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1.  Mutation of the RDR1 gene caused genome-wide changes in gene expression, regional variation in small RNA clusters and localized alteration in DNA methylation in rice 
BMC Plant Biology  2014;14:177.
Background
Endogenous small (sm) RNAs (primarily si- and miRNAs) are important trans/cis-acting regulators involved in diverse cellular functions. In plants, the RNA-dependent RNA polymerases (RDRs) are essential for smRNA biogenesis. It has been established that RDR2 is involved in the 24 nt siRNA-dependent RNA-directed DNA methylation (RdDM) pathway. Recent studies have suggested that RDR1 is involved in a second RdDM pathway that relies mostly on 21 nt smRNAs and functions to silence a subset of genomic loci that are usually refractory to the normal RdDM pathway in Arabidopsis. Whether and to what extent the homologs of RDR1 may have similar functions in other plants remained unknown.
Results
We characterized a loss-of-function mutant (Osrdr1) of the OsRDR1 gene in rice (Oryza sativa L.) derived from a retrotransposon Tos17 insertion. Microarray analysis identified 1,175 differentially expressed genes (5.2% of all expressed genes in the shoot-tip tissue of rice) between Osrdr1 and WT, of which 896 and 279 genes were up- and down-regulated, respectively, in Osrdr1. smRNA sequencing revealed regional alterations in smRNA clusters across the rice genome. Some of the regions with altered smRNA clusters were associated with changes in DNA methylation. In addition, altered expression of several miRNAs was detected in Osrdr1, and at least some of which were associated with altered expression of predicted miRNA target genes. Despite these changes, no phenotypic difference was identified in Osrdr1 relative to WT under normal condition; however, ephemeral phenotypic fluctuations occurred under some abiotic stress conditions.
Conclusions
Our results showed that OsRDR1 plays a role in regulating a substantial number of endogenous genes with diverse functions in rice through smRNA-mediated pathways involving DNA methylation, and which participates in abiotic stress response.
doi:10.1186/1471-2229-14-177
PMCID: PMC4083042  PMID: 24980094
Gene expression; Epigenetics; Small RNA; DNA methylation; RDR1; Oryza sativa L
2.  Targeting of erbB3 receptor to overcome resistance in cancer treatment 
Molecular Cancer  2014;13:105.
The erbB receptors, including the epidermal growth factor receptor (EGFR), erbB2 (also known as HER2/neu), erbB3 (or HER3), and erbB4 (or HER4), are often aberrantly activated in a wide variety of human cancers. They are excellent targets for selective anti-cancer therapies because of their transmembrane location and pro-oncogenic activity. While several therapeutic agents against erbB2 and/or EGFR have been used in the treatment of human cancers with efficacy, there has been relatively less emphasis on erbB3 as a molecular target. Elevated expression of erbB3 is frequently observed in various malignancies, where it promotes tumor progression via interactions with other receptor tyrosine kinases (RTKs) due to its lack of or weak intrinsic kinase activity. Studies on the underlying mechanisms implicate erbB3 as a major cause of treatment failure in cancer therapy, mainly through activation of the PI-3 K/Akt, MEK/MAPK, and Jak/Stat signaling pathways as well as Src kinase. It is believed that inhibition of erbB3 signaling may be required to overcome therapeutic resistance and effectively treat cancers. To date, no erbB3-targeted therapy has been approved for cancer treatment. Targeting of erbB3 receptor with a monoclonal antibody (Ab) is the only strategy currently under preclinical study and clinical evaluation. In this review, we focus on the role of erbB3-initiated signaling in the development of cancer drug resistance and discuss the latest advances in identifying therapeutic strategies inactivating erbB3 to overcome the resistance and enhance efficacy of cancer therapeutics.
doi:10.1186/1476-4598-13-105
PMCID: PMC4022415  PMID: 24886126
erbB3; Cell signaling; Drug resistance; Targeted therapy; Cancer
3.  Regulation of Endothelial Progenitor Cell Release by Wnt Signaling in Bone Marrow 
Purpose.
Endothelial progenitor cells (EPC) have been shown to participate in ischemia-induced retinal neovascularization (NV). Overactivation of Wnt signaling has a pathogenic role in ischemia-induced retinal NV. The purpose of this study is to determine whether Wnt signaling regulates EPC release.
Methods.
Oxygen-induced retinopathy (OIR) was used as a model of retinal NV and Wnt pathway activation. The EPC, marked as c-Kit+/Tie-2+ cells in the peripheral blood and bone marrow, were quantified using flow cytometry following immunolabeling. The Wnt signaling activity was evaluated by measuring nonphosphorylated β-catenin levels and X-gal staining in the Wnt reporter mice (Bat-gal mice).
Results.
The c-Kit+/Tie-2+ cells were increased significantly in the peripheral blood and bone marrow of mice with OIR, compared to non-OIR mice. Overexpression of kallistatin, an endogenous inhibitor of the Wnt pathway, in kallistatin transgenic (kallistatin-TG) mice with OIR attenuated the increases of c-Kit+/Tie-2+ cells in the peripheral blood and bone marrow, compared to WT mice with OIR. When the Bat-gal mice were crossed with kallistatin-TG mice, kallistatin overexpression suppressed the OIR-induced increases of X-gal–positive cells in the retinas and bone marrow, suggesting inhibition of Wnt signaling in these tissues. Furthermore, intraperitoneal injection of LiCl, a Wnt signaling activator, increased c-Kit+/Tie-2+ cells in the peripheral blood of normal mice. Consistently, LiCl activated Wnt signaling in the retina and bone marrow cells in Bat-gal mice.
