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1.  Microbial Biotransformation of Gentiopicroside by the Endophytic Fungus Penicillium crustosum 2T01Y01 
Endophytic fungi are symbiotic with plants and possess multienzyme systems showing promising metabolite potency with region selectivity and stereoselectivity. The aim of this study was to use these special microorganisms as an in vitro model to mimic the potential mammalian metabolites of a natural iridoid gentiopicroside (GPS, compound 1). The fungi isolated from a medicinal plant, Dendrobium candidum Wall. ex Lindl., were screened for their biotransformation abilities with GPS as the substrate, and one strain with high converting potency was identified as Penicillium crustosum 2T01Y01 on the basis of the sequence of the internal transcribed spacer of the ribosomal DNA region. Upon the optimized incubation of P. crustosum 2T01Y01 with the substrate, seven deglycosylated metabolites were detected by ultraperformance liquid chromatography/quadrupole time of flight mass spectrometry (UPLC/Q-TOF MS). Preparative-scale biotransformation with whole cells of the endophytic fungus resulted in the production of five metabolites, including three novel ones, 5α-(hydroxymethyl)-6β-methyl-3,4,5,6-tetrahydropyrano[3,4-c]pyran-1(8H)-one (compound 2), (Z)-4-(1-hydroxybut-3-en-2-yl)-5,6-dihydropyran-2-one (compound 3), and (E)-4-(1-hydroxybut-3-en-2-yl)-5,6-dihydropyran-2-one (compound 4), along with two known ones, 5α-(hydroxymethyl)-6β-methyl-1H,3H-5,6-dihydropyrano[3,4-c]pyran-1(3H)-one (compound 5) and 5α-(hydroxymethyl)-6α-methyl-5,6-dihydropyrano[3,4-c]pyran-1(3H)-one (compound 6), aided by nuclear magnetic resonance and high-resolution mass spectral analyses. The other two metabolites were tentatively identified by online UPLC/Q-TOF MS as 5-hydroxymethyl-5,6-dihydroisochromen-1-one (compound 7) and 5-hydroxymethyl-3,4,5,6-tetrahydroisochromen-1-one (compound 8), and compound 8 is a new metabolite. To test the metabolic mechanism, the β-glucosidase activity of the fungus P. crustosum 2T01Y01 was assayed with ρ-nitrophenyl-β-d-glucopyranoside as a probe substrate, and the pathway of GPS biotransformation by strain 2T01Y01 is proposed. In addition, the hepatoprotective activities of GPS and metabolite compounds 2, 5, and 6 against human hepatocyte line HL-7702 injury induced by hydrogen peroxide were evaluated.
doi:10.1128/AEM.02309-13
PMCID: PMC3911023  PMID: 24141132
2.  Effects of lactic acid bacteria isolated from fermented mustard on lowering cholesterol 
Objective
To evaluate the ability of lactic acid bacteria (LAB) strains isolated from fermented mustard to lower the cholesterol in vitro.
Methods
The ability of 50 LAB strains isolated from fermented mustard on lowering cholesterol in vitro was determined by modified o-phtshalaldehyde method. The LAB isolates were analyzed for their resistance to acid and bile salt. Strains with lowering cholesterol activity, were determined adherence to Caco-2 cells.
Results
Strain B0007, B0006 and B0022 assimilated more cholesterol than BCRC10474 and BCRC 17010. The isolated strains showed tolerance to pH 3.0 for 3 h despite variations in the degree of viability and bile-tolerant strains, with more than 108 CFU/mL after incubation for 24 h at 1% oxigall in MRS. In addition, strain B0007 and B0022 identified as Lactobacillus plantarum with 16S rDNA sequences were able to adhere to the Caco-2 cell lines.
Conclusions
These strains B0007 and B0022 may be potential functional sources for cholesterol-lowering activities as well as adhering to Caco-2 cell lines.
doi:10.12980/APJTB.4.201414B54
PMCID: PMC4032825
Cholesterol-lowering activity; Probiotic; Lactic acid bacteria; Acid; Bile tolerance
3.  Post-Receptor Crosstalk between Growth Hormone and Insulin Signal in Rats Born Small for Gestational Age with Catch-Up Growth 
PLoS ONE  2014;9(6):e100459.
