showed good correlation with 95% limits of agreement ranged from -6.04 to 6.78cpd, -0.05 to 0.05, -0.20 to 0.23, -0.29 to 0.32, -0.40 to 0.42, -0.23 to 0.21 in inter-observer, and -6.56 to 7.42cpd, -0.06 to 0.06, -0.22 to 0.24, -0.30 to 0.32, -0.35 to 0.34, -0.24 to 0.23 in inter-visit, respectively.
Conclusion
The OQASII system yields excellent repeatability and good reproducibility for objective measurements of overall optical quality in clinic.
doi:10.1371/journal.pone.0117587
PMCID: PMC4315520  PMID: 25646846
4.  NLRP1 inflammasome is activated in patients with medial temporal lobe epilepsy and contributes to neuronal pyroptosis in amygdala kindling-induced rat model 
Background
Temporal lobe epilepsy (TLE) is often characterized pathologically by severe neuronal loss in the hippocampus. Understanding the mechanisms of neuron death is key to preventing the neurodegeneration associated with TLE. However, the involvement of neuronal loss to the epileptogenic process has yet to be fully determined. Recent studies have shown that the activation of NLRP1 can generate a functional caspase-1-containing inflammasome in vivo to drive the proinflammatory programmed cell death termed ‘pyroptosis’, which has a key role in the pathogenesis of neurological disorders. To the best of our knowledge, there are no reported studies that performed detailed identification and validation of NLRP1 inflammasome during the epileptogenic process.
Methods
We first compared expression of NLRP1 and caspase-1 in resected hippocampus from patients with intractable mesial temporal lobe epilepsy (mTLE) with that of matched control samples. To further examine whether the activation of NLRP1 inflammasome contributes to neuronal pyroptosis, we employed a nonviral strategy to knock down the expression of NLRP1 and caspase-1 in the amygdala kindling-induced rat model. Proinflammatory cytokines levels and hippocampal neuronal loss were evaluated after 6 weeks of treatment in these NLRP1 or caspase-1 deficiency TLE rats.
Results
Western blotting detected upregulated NLRP1 levels and active caspase-1 in mTLE patients in comparison to those levels seen in the controls, suggesting a role for this inflammasome in mTLE. Moreover, we employed direct in vivo infusion of nonviral small interfering RNA to knockdown NLRP1 or caspase-1 in the amygdala kindling-induced rat model, and discovered that these NLRP1 or caspase-1 silencing rats resulted in significantly reduced neuronal pyroptosis.
Conclusions
Our data suggest that NLRP1/caspase-1 signaling participates in the seizure-induced degenerative process in humans and in the animal model of TLE and points to the silencing of NLRP1 inflammasome as a promising strategy for TLE therapy.
Electronic supplementary material
The online version of this article (doi:10.1186/s12974-014-0233-0) contains supplementary material, which is available to authorized users.
doi:10.1186/s12974-014-0233-0
PMCID: PMC4314732  PMID: 25626361
NLRP1; pyroptosis; inflammasome; Caspase-1; temporal lobe epilepsy
5.  The Arabidopsis SWI2/SNF2 Chromatin Remodeler BRAHMA Regulates Polycomb Function during Vegetative Development and Directly Activates the Flowering Repressor Gene SVP 
PLoS Genetics  2015;11(1):e1004944.
The chromatin remodeler BRAHMA (BRM) is a Trithorax Group (TrxG) protein that antagonizes the functions of Polycomb Group (PcG) proteins in fly and mammals. Recent studies also implicate such a role for Arabidopsis (Arabidopsis thaliana) BRM but the molecular mechanisms underlying the antagonism are unclear. To understand the interplay between BRM and PcG during plant development, we performed a genome-wide analysis of trimethylated histone H3 lysine 27 (H3K27me3) in brm mutant seedlings by chromatin immunoprecipitation followed by next generation sequencing (ChIP-seq). Increased H3K27me3 deposition at several hundred genes was observed in brm mutants and this increase was partially supressed by removal of the H3K27 methyltransferase CURLY LEAF (CLF) or SWINGER (SWN). ChIP experiments demonstrated that BRM directly binds to a subset of the genes and prevents the inappropriate association and/or activity of PcG proteins at these loci. Together, these results indicate a crucial role of BRM in restricting the inappropriate activity of PcG during plant development. The key flowering repressor gene SHORT VEGETATIVE PHASE (SVP) is such a BRM target. In brm mutants, elevated PcG occupancy at SVP accompanies a dramatic increase in H3K27me3 levels at this locus and a concomitant reduction of SVP expression. Further, our gain- and loss-of-function genetic evidence establishes that BRM controls flowering time by directly activating SVP expression. This work reveals a genome-wide functional interplay between BRM and PcG and provides new insights into the impacts of these proteins in plant growth and development.