Conclusions.
The Wnt signaling pathway has an important role in EPC release during retinal NV in OIR.
The canonical Wnt pathway has regulatory role in release of EPC.
doi:10.1167/iovs.13-13163
PMCID: PMC3825569  PMID: 24130179
EPC; bone marrow; peripheral blood; retina; Wnt
4.  Validation of a Novel Clinical Prediction Score for Severe Coronary Artery Diseases before Elective Coronary Angiography 
PLoS ONE  2014;9(4):e94493.
Objectives
Coronary artery disease (CAD) severity is associated with patient prognosis. However, few efficient scoring systems have been developed to screen severe CAD in patients with stable angina and suspected CAD before coronary angiography. Here, we present a novel scoring system for CAD severity before elective coronary angiography.
Methods
Five hundred fifty-one patients with stable angina who were admitted for coronary angiography were enrolled in this study. Patients were divided into training (n = 347) and validation (n = 204) cohorts. Severe CAD was defined as having a Gensini score of 20 or more. All patients underwent echocardiography (ECG) to detect ejection fraction and aortic valve calcification (AVC). Multivariable analysis was applied to determine independent risk factors and develop the scoring system.
Results
In the training cohort, age, male sex, AVC, abnormal ECG, diabetes, hyperlipidemia, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol were identified as independent factors for severe CAD by multivariable analysis, and the Severe Prediction Scoring (SPS) system was developed. C-indices of receiver operating characteristic (ROC) curves for severe CAD were 0.744 and 0.710 in the training and validation groups, respectively. The SPS system also performed well during calibration, as demonstrated by Hosmer-Lemeshow analysis in the validation group. Compared with the Diamond-Forrester score, the SPS system performed better for severe CAD prediction before elective coronary angiography.
Conclusions
Severe CAD prediction was achieved by analyzing age, sex, AVC, ECG, diabetes status, and lipid levels. Angina patients who achieve high scores using this predicting system should undergo early coronary angiography.
doi:10.1371/journal.pone.0094493
PMCID: PMC3979855  PMID: 24714416
5.  Nitrosative Stress Plays an Important Role in Wnt Pathway Activation in Diabetic Retinopathy 
Antioxidants & Redox Signaling  2013;18(10):1141-1153.
Abstract
Aims: Diabetes is associated with nitrosative stress in multiple tissues. Overactivation of the Wnt pathway has been shown to play a pathogenic role in diabetic retinopathy (DR). The purpose of this study was to investigate whether nitrosative stress contributes to aberrant activation of Wnt signaling in diabetes. Results: Nitrosative stress induced by peroxynitrite (PN), 4-hydroxynonenal (HNE), or high glucose (HG) in retinal cells was assessed by a dichlorofluorescein fluorescence assay or by Western blot analysis and enzyme-linked immunosorbent assay of 3-nitrotyrosine (3-NT). These nitrosative stress inducers activated the canonical Wnt pathway, as shown by Western blot analysis of phosphorylated low-density lipoprotein receptor-related protein 6 (pLRP6), total and nuclear β-catenin levels, Luciferase reporter assay, and expression of the Wnt target genes intercellular adhesion molecule 1 (ICAM-1) and vascular endothelial growth factor (VEGF). Uric acid (UA), a PN scavenger, and 5,10,15,20-Tetrakis (4-sulfonatophenyl) porphyrinato Iron III Chloride (FeTPPS), a PN decomposition catalyst, suppressed Wnt signaling and ICAM-1 and VEGF overexpression induced by PN, HNE, and HG. Furthermore, UA and FeTPPS also inhibited Wnt signaling induced by the Wnt ligand. In streptozotocin-induced diabetic rats, retinal levels of 3-NT, β-catenin, nuclear β-catenin, pLRP6, VEGF, and ICAM-1 were markedly increased. UA treatment for 6 weeks ameliorated diabetes-induced Wnt signaling in the diabetic rat retina. The UA treatment also decreased inflammatory cell infiltration and extraverted serum albumin in the perfused retina of diabetic rats, suggesting decreased retinal inflammation and vascular leakage. Innovation and Conclusion: Nitrosative stress in diabetes contributes to Wnt pathway activation in the retina, and Wnt signaling may mediate the pathogenic effects of nitrosative stress in DR. Antioxid. Redox Signal. 18, 1141–1153.
doi:10.1089/ars.2012.4583
PMCID: PMC3579458  PMID: 23066786
6.  Construction of a SSR-Based Genetic Map and Identification of QTLs for Catechins Content in Tea Plant (Camellia sinensis) 
PLoS ONE  2014;9(3):e93131.