Objective
Insulin resistance has been observed in individuals born small for gestational age (SGA) with catch-up growth (CUG), yet the mechanisms involved remain unclear. This study examined the role of GH and insulin signaling crosstalk in insulin resistance of SGA rats with CUG.
Design and Methods
SGA rats were developed by dietary restriction in pregnant rats. GH receptor inhibition was performed on four-week old CUG-SGA and AGA rats. Phosphorylation of IRS-1, AKT, and ERK, and expression of SOCS3 in the skeletal muscle were determined via immunoblot analysis at baseline and after insulin stimulation in CUG-SGA, NCUG-SGA and AGA groups.
Results
Compared to AGA controls, phosphorylation of IRS-1 and AKT in response to insulin stimulation in CUG-SGA rats was significantly blunted (P<0.05), and phosphorylation of ERK at baseline was dramatically activated (P<0.05). SOCS3 expression was significantly increased in CUG-SGA compared to AGA (P = 0.001) and NCUG-SGA (P = 0.006) rats, and was significantly suppressed following GHR inhibition (P<0.05). Furthermore, phosphorylation of IRS-1 and AKT in response to insulin stimulation increased after GHR inhibition (P<0.05).
Conclusions
Insulin resistance in CUG-SGA rats is associated with impairment of IRS-1-PI3K-AKT signaling, which may result from GH signaling-induced up-regulation of SOCS3.
doi:10.1371/journal.pone.0100459
PMCID: PMC4070916  PMID: 24963636
4.  Clinical Predictive Models for Chemotherapy-Induced Febrile Neutropenia in Breast Cancer Patients: A Validation Study 
PLoS ONE  2014;9(6):e96413.
Background
Predictive models for febrile neutropenia (FN) would be informative for physicians in clinical decision making. This study aims to validate a predictive model (Jenkin’s model) that comprises pretreatment hematological parameters in early-stage breast cancer patients.
Patients and Methods
A total of 428 breast cancer patients who received neoadjuvant/adjuvant chemotherapy without any prophylactic use of colony-stimulating factor were included. Pretreatment absolute neutrophil counts (ANC) and absolute lymphocyte counts (ALC) were used by the Jenkin’s model to assess the risk of FN. In addition, we modified the threshold of Jenkin’s model and generated Model-A and B. We also developed Model-C by incorporating the absolute monocyte count (AMC) as a predictor into Model-A. The rates of FN in the 1st chemotherapy cycle were calculated. A valid model should be able to significantly identify high-risk subgroup of patients with FN rate >20%.
Results
Jenkin’s model (Predicted as high-risk when ANC≦3.1*10∧9/L;ALC≦1.5*10∧9/L) did not identify any subgroups with significantly high risk (>20%) of FN in our population, even if we used different thresholds in Model-A(ANC≦4.4*10∧9/L;ALC≦2.1*10∧9/L) or B(ANC≦3.8*10∧9/L;ALC≦1.8*10∧9/L). However, with AMC added as an additional predictor, Model-C(ANC≦4.4*10∧9/L;ALC≦2.1*10∧9/L; AMC≦0.28*10∧9/L) identified a subgroup of patients with a significantly high risk of FN (23.1%).
Conclusions
In our population, Jenkin’s model, cannot accurately identify patients with a significant risk of FN. The threshold should be changed and the AMC should be incorporated as a predictor, to have excellent predictive ability.
doi:10.1371/journal.pone.0096413
PMCID: PMC4063732  PMID: 24945817
5.  Scientometric trends and knowledge maps of global health systems research 
Background
In the last few decades, health systems research (HSR) has garnered much attention with a rapid increase in the related literature. This study aims to review and evaluate the global progress in HSR and assess the current quantitative trends.
Methods
Based on data from the Web of Science database, scientometric methods and knowledge visualization techniques were applied to evaluate global scientific production and develop trends of HSR from 1900 to 2012.
Results
HSR has increased rapidly over the past 20 years. Currently, there are 28,787 research articles published in 3,674 journals that are listed in 140 Web of Science subject categories. The research in this field has mainly focused on public, environmental and occupational health (6,178, 21.46%), health care sciences and services (5,840, 20.29%), and general and internal medicine (3,783, 13.14%). The top 10 journals had published 2,969 (10.31%) articles and received 5,229 local citations and 40,271 global citations. The top 20 authors together contributed 628 papers, which accounted for a 2.18% share in the cumulative worldwide publications. The most productive author was McKee, from the London School of Hygiene & Tropical Medicine, with 48 articles. In addition, USA and American institutions ranked the first in health system research productivity, with high citation times, followed by the UK and Canada.