Author Summary
In flowering plants, the proper transition from vegetative growth to flowering is critical for their reproductive success and must be controlled precisely. Multiple genes have been shown to regulate the floral transition in response to environmental and endogenous cues. Among them is SHORT VEGETATIVE PHASE (SVP), a key flowering repressor gene in Arabidopsis. SVP is highly expressed during the vegetative phase to promote growth, but the mechanism by which the high expression level of SVP is maintained remains unknown. Here, we report a genome-wide study to examine the functional interplay between the BRM chromatin remodeler and the PcG proteins that catalyze trimethylation of lysine 27 on histone H3 (H3K27me3), a histone mark normally associated with transcriptionally repressed genes. We identify BRM as a direct upstream activator of SVP. BRM acts to keep the levels of H3K27me3 low at the SVP locus by inhibiting the binding and activities of the PcG proteins. Thus, our work identifies a previously unknown mechanism in regulation of flowering time and demonstrates the power of genome-wide approaches in dissecting regulatory networks controlling plant development.
doi:10.1371/journal.pgen.1004944
PMCID: PMC4304717  PMID: 25615622
6.  Employment and financial burden of families with preschool children diagnosed with autism spectrum disorders in urban China: results from a descriptive study 
BMC Psychiatry  2015;15:3.
Background
Autism spectrum disorder (ASD) affects many aspects of family life, such as social and economic burden. Little investigation of this phenomenon has been carried out in China. We designed this study to evaluate the employment and financial burdens of families with ASD-diagnosed preschoolers.
Methods
Four hundred and fifty-nine nuclear families of children with ASD, 418 with some other disability (OD) and 424 with typically developing (TD) children were recruited for this study. Employment and financial burdens of families were evaluated using a structured questionnaire; logistic regression was used to examine differences in job change measures by group, and ordinal logistic regression was used to investigate the association between household income and group.
Results
Fifty-eight percent of families with ASD children and 19% of families with OD children reported that childcare problems had greatly affected their employment decisions, compared with 9% of families with TD children (p < 0.001). Age of child, parental education and parental age notwithstanding, having a child with ASD and having a child with OD were both associated with increased odds of reporting that childcare greatly interfered with employment (ASD, OR: 15.936; OD, OR: 2.502; all p < 0.001) and decreased the odds of living in a higher-income household (ASD, estimate = -1.271; OD, estimate = -0.569; all p < 0.001). The average loss of annual income associated with having a child with ASD was Chinese RenMinBi (RMB) 44,077 ($7,226), compared with RMB 20,788 ($3,408) for families of OD children.
Conclusions
ASD is associated with severe employment and financial burdens, much more than for OD, in families with preschool children.
doi:10.1186/s12888-015-0382-4
PMCID: PMC4307683  PMID: 25608486
Employment burden; Financial burden; Autism spectrum disorder; Chinese
7.  STK33 overexpression in hypopharyngeal squamous cell carcinoma: possible role in tumorigenesis 
BMC Cancer  2015;15:13.
Background
The role of serine/threonine kinase 33 (STK33) gene in tumorigenesis is still controversial. This study was aimed to investigate whether STK33 had the effect on hypopharyngeal squamous cell carcinoma (HSCC) and relevant genes, as well as the potential relation to ERK1/2 pathway.
Methods
Immunohistochemistry was performed to investigate STK33 expression in human HSCC specimens. MTT, immunofluorescence, clone formation and matrigel invasion assays were employed to detect the effects of STK33 knockdown (STK33-RNAi) and/or PD98059 on major oncogenic properties of a HSCC cell line (Fadu), while, real-time PCR and western blot were used to examine the expressions of relevant genes.
Results
STK33 was over-expressed in HSCC specimens, which was significantly associated with certain clinicopathological parameters. STK33-RNAi in Fadu cells resulted in inhibition of proliferation, induction of apoptosis, reduction of clone formation, and decline in the migration and invasion. These effects were potentiated by administration of PD98059. Mechanistic studies revealed that STK33-RNAi led to an increase in Caspse-3, Nm-23-H1 and E-Cadherin expressions and a reduction in Bcl-2, Ki-67 and Vimentin expressions. Moreover, PD98059 significantly reduced both ERK1/2 and STK33 expressions in Fadu cells.
Conclusions
STK33 is a potential oncogene and a promising diagnostic marker for HSCC. STK33 may promote tumorigenesis and progression of HSCC, and serve as a valuable molecular target for treatment of HSCC.
doi:10.1186/s12885-015-1009-3
PMCID: PMC4305229  PMID: 25603720
Serine/threonine kinase 33; Fadu cells; ERK1/2; Tumorigenesis
8.  Pretreatment platelet count as a predictor for survival and distant metastasis in nasopharyngeal carcinoma patients 
Oncology Letters  2015;9(3):1458-1466.