Catechins are the most important bioactive compounds in tea, and have been demonstrated to possess a wide variety of pharmacological activities. To characterize quantitative trait loci (QTLs) for catechins content in the tender shoots of tea plant, we constructed a moderately saturated genetic map using 406 simple sequence repeat (SSR) markers, based on a pseudo-testcross population of 183 individuals derived from an intraspecific cross of two Camellia sinensis varieties with diverse catechins composition. The map consisted of fifteen linkage groups (LGs), corresponding to the haploid chromosome number of tea plant (2n = 2x = 30). The total map length was 1,143.5 cM, with an average locus spacing of 2.9 cM. A total of 25 QTLs associated with catechins content were identified over two measurement years. Of these, nine stable QTLs were validated across years, and clustered into four main chromosome regions on LG03, LG11, LG12 and LG15. The population variability explained by each QTL was predominantly at moderate-to-high levels and ranged from 2.4% to 71.0%, with an average of 17.7%. The total number of QTL for each trait varied from four to eight, while the total population variability explained by all QTLs for a trait ranged between 38.4% and 79.7%. This is the first report on the identification of QTL for catechins content in tea plant. The results of this study provide a foundation for further cloning and functional characterization of catechin QTLs for utilization in improvement of tea plant.
doi:10.1371/journal.pone.0093131
PMCID: PMC3968092  PMID: 24676054
7.  A Disposable Blood Cyanide Sensor 
Analytica chimica acta  2013;768:129-135.
Deaths due to smoke inhalation in fires are often due to poisoning by HCN. Rapid administration of antidotes can result in complete resuscitation of the patient but judicious dosing requires the knowledge of the level of cyanide exposure. Rapid sensitive means for blood cyanide quantitation are needed. Hydroxocyanocobinamide (OH(CN)Cbi) reacts with cyanide rapidly; this is accompanied by a large spectral change. The disposable device consists of a pair of nested petri dish bottoms and a single top that fits the outer bottom dish. The top cover has a diametrically strung porous polypropylene membrane tube filled with aqueous OH(CN)Cbi. One end of the tube terminates in an amber (583 nm) light emitting diode; the other end in a photodiode via an acrylic optical fiber. An aliquot of the blood sample is put in the inner dish, the assembly covered and acid is added through a port in the cover. Evolved HCN diffuses into the OH(CN)Cbi solution and the absorbance in the long path porous membrane tube cell is measured within 160s. The LOD was 0.047, 1.0, 0.15, 5.0 and 2.2 μM, respectively, for water (1 mL), bovine blood (100 μL, 1 mL), and rabbit blood (20μL, 50 μL). RSDs were < 10% in all cases and the linear range extended from 0.5 to 200 μM. The method was validated against a microdiffusion approach and applied to the measurement of cyanide in rabbit and human blood. The disposable device permits field measurement of blood cyanide in < 4 min.
doi:10.1016/j.aca.2013.01.029
PMCID: PMC3596829  PMID: 23473259
Porous membrane; HCN; Cobinamide; Liquid Core Waveguide
8.  A methodological, systematic review of evidence-based independent risk factors for surgical site infections after spinal surgery 
European Spine Journal  2012;22(3):605-615.
Objective
To identify the independent risk factors, based on available evidence in the literature, for patients developing surgical site infections (SSI) after spinal surgery.
Methods
Non-interventional studies evaluating the independent risk factors for patients developing SSI following spinal surgery were searched in Medline, Embase, Sciencedirect and OVID. The quality of the included studies was assessed by a modified quality assessment tool that had been previously designed for observational studies. The effects of studies were combined with the study quality score using a best-evidence synthesis model.
Results
Thirty-six observational studies involving 2,439 patients with SSI after spinal surgery were identified. The included studies covered a wide range of indications and surgical procedures. These articles were published between 1998 and 2012. According to the quality assessment criteria for included studies, 15 studies were deemed to be high-quality studies, 5 were moderate-quality studies, and 16 were low-quality studies. A total of 46 independent factors were evaluated for risk of SSI. There was strong evidence for six factors, including obesity/BMI, longer operation times, diabetes, smoking, history of previous SSI and type of surgical procedure. We also identified 8 moderate-evidence, 31 limited-evidence and 1 conflicting-evidence factors.
Conclusion
Although there is no conclusive evidence for why postoperative SSI occurs, these data provide evidence to guide clinicians in admitting patients who will have spinal operations and to choose an optimal prophylactic strategy. Further research is still required to evaluate the effects of these above risk factors.
doi:10.1007/s00586-012-2514-6
PMCID: PMC3585628  PMID: 23001381
Surgical site infection; Spinal surgery; Postoperative infection; Risk factors; Systematic review
9.  Medaka fish, Oryzias latipes, as a model for human obesity-related glomerulopathy 
Obesity, an ongoing significant public health problem, is a part of complex disease characterized as metabolic syndrome. Medaka and zebrafish are useful aquatic experimental animals widely used in the field of toxicology and environmental health sciences and as a human disease models. In medaka, simple feeding of a high fat diet (HFD) can induce body weight gain, excessive accumulation of visceral adipose tissue, hyperglycemia, hyperlipidemia, and steatohepatists, which mimics human metabolic syndrome. In the present study, to explore the possibility that the adult medaka fed with HFD (HFD-medaka) can be used as an animal model for human metabolic syndrome-associated glomerular disease, including obesity-related glomerulopathy (ORG), we analyzed structural alterations and protein expression in the mesonephric kidney of HFD-medaka. We found that the histopathology was consistent with glomerulomegaly accompanied by the dilation of glomerular capillaries and proliferative expansion of the mesangium, a condition partially comparable to human ORG. Moreover, expressions of several kinds of kidney disease-related proteins (such as MYH9, SM22α) were significantly elevated. Thus, the HFD-medaka has a high potential as an animal model useful for exploring the mechanism underling human ORG.