Conclusions
HSR is an interdisciplinary area. Organization for Economic Co-operation and Development countries showed they are the leading nations in HSR. Meanwhile, American and Canadian institutions and the World Health Organization play a dominant role in the production, collaboration, and citation of high quality articles. Moreover, health policy and analysis research, health systems and sub-systems research, healthcare and services research, health, epidemiology and economics of communicable and non-communicable diseases, primary care research, health economics and health costs, and pharmacy of hospital have been identified as the mainstream topics in HSR fields. These findings will provide evidence of the current status and trends in HSR all over the world, as well as clues to the impact of this popular topic; thus, helping scientific researchers and policy makers understand the panorama of HSR and predict the dynamic directions of research.
doi:10.1186/1478-4505-12-26
PMCID: PMC4065315  PMID: 24903126
Global trend; Health systems research; Knowledge mapping; Scientometric; Web of Science
6.  Patellar resurfacing versus nonresurfacing in total knee arthroplasty: A meta-analysis of randomised controlled trials 
International Orthopaedics  2013;37(6):1075-1083.
Purpose
Patella resurfacing or nonresurfacing in total knee arthroplasty remains controversial. The aim of this study was to evaluate the efficacy of patellar resurfacing through an evaluation of the current literature.
Methods
We carried out a meta-analysis of randomised controlled trials comparing total knee arthroplasties performed with and without patellar resurfacing. Outcomes of reoperation, anterior knee pain and knee scores were analysed.
Results
Fourteen trials assessing 1,725 knees were eligible. The absolute risk of reoperation was reduced by 4 % (95 % confidence interval, 2–6 %) in the patellar resurfacing arm (between-study heterogeneity, P = 0.05, I2 = 42 %), implying that one would have to resurface 25 patellae (95 % confidence interval, 17–50 patellae) in order to prevent one reoperation. There was no difference between the two groups in terms of anterior knee pain, knee pain score, Knee Society score and knee function score. But in the studies followed up for a mean time of not less than five years, a difference was found between the two arms in Knee Society scores (RR = 2.14, 95 % confidence interval, 0.76–3.52; P = 0.002).
Conclusions
The available evidence indicates that patellar resurfacing reduces the risk of reoperation after total knee arthroplasty. Patellar resurfacing patients may make a difference in long-term follow-up (five or more 5 years) of Knee Society scores. In other aspects, the benefit of patellar resurfacing is limited. Additionally, more carefully and scientifically designed randomised controlled trials are required to further prove the claim.
doi:10.1007/s00264-013-1866-9
PMCID: PMC3664152  PMID: 23529719
7.  Lysophosphatidic Acid Enhanced the Angiogenic Capability of Human Chondrocytes by Regulating Gi/NF-kB-Dependent Angiogenic Factor Expression 
PLoS ONE  2014;9(5):e95180.
Lysophosphatidic acid (LPA) has been found to mediate myeloid differentiation, stimulate osteogenesis, alter cell proliferation and migration, and inhibit apoptosis in chondrocytes. The effect of LPA on the angiogenic capability of chondrocytes is not clear. This study aimed to investigate its effect on the angiogenic capability of human chondrocytes and the underlying mechanism of these effects. Human chondrocyte cell line, CHON-001, commercialized human chondrocytes (HC) derived from normal human articular cartilage, and human vascular endothelial cells (HUVECs) were used as cell models in this study. The angiogenic capability of chondrocytes was determined by capillary tube formation, monolayer permeability, cell migration, and cell proliferation. An angiogenesis protein array kit was used to evaluate the secretion of angiogenic factors in conditioned medium. Angiogenin, insulin-like growth factor-binding protein 1 (IGFBP-1), interleukin (IL)-8, monocyte chemoattractant protein-1 (MCP-1), matrix metalloproteinase (MMP)-9, and vascular endothelial growth factor (VEGF) mRNA and protein expressions were evaluated by Q-RT-PCR and EIA, respectively. LPA receptor (LPAR) expression was determined by RT-PCR. Signaling pathways were clarified using inhibitors, Western blot analysis, and reporter assays. The LPA treatment promoted the angiogenic capability of CHON-001 cells and HC, resulting in enhanced HUVEC capillary tube formation, monolayer permeability, migration, and cell growth. Angiogenin, IGFBP-1, IL-8, MCP-1, MMP-9, and VEGF mRNA and protein expressions were significantly enhanced in LPA-treated chondrocytes. LPA2, 3, 4 and 6 were expressed in CHON-001 and HC cells. Pretreatment with the Gi/o type G protein inhibitor, pertussis toxin (PTX), and the NF-kB inhibitor, PDTC, significantly inhibited LPA-induced angiogenin, IGFBP-1, IL-8, MCP-1, MMP-9, and VEGF expressions in chondrocytes. The PTX pretreatment also inhibited LPA-mediated NF-kB activation, suggesting the presence of active Gi/NF-kB signaling in CHON-001 and HC cells. The effect of LPA on the angiogenesis-inducing capacity of chondrocytes may be due to the increased angiogenesis factor expression via the Gi/NF-kB signaling pathway.