The aim of the present study was to investigate the prognostic value of different pretreatment platelet (PLT) counts on the treatment outcome in nasopharyngeal carcinoma (NPC) patients receiving concurrent chemoradiotherapy (CCRT) or radiotherapy (RT) alone. A total of 1,501 NPC patients, including 412 receiving CCRT and 1,089 receiving RT, were enrolled in the present study. The PLT count cut-off points for the CCRT and RT groups were 150 and 300×109/l, respectively, and the PLT counts were categorized it into three groups: Low (PLT≤150×109/l), moderate (150×109/l300×109/l). To identify independent predictors of overall survival (OS), the Cox proportional hazards model was used to determine local-regional recurrence-free survival (LRFS) and distant metastasis-free survival (DMFS) rates in the CCRT and RT patients. Furthermore, univariate and multivariate analysis indicated that compared with a moderate PLT count, a low PLT count was an independent unfavorable prognostic factor for OS rate in CCRT patients [hazard ratio (HR), 2.024; 95% confidence interval (CI), 1.165–3.516], and a high PLT count was an independent unfavorable prognostic factor for OS and DMFS rates in CCRT (OS: HR, 1.742; 95% CI, 1.090–2.786; DFMS: HR, 2.110; 95%CI, 1.084–4.108) and RT (OS: HR, 1.740; 95%CI, 1.283–2.362; DMFS: HR, 2.819; 95% CI, 1.766–4.497) patients. Compared with a low PLT count, a high PLT count was significantly and independently associated with a poor DMFS rate in the RT patients (P=0.025; HR, 2.454; 95% CI, 1.121–5.372). Therefore, the present study indicates that low and high PLT counts may be useful indicators of survival and distant metastasis in NPC patients who have undergone radiation treatment.
doi:10.3892/ol.2015.2872
PMCID: PMC4314978  PMID: 25663931
platelet count; nasopharyngeal carcinoma; radiotherapy; concurrent chemoradiotherapy; predictor; prognosis
9.  Lewis Carroll's Doublets Net of English Words: Network Heterogeneity in a Complex System 
PLoS ONE  2014;9(12):e114177.
Lewis Carroll's English word game Doublets is represented as a system of networks with each node being an English word and each connectivity edge confirming that its two ending words are equal in letter length, but different by exactly one letter. We show that this system, which we call the Doublets net, constitutes a complex body of linguistic knowledge concerning English word structure that has computable multiscale features. Distributed morphological, phonological and orthographic constraints and the language's local redundancy are seen at the node level. Phonological communities are seen at the network level. And a balancing act between the language's global efficiency and redundancy is seen at the system level. We develop a new measure of intrinsic node-to-node distance and a computational algorithm, called community geometry, which reveal the implicit multiscale structure within binary networks. Because the Doublets net is a modular complex cognitive system, the community geometry and computable multi-scale structural information may provide a foundation for understanding computational learning in many systems whose network structure has yet to be fully analyzed.
doi:10.1371/journal.pone.0114177
PMCID: PMC4269387  PMID: 25517974
10.  Inhibition of the NLRP3 inflammasome provides neuroprotection in rats following amygdala kindling-induced status epilepticus 
Background
NLRP3 inflammasome is proposed to regulate inflammation in several neurological diseases, but its role in epilepsy remains largely unknown. This study aimed to investigate the role of the NLRP3 inflammasome in neuroinflammation, spontaneous recurrent seizures (SRS) and hippocampal neuronal loss in rat brain following amygdala kindling-induced status epilepticus (SE).
Methods
We detected the protein levels of IL-1β and NLRP3 inflammasome components by Western blot in the hippocampus of shams and SE rats at different time points following SE. To further examine whether the activation of the NLRP3 inflammasome contributes to SE-associated neuronal damage, we employed a nonviral strategy to knock down NLRP3 and caspase-1 expression in brain before undergoing SE. Proinflammatory cytokine levels and hippocampal neuronal loss were evaluated at 12 hours and at 6 weeks following SE respectively in these NLRP3 and caspase-1 deficient rats. Meanwhile, SRS occurrence was evaluated through a 4-week video recording started 2 weeks after SE in these NLRP3 and caspase-1 deficient rats.
Results
IL-1β levels and NLRP3 inflammasome components levels dramatically increased at 3 hours after SE, and reached a maximum at 12 hours after SE compared with the control group. Knock down of NLRP3 or caspase-1 decreased the levels of IL-1β and IL-18 at 12 hours after SE, which was accompanied by a significant suppression in the development and severity of SRS during the chronic epileptic phase. Meanwhile, knock down of NLRP3 or caspase-1 led to a remarkable reduction of hippocampal neuronal loss in the CA1 and CA3 area of the hippocampus at 6 weeks after SE.