doi:10.1016/j.bbrc.2013.01.053
PMCID: PMC3587682  PMID: 23353086
high fat diet; glomerulus; medaka; obesity-related glomerulopathy
11.  A network-assisted co-clustering algorithm to discover cancer subtypes based on gene expression 
BMC Bioinformatics  2014;15:37.
Background
Cancer subtype information is critically important for understanding tumor heterogeneity. Existing methods to identify cancer subtypes have primarily focused on utilizing generic clustering algorithms (such as hierarchical clustering) to identify subtypes based on gene expression data. The network-level interaction among genes, which is key to understanding the molecular perturbations in cancer, has been rarely considered during the clustering process. The motivation of our work is to develop a method that effectively incorporates molecular interaction networks into the clustering process to improve cancer subtype identification.
Results
We have developed a new clustering algorithm for cancer subtype identification, called “network-assisted co-clustering for the identification of cancer subtypes” (NCIS). NCIS combines gene network information to simultaneously group samples and genes into biologically meaningful clusters. Prior to clustering, we assign weights to genes based on their impact in the network. Then a new weighted co-clustering algorithm based on a semi-nonnegative matrix tri-factorization is applied. We evaluated the effectiveness of NCIS on simulated datasets as well as large-scale Breast Cancer and Glioblastoma Multiforme patient samples from The Cancer Genome Atlas (TCGA) project. NCIS was shown to better separate the patient samples into clinically distinct subtypes and achieve higher accuracy on the simulated datasets to tolerate noise, as compared to consensus hierarchical clustering.
Conclusions
The weighted co-clustering approach in NCIS provides a unique solution to incorporate gene network information into the clustering process. Our tool will be useful to comprehensively identify cancer subtypes that would otherwise be obscured by cancer heterogeneity, using high-throughput and high-dimensional gene expression data.
doi:10.1186/1471-2105-15-37
PMCID: PMC3916445  PMID: 24491042
Cancer subtype; Clustering; Gene expression
12.  Finding the missing honey bee genes: lessons learned from a genome upgrade 
BMC Genomics  2014;15:86.
Background
The first generation of genome sequence assemblies and annotations have had a significant impact upon our understanding of the biology of the sequenced species, the phylogenetic relationships among species, the study of populations within and across species, and have informed the biology of humans. As only a few Metazoan genomes are approaching finished quality (human, mouse, fly and worm), there is room for improvement of most genome assemblies. The honey bee (Apis mellifera) genome, published in 2006, was noted for its bimodal GC content distribution that affected the quality of the assembly in some regions and for fewer genes in the initial gene set (OGSv1.0) compared to what would be expected based on other sequenced insect genomes.
Results
Here, we report an improved honey bee genome assembly (Amel_4.5) with a new gene annotation set (OGSv3.2), and show that the honey bee genome contains a number of genes similar to that of other insect genomes, contrary to what was suggested in OGSv1.0. The new genome assembly is more contiguous and complete and the new gene set includes ~5000 more protein-coding genes, 50% more than previously reported. About 1/6 of the additional genes were due to improvements to the assembly, and the remaining were inferred based on new RNAseq and protein data.
Conclusions
Lessons learned from this genome upgrade have important implications for future genome sequencing projects. Furthermore, the improvements significantly enhance genomic resources for the honey bee, a key model for social behavior and essential to global ecology through pollination.
doi:10.1186/1471-2164-15-86
PMCID: PMC4028053  PMID: 24479613
Apis mellifera; GC content; Gene annotation; Gene prediction; Genome assembly; Genome improvement; Genome sequencing; Repetitive DNA; Transcriptome
13.  Microbial synthesized biodegradable PHBHHxPEG hybrid copolymer as an efficient intracellular delivery nanocarrier for kinase inhibitor 
BMC Biotechnology  2014;14:4.
Background
Protein Kinases are key regulators of cell function and play essential roles in the occurrence and development of many human diseases. Many kinase inhibitors have been used for molecular targeted treatment of those diseases such as cancer and inflammation. However, those highly hydrophobic kinase inhibitors shared the common features of poor bioavailability and limited in vivo half-life, which strongly impeded their practical applications. Our previous study demonstrated that microbial synthesized biodegradable polyester poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) (PHBHHx), a member of polyhydroxyalkanoates (PHAs) family, could serve as a promising delivery nanocarrier for those hydrophobic kinase inhibitors. Recently, a novel natural synthesized hybrid copolymer, PEG200 end-capped PHBHHx (PHBHHxPEG) was produced by Aeromonas hydrophila fermentation. In this study, the novel PHBHHxPEG NPs were prepared and investigated to serve as intracellular delivery nanocarriers for sustained release of hydrophobic kinase inhibitors.