doi:10.1371/journal.pone.0095180
PMCID: PMC4039431  PMID: 24879414
9.  Outcome of Hemiarthroplasty and Total Hip Replacement for Active Elderly Patients with Displaced Femoral Neck Fractures: A Meta-Analysis of 8 Randomized Clinical Trials 
PLoS ONE  2014;9(5):e98071.
Background
Displaced fracture of the femoral neck has been a common clinical problem, especially in aged patients. However, the optimal treatment choice remains controversial. The purpose of this study is to conduct a systematic review of randomized clinical trials assessing the results of hemiarthroplasty and total hip replacement in patients undergoing either alternative using meta-analysis.
Methods
A literature search for randomized clinical trials was conducted through Medline, Embase and Cochrane library between 1969 and 2013 with no restrictions. Additional relevant articles were referred as source of information by way of manual searches on major orthopedic journals. Upon the search, two authors independently evaluated study quality and relevant data was extracted.
Results
A total of 8 studies with 983 patients were included in this meta-analysis. After pooling the available data, a significant dominance of Harris hip score was found for total hip replacement compared with hemiarthroplasty (SMD: −7.11, 95%:−10.70,−3.53) one year postoperatively and the advantage kept over (SMD: −6.91, 95%:−12.98, −0.85) two years after surgery. A trend toward a higher dislocation rate was found in total hip replacement group (RR: 0.46, 95%: 0.21, 1.02), of which the difference was considered insignificant. The risk of revision in group hemiarthroplasty appeared to be more than two folds higher than that after total hip replacement (RR: 4.14, 95%CI: 2.09, 8.19).
Conclusion
Even though there is a higher rate of dislocation after total hip replacement, this disadvantage could be accounted for, on the basis of a better functional score and the lower revision rate. However, from the results, it stands to reason that total hip replacement should be strongly suggested in elderly active patients with femoral neck fracture.
doi:10.1371/journal.pone.0098071
PMCID: PMC4031167  PMID: 24854195
10.  Computational Exploration of Zinc Binding Groups for HDAC Inhibition 
The Journal of organic chemistry  2013;78(10):5051-5055.
Histone deacetylases (HDACs) emerged as important drug targets in epigenetics. The most common HDAC inhibitors use hydroxamic acids as zinc binding groups despite unfavorable pharmacokinetic properties. A two-stage protocol of M05-2X calculations of a library of 48 fragments in a small model active site, followed by QM/MM hybrid calculations of the full enzyme with selected binders is used to prospectively select potential bidentate zinc binders. The energetics and interaction patterns of several zinc binders not previously used for the inhibition of HDACs are discussed.
doi:10.1021/jo400406g
PMCID: PMC3703144  PMID: 23586590
11.  Learning from the past: Rare ε-Fe2O3 in the ancient black-glazed Jian (Tenmoku) wares 
Scientific Reports  2014;4:4941.