Conclusions
Our study provides the first evidence that the NLRP3 inflammasome was significantly up-regulated following SE. More importantly, we show that inhibition of the NLRP3 inflammasome provides neuroprotection in rats following SE. These findings suggest that NLRP3 may represent a potential target for the treatment of epileptogenesis
Electronic supplementary material
The online version of this article (doi:10.1186/s12974-014-0212-5) contains supplementary material, which is available to authorized users.
doi:10.1186/s12974-014-0212-5
PMCID: PMC4275944  PMID: 25516224
NLRP3; Inflammasome; Status epilepticus; Cytokine; IL-1β; IL-18; Caspase-1; Neuroinflammation; Spontaneous recurrent seizures; Hippocampal neuronal loss
11.  Generation and characterization of spiking and non-spiking oligodendroglial progenitor cells from embryonic stem cells 
Stem cells (Dayton, Ohio)  2013;31(12):2620-2631.
Pluripotent stem cells (PSCs) have been differentiated into oligodendroglial progenitor cells (OPCs), providing promising cell replacement therapies for many CNS disorders. Studies from rodents have shown that brain OPCs express a variety of ion channels, and that a subset of brain OPCs express voltage-gated sodium channel (NaV), mediating the spiking properties of OPCs. However, it is unclear whether PSC-derived OPCs exhibit electrophysiological properties similar to brain OPCs and the role of NaV in the functional maturation of OPCs is unknown. Here, using a mouse embryonic stem cell (mESC) GFP-Olig2 knockin reporter line, we demonstrated that unlike brain OPCs, all of the GFP+/Olig2+ mESC-derived OPCs (mESC-OPCs) did not express functional NaV and failed to generate spikes (hence termed “non-spiking mESC-OPCs”), while expressing the delayed rectifier and inactivating potassium currents. By ectopically expressing NaV1.2 α subunit via viral transduction, we successfully generated mESC-OPCs with spiking properties (termed “spiking mESC-OPCs”). After transplantation into the spinal cord and brain of myelin-deficient shiverer mice, the spiking mESC-OPCs demonstrated better capability in differentiating into MBP expressing oligodendrocytes and in myelinating axons in vivo than the non-spiking mESC-OPCs. Thus, by generating spiking and non-spiking mESC-OPCs, this study reveals a novel function of NaV in OPCs in their functional maturation and myelination, and sheds new light on ways to effectively develop PSC-derived OPCs for future clinical applications.
doi:10.1002/stem.1515
PMCID: PMC3923867  PMID: 23940003
Embryonic stem cell; oligodendroglial progenitor cell; voltage-gated ion channel; action potential; myelination
13.  Comparison of a Novel Computerized Analysis Program and Visual Interpretation of Cardiotocography 
PLoS ONE  2014;9(12):e112296.
Objective
To compare a novel computerized analysis program with visual cardiotocography (CTG) interpretation results.
Methods
Sixty-two intrapartum CTG tracings with 20- to 30-minute sections were independently interpreted using a novel computerized analysis program, as well as the visual interpretations of eight obstetricians, to evaluate the baseline fetal heart rate (FHR), baseline FHR variability, number of accelerations, number/type of decelerations, uterine contraction (UC) frequency, and the National Institute of Child Health and Human Development (NICHD) 3-Tier FHR classification system.
Results
There was no significant difference in interobserver variation after adding the components of computerized analysis to results from the obstetricians' visual interpretations, with excellent agreement for the baseline FHR (ICC 0.91), the number of accelerations (ICC 0.85), UC frequency (ICC 0.97), and NICHD category I (kappa statistic 0.91); good agreement for baseline variability (kappa statistic 0.68), the numbers of early decelerations (ICC 0.78) and late decelerations (ICC 0.67), category II (kappa statistic 0.78), and overall categories (kappa statistic 0.80); and moderate agreement for the number of variable decelerations (ICC 0.60), and category III (kappa statistic 0.50).
Conclusions
This computerized analysis program is not inferior to visual interpretation, may improve interobserver variations, and could play a vital role in prenatal telemedicine.
doi:10.1371/journal.pone.0112296
PMCID: PMC4249819  PMID: 25437442
14.  Predictive factors of cardiac rupture in patients with ST-elevation myocardial infarction*  
Cardiac rupture (CR) is a potentially fatal mechanical complication of ST-elevation myocardial infarction (STEMI). We aimed to determine the incidence and risk factors of CR in Chinese STEMI patients. A total of 9798 consecutive STEMI patients from four centers in China were retrospectively analyzed, among which 178 patients had CR. STEMI patients without CR were chosen as a control group. Clinical characteristics were compared between STEMI patients with CR and those without CR. The incidence of CR in STEMI patients was 1.82%, and the 30-d mortality was up to 61.2%. CR patients were significantly older, more female, and associated with a longer time from onset of pain to hospital admission than their non-CR counterparts (P<0.001). More patients with anterior myocardial infarction (82.1%) were found in the CR group, and CR patients had significantly higher heart rates than the control group ((91±19) bpm vs. (71±16) bpm; P<0.001). In multiple-adjusted models, the independent risk factors of CR were advanced age, female gender, anaemia, increased heart rate, anterior myocardial infarction, increased white blood cell (WBC) count, delayed admission, and renal dysfunction. The level of hemoglobin remained a significant determinant factor of CR (OR (95% CI): 0.82 (0.75–0.89); P<0.001) after adjusting for various potential confounding factors. Counts of WBC also remained a significant determinant of the CR (OR (95% CI): 1.08 (1.04–1.12); P<0.001). A number of variables were independently related to CR. This study indicated, for the first time, that both hemoglobin and WBC levels were independently correlated with occurrence of CR.