Results
PHBHHxPEG nanoparticles (NPs) prepared by an emulsification–solvent evaporation method were spherical with a diameter around 200 nm. The entrapment efficiency on rapamycin in PHBHHxPEG NPs was 91.9% and the sustained release of rapamycin from PHBHHxPEG NPs could be achieved for almost 10 days. The cellular uptake of PHBHHxPEG NPs was significant higher than that of PHBHHx NPs. The anti-proliferation effect and mTOR inhibition ability of rapamycin-loaded PHBHHxPEG NPs was stronger than that of drug-loaded PHBHHx NPs and free rapamycin.
Conclusions
PHBHHxPEG NPs could achieve the efficient entrapment and sustained release of rapamycin. The novel biodegradable PHBHHxPEG appeared a promising nanocarrier for sustained delivery of hydrophobic kinase inhibitors with improved cellular uptake and kinase inhibition efficiency.
doi:10.1186/1472-6750-14-4
PMCID: PMC3909372  PMID: 24438107
Polyhydroxyalkanoate; PEG; Rapamycin; Nanoparticle; Drug delivery
14.  Therapeutic Effects of PPARα Agonists on Diabetic Retinopathy in Type 1 Diabetes Models 
Diabetes  2012;62(1):261-272.
Retinal vascular leakage, inflammation, and neovascularization (NV) are features of diabetic retinopathy (DR). Fenofibrate, a peroxisome proliferator–activated receptor α (PPARα) agonist, has shown robust protective effects against DR in type 2 diabetic patients, but its effects on DR in type 1 diabetes have not been reported. This study evaluated the efficacy of fenofibrate on DR in type 1 diabetes models and determined if the effect is PPARα dependent. Oral administration of fenofibrate significantly ameliorated retinal vascular leakage and leukostasis in streptozotocin-induced diabetic rats and in Akita mice. Favorable effects on DR were also achieved by intravitreal injection of fenofibrate or another specific PPARα agonist. Fenofibrate also ameliorated retinal NV in the oxygen-induced retinopathy (OIR) model and inhibited tube formation and migration in cultured endothelial cells. Fenofibrate also attenuated overexpression of intercellular adhesion molecule-1, monocyte chemoattractant protein-1, and vascular endothelial growth factor (VEGF) and blocked activation of hypoxia-inducible factor-1 and nuclear factor-κB in the retinas of OIR and diabetic models. Fenofibrate’s beneficial effects were blocked by a specific PPARα antagonist. Furthermore, Pparα knockout abolished the fenofibrate-induced downregulation of VEGF and reduction of retinal vascular leakage in DR models. These results demonstrate therapeutic effects of fenofibrate on DR in type 1 diabetes and support the existence of the drug target in ocular tissues and via a PPARα-dependent mechanism.
doi:10.2337/db11-0413
PMCID: PMC3526044  PMID: 23043158
15.  Personalized Ovarian Cancer Disease Surveillance and Detection of Candidate Therapeutic Drug Target in Circulating Tumor DNA12 
Neoplasia (New York, N.Y.)  2014;16(1):97-103.
Retrospective studies have demonstrated that nearly 50% of patients with ovarian cancer with normal cancer antigen 125 (CA125) levels have persistent disease; however, prospectively distinguishing between patients is currently impossible. Here, we demonstrate that for one patient, with the first reported fibroblast growth factor receptor 2 (FGFR2) fusion transcript in ovarian cancer, circulating tumor DNA (ctDNA) is a more sensitive and specific biomarker than CA125, and it can also inform on a candidate therapeutic. For a 4-year period, during which the patient underwent primary debulking surgery and chemotherapy, tumor recurrences, and multiple chemotherapeutic regimens, blood samples were longitudinally collected and stored. Whereas postsurgical CA125 levels were elevated only three times for 28 measurements, the FGFR2 fusion ctDNA biomarker was readily detectable by quantitative real-time reverse transcription-polymerase chain reaction (PCR) in all of these same blood samples and in the tumor recurrences. Given the persistence of the FGFR2 fusion, we treated tumor cells derived from this patient and others with the FGFR2 inhibitor BGJ398. Only tumor cells derived from this patient were sensitive to FGFR2 inhibitor treatment. Using the same methodologic approach, we demonstrate in a second patient with a different fusion that PCR and agarose gel electrophoresis can also be used to identify tumor-specific DNA in the circulation. Taken together, we demonstrate that a relatively inexpensive, PCR-based ctDNA surveillance assay can outperform CA125 in identifying occult disease.
PMCID: PMC3924545  PMID: 24563622
16.  hERG Potassium Channel Blockage by Scorpion Toxin BmKKx2 Enhances Erythroid Differentiation of Human Leukemia Cells K562 
PLoS ONE  2013;8(12):e84903.
Background
The hERG potassium channel can modulate the proliferation of the chronic myelogenous leukemic K562 cells, and its role in the erythroid differentiation of K562 cells still remains unclear.