doi:10.1631/jzus.B1400095
PMCID: PMC4265559  PMID: 25471834
ST-elevation myocardial infarction; Risk factor; Anaemia; Cardiac rupture
15.  Genome-wide ChIP-seq analysis of TCF4 binding regions in colorectal cancer cells 
Objective: TCF4 (transcriptional factor 4) forms a complex with its transcriptional coactivator β-catenin and the coactivator carries the final signal output from the canonical Wnt signaling pathway, which is essential for the growth of normal epithelium and also plays important roles in carcinogenesis of colon epithelium. We aimed to gain a better understanding of the genes bound by TCF4 in colorectal cancer cells. Methods: SW620 human colorectal cancer cells were cultured. The TCF4 antibody of this study was confirmed in SW620 cells by Western Blot. A ChIP-seq based genome-wide analysis of TCF4 chromatin occupancy in colorectal cancer cells was conducted and 1506 high confidence TCF4 binding sites wereidentified. Results: Sequence analysis revealed that the binding sites harbor a consensus sequence of C-G/C-A-G-C-T/C-C-T-T-C. Gene ontology and pathway analysis showed that TCF4 regulated 18 genes in Wnt signaling pathway and 97 other transcription factors. Conclusion: Our results suggest TCF4 binding regions were enriched with a motif of C-G/C-A-G-C-T/C-C-T-T-C. The gene regulation of TCF4 may be conserved in colorectal cancer and glioma cells. TCF4 may be involved in a series of important biological processes such as regulation of metabolic and biosynthetic (GO: 0010604, GO: 0031328, GO: 0009891, GO: 0051173, GO: 0010557, GO: 0045935), adhesion (GO: 0007155, GO: 0022610), apoptosis (GO: 0042981, GO: 0043067, GO: 0010941), and important signaling pathways (Wnt, Chemokine, Calciu, GnRH).
PMCID: PMC4276198  PMID: 25550940
TCF4; ChIP-seq; colorectal cancer; Wnt signaling pathway
16.  Nuclear translocation of telomerase reverse transcriptase is a critical process in lymphatic metastasis of nasopharyngeal carcinoma 
Oncology Letters  2014;9(1):265-269.
Telomerase reverse transcriptase (TERT) is the predominant functional unit of telomerase and maintains the telomere length and the stability of chromosomes. Recently, TERT has been shown to be a critical factor in a number of other biological processes, including cell proliferation and cancer metastasis. In addition, although numerous studies have been conducted, the subcellular localization of the TERT protein and the association of such with cancer metastasis remains unclear. To investigate the involvement of TERT in in vivo metastasis, quantum dots-based immunofluorescence and western blot analysis were conducted to detect changes in the subcellular localization of TERT in human nasopharyngeal carcinoma (NPC) tissues and metastatic lymph nodes. To further investigate, metastatic and non-metastatic models of NPC were generated using 5–8F (high metastasis capability) and 6–10B (low metastasis capability) cell lines, respectively. It was found that TERT protein was overexpressed in NPC tissue samples and metastatic lymph nodes and TERT was predominantly located in the cytoplasm of primary NPC tissues, while TERT was predominantly located in the nucleus of the metastatic lymph nodes. The ratio of cytoplasmic TERT/nuclear TERT for the primary tumor of the 6–10B cell line was almost six-fold higher than that of the metastatic lymph nodes of the 5–8F cell line. TERT translocation from the cytoplasm to nucleus may present a critical step in the lymphatic metastasis of NPC. Thus, TERT translocation may be more useful than TERT expression level and telomerase activity for predicting the metastasis of NPC.
doi:10.3892/ol.2014.2689
PMCID: PMC4246691  PMID: 25435972
nasopharyngeal carcinoma; metastasis; translocation; telomerase reverse transcriptase
17.  Derivation and Validation of Diagnostic Thresholds for Central Blood Pressure Measurements Based on Long-Term Cardiovascular Risks 
Journal of the American College of Cardiology  2013;62(19):10.1016/j.jacc.2013.06.029.
Objectives
This study sought to derive and validate outcome-driven thresholds of central blood pressure (CBP) for diagnosing hypertension.
Background
Current guidelines for managing patients with hypertension mainly rely on blood pressure (BP) measured at brachial arteries (cuff BP). However, BP measured at the central aorta (central BP [CBP]) may be a better prognostic factor for predicting future cardiovascular events than cuff BP.