Principal Findings
The hERG potassium channel blockage by a new 36-residue scorpion toxin BmKKx2, a potent hERG channel blocker with IC50 of 6.7±1.7 nM, enhanced the erythroid differentiation of K562 cells. The mean values of GPA (CD235a) fluorescence intensity in the group of K562 cells pretreated by the toxin for 24 h and followed by cytosine arabinoside (Ara-C) treatment for 72 h were about 2-fold stronger than those of K562 cells induced by Ara-C alone. Such unique role of hERG potassium channel was also supported by the evidence that the effect of the toxin BmKKx2 on cell differentiation was nullified in hERG-deficient cell lines. During the K562 cell differentiation, BmKKx2 could also suppress the expression of hERG channels at both mRNA and protein levels. Besides the function of differentiation enhancement, BmKKx2 was also found to promote the differentiation-dependent apoptosis during the differentiation process of K562 cells. In addition, the blockage of hERG potassium channel by toxin BmKKx2 was able to decrease the intracellular Ca2+ concentration during the K562 cell differentiation, providing an insight into the mechanism of hERG potassium channel regulating this cellular process.
Conclusions/Significance
Our results revealed scorpion toxin BmKKx2 could enhance the erythroid differentiation of leukemic K562 cells via inhibiting hERG potassium channel currents. These findings would not only accelerate the functional research of hERG channel in different leukemic cells, but also present the prospects of natural scorpion toxins as anti-leukemic drugs.
doi:10.1371/journal.pone.0084903
PMCID: PMC3873423  PMID: 24386436
17.  How long is the interval of onsets of bilateral retinoblastoma? 
doi:10.3980/j.issn.2222-3959.2013.06.29
PMCID: PMC3874537  PMID: 24392346
18.  A Pilot Study Comparing the Development of EIAV Env-Specific Antibodies Induced by DNA/Recombinant Vaccinia-Vectored Vaccines and an Attenuated Chinese EIAV Vaccine 
Viral Immunology  2012;25(6):477-484.
Abstract
Data from successful attenuated lentiviral vaccine studies indicate that fully mature Env-specific antibodies characterized by high titer, high avidity, and the predominant recognition of conformational epitopes are associated with protective efficacy. Although vaccination with a DNA prime/recombinant vaccinia-vectored vaccine boost strategy has been found to be effective in some trials with non-human primate/simian/human immunodeficiency virus (SHIV) models, it remains unclear whether this vaccination strategy could elicit mature equine infectious anemia virus (EIAV) Env-specific antibodies, thus protecting vaccinated horses against EIAV infection. Therefore, in this pilot study we vaccinated horses using a strategy based on DNA prime/recombinant Tiantan vaccinia (rTTV)-vectored vaccines encoding EIAV env and gag genes, and observed the development of Env-specific antibodies, neutralizing antibodies, and p26-specific antibodies. Vaccination with DNA induced low titer, low avidity, and the predominant recognition of linear epitopes by Env-specific antibodies, which was enhanced by boosting vaccinations with rTTV vaccines. However, the maturation levels of Env-specific antibodies induced by the DNA/rTTV vaccines were significantly lower than those induced by the attenuated vaccine EIAVFDDV. Additionally, DNA/rTTV vaccines did not elicit broadly neutralizing antibodies. After challenge with a virulent EIAV strain, all of the vaccinees and control horses died from EIAV disease. These data indicate that the regimen of DNA prime/rTTV vaccine boost did not induce mature Env-specific antibodies, which might have contributed to immune protection failure.
doi:10.1089/vim.2012.0014
PMCID: PMC3518545  PMID: 23171359
19.  β-catenin/TCF-1 pathway in T cell development and differentiation 
T cells must undergo two critical differentiation processes before they become competent effectors that can mediate actual immune responses. Progenitor T cells undergo defined stages of differentiation in the thymus, which include positive and negative selection, to generate a repertoire of T cells that will respond to foreign but not self antigens. When these immunocompetent T cells first migrate out of thymus into peripheral lymphoid tissues, they are naïve and are unable to mediate immune responses. However, upon antigen encounter, peripheral CD4+ naïve T cells undergo another differentiation process to become armed effector T cells including Th1, Th2, Th17 or regulatory T cells, all of which are capable of regulating immune responses. A canonical Wnt/β-catenin/T cell factor (TCF) pathway has been shown to regulate T cell differentiation in both the thymus and in peripheral lymphoid tissues. Dysfunction of this pathway at any stage of T cell differentiation could lead to severe autoimmunity including experimental autoimmune encephalomyelitis or immune deficiency. Understanding the role played by β-catenin/TCF-1 in T cell differentiation will facilitate our understanding of the mechanisms that regulate T cell function and assist in identifying novel therapy targets for treating both autoimmune and immune diseases. Therefore, in this review, we will focus on the function of β-catenin/TCF-1 pathway in the regulation of thymic and peripheral T cell differentiation processes.
doi:10.1007/s11481-012-9367-y
PMCID: PMC3582214  PMID: 22535304
20.  UnSplicer: mapping spliced RNA-seq reads in compact genomes and filtering noisy splicing 
Nucleic Acids Research  2013;42(4):e25.
Accurate mapping of spliced RNA-Seq reads to genomic DNA has been known as a challenging problem. Despite significant efforts invested in developing efficient algorithms, with the human genome as a primary focus, the best solution is still not known. A recently introduced tool, TrueSight, has demonstrated better performance compared with earlier developed algorithms such as TopHat and MapSplice. To improve detection of splice junctions, TrueSight uses information on statistical patterns of nucleotide ordering in intronic and exonic DNA. This line of research led to yet another new algorithm, UnSplicer, designed for eukaryotic species with compact genomes where functional alternative splicing is likely to be dominated by splicing noise. Genome-specific parameters of the new algorithm are generated by GeneMark-ES, an ab initio gene prediction algorithm based on unsupervised training. UnSplicer shares several components with TrueSight; the difference lies in the training strategy and the classification algorithm. We tested UnSplicer on RNA-Seq data sets of Arabidopsis thaliana, Caenorhabditis elegans, Cryptococcus neoformans and Drosophila melanogaster. We have shown that splice junctions inferred by UnSplicer are in better agreement with knowledge accumulated on these well-studied genomes than predictions made by earlier developed tools.
doi:10.1093/nar/gkt1141
PMCID: PMC3936741  PMID: 24259430
21.  HIF-1α 1772 C/T and 1790 G/A Polymorphisms Are Significantly Associated with Higher Cancer Risk: An Updated Meta-Analysis from 34 Case-Control Studies 
PLoS ONE  2013;8(11):e80396.
Background
HIF-1 activates various genes in cancer progression and metastasis. HIF-1α 1772 C/T and 1790 G/A polymorphisms are reportedly associated with cancer risk; however, the results are inconclusive.
Methodology/Principal Findings
A meta-analysis of 34 studies that involved 7522 cases and 9847 controls for 1772 C/T and 24 studies that involved 4884 cases and 8154 controls for 1790 G/A was conducted to identify the association of C/T and G/A polymorphisms with cancer risk. Odds ratio (OR) and 95% confidence intervals (95% CI) were used to assess the strength of association.
HIF-1α 1772 C/T and 1790 G/A polymorphisms were associated with higher cancer risk in homozygote comparison (1772C/T: TT vs. CC: OR = 2.45, 95% CI: 1.52, 3.96; Pheterogeneity = 0.028; 1790G/A: AA vs. GG: OR=4.74, 95% CI: 1.78, 12.6; Pheterogeneity < 0.01), dominant model (1772C/T: TT/CT vs. CC: OR = 1.27, 95% CI: 1.04, 1.55; Pheterogeneity < 0.01, 1790G/A: AA/GA vs. GG: OR = 1.65, 95% CI: 1.05, 2.60; Pheterogeneity < 0.01), T allele versus C allele (T vs. C: OR = 1.42, 95% CI: 1.18, 1.70; Pheterogeneity < 0.01), and A allele versus G allele (A vs. G: OR = 1.83, 95% CI: 1.13, 2.96; Pheterogeneity < 0.01). On a subgroup analysis, the 1772 C/T polymorphism was significantly linked to higher risks for breast cancer, lung cancer, prostate cancer, and cervical cancer, whereas the 1790 G/A polymorphism was significantly linked to higher risks for lung cancer and prostate cancer. A significantly increased cancer risk was found in both Asians and Caucasians for 1772C/T polymorphism, whereas a significantly increased cancer risk was found in Caucasians in the heterozygote comparison and recessive model for 1790G/A polymorphism.
Conclusions
HIF-1α 1772 C/T and 1790 G/A polymorphisms are significantly associated with higher cancer risk.
doi:10.1371/journal.pone.0080396
PMCID: PMC3832403  PMID: 24260383
22.  Sequence-Based Analysis of Translocations and Inversions in Bread Wheat (Triticum aestivum L.) 
PLoS ONE  2013;8(11):e79329.
Structural changes of chromosomes are a primary mechanism of genome rearrangement over the course of evolution and detailed knowledge of such changes in a given species and its close relatives should increase the efficiency and precision of chromosome engineering in crop improvement. We have identified sequences bordering each of the main translocation and inversion breakpoints on chromosomes 4A, 5A and 7B of the modern bread wheat genome. The locations of these breakpoints allow, for the first time, a detailed description of the evolutionary origins of these chromosomes at the gene level. Results from this study also demonstrate that, although the strategy of exploiting sorted chromosome arms has dramatically simplified the efforts of wheat genome sequencing, simultaneous analysis of sequences from homoeologous and non-homoeologous chromosomes is essential in understanding the origins of DNA sequences in polyploid species.
doi:10.1371/journal.pone.0079329
PMCID: PMC3829836  PMID: 24260197
23.  Therapeutic Potential of a Monoclonal Antibody Blocking the Wnt Pathway in Diabetic Retinopathy 
Diabetes  2012;61(11):2948-2957.