Methods
In a derivation cohort (1,272 individuals and a median follow-up of 15 years), we determined diagnostic thresholds for CBP by using current guideline-endorsed cutoffs for cuff BP with a bootstrapping (resampling by drawing randomly with replacement) and an approximation method. To evaluate the discriminatory power in predicting cardiovascular outcomes, the derived thresholds were tested in a validation cohort (2,501 individuals with median follow-up of 10 years).
Results
The 2 analyses yielded similar diagnostic thresholds for CBP. After rounding, systolic/diastolic threshold was 110/80 mm Hg for optimal BP and 130/90 mm Hg for hypertension. Compared with optimal BP, the risk of cardiovascular mortality increased significantly in subjects with hypertension (hazard ratio: 3.08, 95% confidence interval: 1.05 to 9.05). Of the multivariate Cox proportional hazards model, incorporation of a dichotomous variable by defining hypertension as CBP ≥130/90 mm Hg was associated with the largest contribution to the predictive power.
Conclusions
CBP of 130/90 mm Hg was determined to be the cutoff limit for normality and was characterized by a greater discriminatory power for long-term events in our validation cohort. This report represents an important step toward the application of the CBP concept in clinical practice.
doi:10.1016/j.jacc.2013.06.029
PMCID: PMC3884552  PMID: 23850921
central blood pressure; diagnostic thresholds; high blood pressure; hypertension
18.  Sclerotium rolfsii Lectin Induces Stronger Inhibition of Proliferation in Human Breast Cancer Cells than Normal Human Mammary Epithelial Cells by Induction of Cell Apoptosis 
PLoS ONE  2014;9(11):e110107.
Sclerotium rolfsii lectin (SRL) isolated from the phytopathogenic fungus Sclerotium rolfsii has exquisite binding specificity towards O-linked, Thomsen-Freidenreich (Galβ1-3GalNAcα1-Ser/Thr, TF) associated glycans. This study investigated the influence of SRL on proliferation of human breast cancer cells (MCF-7 and ZR-75), non-tumorigenic breast epithelial cells (MCF-10A) and normal mammary epithelial cells (HMECs). SRL caused marked, dose-dependent, inhibition of proliferation of MCF-7 and ZR-75 cells but only weak inhibition of proliferation of non-tumorigenic MCF-10A and HMEC cells. The inhibitory effect of SRL on cancer cell proliferation was shown to be a consequence of SRL cell surface binding and subsequent induction of cellular apoptosis, an effect that was largely prevented by the presence of inhibitors against caspases -3, -8, or -9. Lectin histochemistry using biotin-labelled SRL showed little binding of SRL to normal human breast tissue but intense binding to cancerous tissues. In conclusion, SRL inhibits the growth of human breast cancer cells via induction of cell apoptosis but has substantially less effect on normal epithelial cells. As a lectin that binds specifically to a cancer-associated glycan, has potential to be developed as an anti-cancer agent.
doi:10.1371/journal.pone.0110107
PMCID: PMC4217719  PMID: 25364905
19.  The relationship between cholesterol and cognitive function is homocysteine-dependent 
Introduction
Previous studies have identified hyperlipidemia as a potential risk factor for dementia and Alzheimer’s disease. However, studies on cholesterol measured in late-life and cognitive function have been inconsistent. Few studies have explored nonlinear relationships or considered interactions with other biomarker measures.
Methods
A cross-sectional sample of 1,889 participants from four rural counties in the People’s Republic of China was included in this analysis. Serum total cholesterol, high-density lipoprotein, triglycerides, and homocysteine levels were measured in fasting blood samples. A composite cognitive score was derived based on nine standardized cognitive test scores. Analysis of covariance models were used to investigate the association between biomarker measures and the composite cognitive scores.
Results
There was a significant interaction between the homocysteine quartile group and the cholesterol quartile group on cognitive scores (P=0.0478). In participants with normal homocysteine levels, an inverse U-shaped relationship between total cholesterol level and cognitive score was found, indicating that both low and high cholesterol levels were associated with lower cognitive scores. In participants with high homocysteine levels, no significant association between cholesterol and cognition was found.
Conclusion
The relationship between cholesterol levels and cognitive function depends upon homocysteine levels, suggesting an interactive role between cholesterol and homocysteine on cognitive function in the elderly population. Additional research is required to confirm our findings in other populations, and to explore potential mechanisms underlying the lipid–homocysteine interaction.
doi:10.2147/CIA.S64766
PMCID: PMC4211868  PMID: 25364240
cholesterol; homocysteine; cognitive function
20.  Arsenite-induced ROS/RNS generation causes zinc loss and inhibits the activity of poly (ADP-ribose) polymerase-1 
Arsenic enhances genotoxicity of other carcinogenic agents such as ultraviolet radiation and benzo[a]pyrene. Recent reports suggest that inhibition of DNA repair is an important aspect of arsenic co-carcinogenesis, and DNA repair proteins such as poly (ADP ribose) polymerase (PARP)-1 are direct molecular targets of arsenic. Although arsenic has been shown to generate reactive oxygen/nitrogen species (ROS/RNS), little is known about the role of arsenic-induced ROS/RNS in the mechanism underlying arsenic inhibition of DNA repair. We report herein that arsenite-generated ROS/RNS inhibits PARP-1 activity in cells. Cellular exposure to arsenite, as well as hydrogen peroxide and NONOate (nitric oxide donor), decreased PARP-1 zinc content, enzymatic activity, and PARP-1 DNA binding. Furthermore, the effects of arsenite on PARP-1 activity, DNA binding, and zinc content were partially reversed by the antioxidant ascorbic acid, catalase, and the NOS inhibitor, aminoguanidine. Most importantly, arsenite incubation with purified PARP-1 protein in vitro did not alter PARP-1 activity or DNA binding ability, whereas hydrogen peroxide or NONOate retained PARP-1 inhibitory activity. These results strongly suggest that cellular generation of ROS/RNS plays an important role in arsenite inhibition of PARP-1 activity, leading to the loss of PARP-1 DNA binding ability and enzymatic activity.
doi:10.1016/j.freeradbiomed.2013.04.019
PMCID: PMC3766412  PMID: 23602911
arsenic; PARP-1; ROS; RNS
21.  Biomarkers for cancer-related fatigue and adverse reactions to chemotherapy in lung cancer patients 
Molecular and Clinical Oncology  2014;3(1):163-166.
This study was conducted to investigate the biomarkers that appear to be correlated with cancer-related fatigue (CRF) and the adverse reactions (ADRs) to chemotherapy. A total of 100 lung cancer patients were selected and CRF prior to and following chemotherapy was evaluated. The plasma levels of tumor necrosis factor (TNF)-α and interleukin (IL)-1 and the level of 17-hydroxycorticosteroid (17-OHCS) in the urine were analyzed and correlated with CRF and the ADRs associated with chemotherapy. The incidence of CRF was found to be 88.0% and ADRs following chemotherapy occurred in 15.0% of the patients. An increase in the TNF-α and IL-1 levels was detected in patients with CRF. The level of 17-OHCS in the urine was found to be elevated in cases that experienced ADRs following chemotherapy. In conclusion, CRF is closely correlated with increased plasma levels of TNF-α and IL-1. Furthermore, an abnormally elevated 17-OHCS level in the urine may be an important indicator predicting ADR development following chemotherapy.
doi:10.3892/mco.2014.439
PMCID: PMC4251268  PMID: 25469288
lung cancer; cancer-related fatigue; adverse reactions to chemotherapy; tumor necrosis factor-α; interleukin 1; 17-hydroxycorticosteroid
22.  Manipulation of KLF4 Expression Generates iPSCs Paused at Successive Stages of Reprogramming 
Stem Cell Reports  2014;3(5):915-929.
Summary
The detailed mechanism of reprogramming somatic cells into induced pluripotent stem cells (iPSCs) remains largely unknown. Partially reprogrammed iPSCs are informative and useful for understanding the mechanism of reprogramming but remain technically difficult to generate in a predictable and reproducible manner. Using replication-defective and persistent Sendai virus (SeVdp) vectors, we analyzed the effect of decreasing the expression levels of OCT4, SOX2, KLF4, and c-MYC and found that low KLF4 expression reproducibly gives rise to a homogeneous population of partially reprogrammed iPSCs. Upregulation of KLF4 allows these cells to resume reprogramming, indicating that they are paused iPSCs that remain on the path toward pluripotency. Paused iPSCs with different KLF4 expression levels remain at distinct intermediate stages of reprogramming. This SeVdp-based stage-specific reprogramming system (3S reprogramming system) is applicable for both mouse and human somatic cells and will facilitate the mechanistic analysis of reprogramming.
Graphical Abstract
Highlights
•Reducing KLF4 expression generates partially reprogrammed cells•Different KLF4 levels produce iPSCs stably paused at distinct stages of reprogramming•Upregulation of KLF4 allows paused iPSCs to resume reprogramming•Homogenous populations of paused iPSCs are generated predictably and reproducibly
In this article, Hisatake, Nishimura, and colleagues report an SeVdp-based vector system that generates partially reprogrammed iPSCs by the precise control of the KLF4 expression level via an FKBP-derived degradation domain and Shield1. The system generates homogeneous populations of partially reprogrammed iPSCs stably paused at distinct stages of reprogramming and is applicable for both mouse and human somatic cells.
doi:10.1016/j.stemcr.2014.08.014
PMCID: PMC4235142  PMID: 25418733
23.  Screening of Duchenne Muscular Dystrophy (DMD) Mutations and Investigating Its Mutational Mechanism in Chinese Patients 
PLoS ONE  2014;9(9):e108038.