Dysregulation of Wnt/β-catenin signaling contributes to the development of diabetic retinopathy by inducing retinal inflammation, vascular leakage, and neovascularization. Here, we evaluated the inhibitory effect of a monoclonal antibody (Mab) specific for the E1E2 domain of Wnt coreceptor low-density lipoprotein receptor–related protein 6, Mab2F1, on canonical Wnt signaling and its therapeutic potential for diabetic retinopathy. Mab2F1 displayed robust inhibition on Wnt signaling with a half-maximal inhibitory concentration (IC50) of 20 μg/mL in retinal pigment epithelial cells. In addition, Mab2F1 also attenuated the accumulation of β-catenin and overexpression of vascular endothelial growth factor, intercellular adhesion molecule-1, and tumor necrosis factor-α induced by high-glucose medium in retinal endothelial cells. In vivo, an intravitreal injection of Mab2F1 significantly reduced retinal vascular leakage and decreased preretinal vascular cells in oxygen-induced retinopathy (OIR) rats, demonstrating its inhibitory effects on ischemia-induced retinal neovascularization. Moreover, Mab2F1 blocked the overexpression of the inflammatory/angiogenic factors, attenuated leukostasis, and reduced retinal vascular leakage in both early and late stages of streptozotocin-induced diabetes. In conclusion, Mab2F1 inhibits canonical Wnt signaling, vascular leakage, and inflammation in the retina of diabetic retinopathy models, suggesting its potential to be used as a therapeutic agent in combination with other antiangiogenic compounds.
doi:10.2337/db11-0300
PMCID: PMC3478529  PMID: 22891217
24.  Isolation and Characterization of Collagen and Antioxidant Collagen Peptides from Scales of Croceine Croaker (Pseudosciaena crocea) 
Marine Drugs  2013;11(11):4641-4661.
Acid soluble collagen (ASC) from scales of croceine croaker (ASC-C) was successfully isolated with the yield of 0.37% ± 0.08% (dry weight basis), and characterized as type I collagen on the basis of amino acid analysis and electrophoretic pattern. The antioxidant hydrolysate of ASC-C (ACH) was prepared through a two-stage in vitro digestion (4-h trypsin followed by 4-h pepsin), and three antioxidant peptides (ACH-P1, ACH-P2, and ACH-P3) were further isolated from ACH using ultrafiltration, gel chromatography, and RP-HPLC, and their amino acid sequences were identified as GFRGTIGLVG (ACH-P1), GPAGPAG (ACH-P2), and GFPSG (ACH-P3). ACH-P1, ACH-P2, and ACH-P3 showed good scavenging activities on hydroxyl radical (IC50 0.293, 0.240, and 0.107 mg/mL, respectively), DPPH radical (IC50 1.271, 0.675, and 0.283 mg/mL, respectively), superoxide radical (IC50 0.463, 0.099, and 0.151 mg/mL, respectively), and ABTS radical (IC50 0.421, 0.309, and 0.210 mg/mL, respectively). ACH-P3 was also effectively against lipid peroxidation in the model system. The antioxidant activities of three collagen peptides were due to the presence of hydrophobic amino acid residues within the peptide sequences. The collagen peptides might be used as antioxidant for the therapy of diseases associated with oxidative stress, or reducing oxidative changes during storage.
doi:10.3390/md11114641
PMCID: PMC3853751  PMID: 24284428
croceine croaker (Pseudosciaena crocea); scale; acid soluble collagen (ASC); peptide; antioxidant activity
25.  Balloon kyphoplasty versus percutaneous vertebroplasty in treating osteoporotic vertebral compression fracture: grading the evidence through a systematic review and meta-analysis 
European Spine Journal  2012;21(9):1844-1859.
Objective
To assess the safety and efficacy of balloon kyphoplasty (KP) compared with percutaneous vertebroplasty (VP) and provide recommendations for using these procedures to treat osteoporotic vertebral compression fractures (OVCF).
Methods
A systematic search of all studies published through March 2012 was conducted using the MEDLINE, EMBASE, OVID, ScienceDirect and Cochrane CENTRAL databases. The randomized controlled trials (RCTs) and non-randomized controlled trials that compared KP to VP and provided data on safety and clinical effects were identified. Demographic characteristics, adverse events and clinical outcomes were manually extracted from all of the selected studies. The evidence quality levels and recommendations were assessed using the GRADE system.
Results
Twelve studies encompassing 1,081 patients met the inclusion criteria. Subgroup meta-analyses were performed according to the study design. In the RCT subgroup, there were significant differences between the two procedures in short-term visual analog scale (VAS), long-term kyphosis angles, operative times and anterior vertebrae heights. In the cohort study subgroup, there were significant differences between the two procedures in short- and long-term VAS, short- and long-term Oswestry Disability Index (ODI), cement leakage rates, short- and long-term kyphosis angles, operative times and anterior vertebrae heights. However, there were no significant differences in long-term VAS or adjacent vertebral fracture rates in the RCT subgroup. There were no significant differences in short- or long-term VAS, short- or long-term ODI, cement leakage rates, adjacent vertebral fracture rates, short- or long-term kyphosis angles or anterior vertebrae heights in the CCT subgroup, and the adjacent vertebral fracture rates did not differ significantly in the cohort study subgroup. The overall GRADE system evidence quality was very low, which lowers our confidence in their recommendations.
Conclusions
KP and VP are both safe and effective surgical procedures for treating OVCF. KP may be superior to VP in patients with large kyphosis angles, vertebral fissures, fractures in the posterior edge of the vertebral body or significant height loss in the fractured vertebrae. Due to the poor quality of the evidence currently available, high-quality RCTs are required.
doi:10.1007/s00586-012-2441-6
PMCID: PMC3459117  PMID: 22832872
Osteoporosis; Kyphoplasty; Vertebroplasty; Vertebral compression fracture; Systematic review

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