Duchenne muscular dystrophy (DMD) is a common X-linked recessive disease of muscle degeneration and death. In order to provide accurate and reliable genetic counseling and prenatal diagnosis, we screened DMD mutations in a cohort of 119 Chinese patients using multiplex ligation-dependent probe amplification (MLPA) and denaturing high performance liquid chromatography (DHPLC) followed by Sanger sequencing. In these unrelated DMD patients, we identified 11 patients with DMD small mutations (9.2%) and 81 patients with DMD deletions/duplications (del/dup) (68.1%), of which 64 (79.0%) were deletions, 16 (19.8%) were duplications, and one (1.2%) was both deletion and duplication. Furthermore, we analyzed the frequency of DMD breakpoint in the 64 deletion cases by calculating exon-deletion events of certain exon interval that revealed a novel mutation hotspot boundary. To explore why DMD rearrangement breakpoints were predisposed to specific regions (hotspot), we precisely characterized junction sequences of breakpoints at the nucleotide level in 21 patients with exon deleted/duplicated in DMD with a high-resolution SNP microarray assay. There were no exactly recurrent breakpoints and there was also no significant difference between single-exon del/dup and multiple-exon del/dup cases. The data from the current study provided a comprehensive strategy to detect DMD mutations for clinical practice, and identified two deletion hotspots at exon 43–55 and exon 10–23 by calculating exon-deletion events of certain exon interval. Furthermore, this is the first study to characterize DMD breakpoint at the nucleotide level in a Chinese population. Our observations provide better understanding of the mechanism for DMD gene rearrangements.
doi:10.1371/journal.pone.0108038
PMCID: PMC4171529  PMID: 25244321
24.  Effect of the Herbal Drug Guilu Erxian Jiao on Muscle Strength, Articular Pain, and Disability in Elderly Men with Knee Osteoarthritis 
Background. Guilu Erxian Jiao (GEJ) is a widely used Chinese herbal remedy for knee osteoarthritis, but its clinical efficacy is unknown. Methods. We enrolled 42 elderly male patients with knee OA, including 21 patients who received the herbal drug GEJ as the case group and 21 patients who did not receive GEJ as the control group. The effects of 12 weeks of GEJ treatment on muscle strength of lower limbs were measured by a Biodex dynamometer, with disability evaluated on the Lequesne index and articular pain measured on the visual analog scale (VAS) between the two groups on the baseline and after treatment. Results. There were significant increases in the levels of muscle strength of TQ/BW-ext-dominant and TQ/BW-flex-dominant between the two groups after treatment (P < 0.05). There were also significant increases in muscle strength of knee extensor muscles in the GEJ-treated group (n = 21) self-controlled before and after 12 weeks of treatment (all P < 0.01). There were significant decreases in articular pain (P < 0.01) and Lequesne index scores (P < 0.01) in the GEJ-treated group when compared to the non-GEJ-treated group. Conclusions. Our results showed that GEJ is effective and is tolerated well in elderly men with knee OA.
doi:10.1155/2014/297458
PMCID: PMC4182023  PMID: 25309612
25.  Distribution and Functional Expression of Kv4 Family α Subunits and Associated KChIP β Subunits in the Bed Nucleus of the Stria Terminalis 
Regulation of BNSTALG neuronal firing activity is tightly regulated by the opposing actions of the fast outward potassium current, IA, mediated by α subunits of the Kv4 family of ion channels, and the transient inward calcium current, IT. Together, these channels play a critical role in regulating the latency to action potential onset, duration, and frequency, as well as dendritic back-propagation and synaptic plasticity. Previously we have shown that Type I–III BNSTALG neurons express mRNA transcripts for each of the Kv4 α subunits. However, the biophysical properties of native IA channels are critically dependent on the formation of macromolecular complexes of Kv4 channels with a family of chaperone proteins, the potassium channel-interacting proteins (KChIP1–4). Here we used a multidisciplinary approach to investigate the expression and function of Kv4 channels and KChIPs in neurons of the rat BNSTALG. Using immunofluorescence we demonstrated the pattern of localization of Kv4.2, Kv4.3, and KChIP1–4 proteins in the BNSTALG. Moreover, our single-cell reverse-transcription polymerase chain reaction (scRT-PCR) studies revealed that mRNA transcripts for Kv4.2, Kv4.3, and all four KChIPs were differentially expressed in Type I–III BNSTALG neurons. Furthermore, immunoelectron microscopy revealed that Kv4.2 and Kv4.3 channels were primarily localized to the dendrites and spines of BNSTALG neurons, and are thus ideally situated to modulate synaptic transmission. Consistent with this observation, in vitro patch clamp recordings showed that reducing postsynaptic IA in these neurons lowered the threshold for long-term potentiation (LTP) induction. These results are discussed in relation to potential modulation of IA channels by chronic stress.
doi:10.1002/cne.23435
PMCID: PMC4154538  PMID: 24037673
patch clamp; LTP; single cell RT-PCR; electron microscopy; voltage-dependent potassium channel

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