Ancient Jian wares are famous for their lustrous black glaze that exhibits unique colored patterns. Some striking examples include the brownish colored “Hare's Fur” (HF) strips and the silvery “Oil Spot” (OS) patterns. Herein, we investigated the glaze surface of HF and OS samples using a variety of characterization methods. Contrary to the commonly accepted theory, we identified the presence of ε-Fe2O3, a rare metastable polymorph of Fe2O3 with unique magnetic properties, in both HF and OS samples. We found that surface crystals of OS samples are up to several micrometers in size and exclusively made of ε-Fe2O3. Interestingly, these ε-Fe2O3 crystals on the OS sample surface are organized in a periodic two dimensional fashion. These results shed new lights on the actual mechanisms and kinetics of polymorphous transitions of Fe2O3. Deciphering technologies behind the fabrication of ancient Jian wares can thus potentially help researchers improve the ε-Fe2O3 synthesis.
doi:10.1038/srep04941
PMCID: PMC4018809  PMID: 24820819
12.  CGG Repeat Associated Translation Mediates Neurodegeneration in Fragile X Tremor Ataxia Syndrome 
Neuron  2013;78(3):10.1016/j.neuron.2013.03.026.
Fragile X-associated Tremor Ataxia Syndrome (FXTAS) results from a CGG repeat expansion in the 5’UTR of FMR1. This repeat is thought to elicit toxicity as RNA yet disease brains contain ubiquitin-positive neuronal inclusions, a pathologic hallmark of protein-mediated neurodegeneration. We explain this paradox by demonstrating that CGG repeats trigger repeat associated non-AUG initiated (RAN) translation of a cryptic polyglycine-containing protein, FMRpolyG. FMRpolyG accumulates in ubiquitin-positive inclusions in Drosophila, cell culture, mouse disease models and FXTAS patient brains. CGG RAN translation occurs in at least two of three possible reading frames at repeat sizes ranging from normal (25) to pathogenic (90), but inclusion formation only occurs with expanded repeats. In Drosophila, CGG repeat toxicity is suppressed by eliminating RAN translation and enhanced by increased polyglycine protein production. These studies expand the growing list of nucleotide repeat disorders where RAN translation occurs and provide evidence that RAN translation contributes to neurodegeneration.
doi:10.1016/j.neuron.2013.03.026
PMCID: PMC3831531  PMID: 23602499
13.  A microRNA miR-34a Regulated Bimodal Switch targets Notch in Colon Cancer Stem Cells 
Cell stem cell  2013;12(5):602-615.
SUMMARY
microRNAs regulate developmental cell fate decisions, tissue homeostasis and oncogenesis in distinct ways relative to proteins. Here, we show that the tumor suppressor microRNA miR-34a is a cell fate determinant in early stage dividing colon cancer stem cells (CCSCs). In pair-cell assays, miR34a distributes at high levels in differentiating progeny, while low levels of miR34a demarcate self renewing CCSCs. Moreover, miR34a loss of function and gain of function alters the balance between self-renewal and differentiation both in vitro and in vivo. Mechanistically, miR34a sequesters Notch1 mRNA to generate a sharp threshold response where a bimodal Notch signal specifies the choice between self-renewal versus differentiation. In contrast, the canonical cell fate determinant Numb regulates Notch levels in a continuously graded manner. Taken together, our findings highlight a unique microRNA regulated mechanism that converts noisy input into a toggle switch for robust cell fate decisions in CCSCs.
doi:10.1016/j.stem.2013.03.002
PMCID: PMC3646336  PMID: 23642368
14.  Reassessment of QTLs for Late Blight Resistance in the Tomato Accession L3708 Using a Restriction Site Associated DNA (RAD) Linkage Map and Highly Aggressive Isolates of Phytophthora infestans 
PLoS ONE  2014;9(5):e96417.
Tomato late blight caused by the oomycete pathogen Phytophthora infestans (Mont.) de Bary is a major threat to tomato production in cool and wet environments. Intensified outbreaks of late blight have been observed globally from the 1980s, and are associated with migration of new and more aggressive populations of P. infestans in the field. The objective of this study was to reassess late blight resistance in the wild tomato accession L3708 (Solanum pimpinellifolium L.) against pathogens of different aggressiveness. An F2:3 genetic mapping population was developed using L3708 as the paternal parent. Two isolates of P. infestans, Pi39A and Pi733, were used for inoculation. Pi733 is a highly aggressive genotype that defeats three known late blight resistance genes, Ph-1, Ph-2, and Ph-5t in tomato. In contrast, Pi39A is a less aggressive genotype that defeats only Ph-1. Restriction site Associated DNA Sequencing (RAD-Seq) technology was used to massively sequence 90 bp nucleotides adjacent to both sides of PstI restriction enzyme cutting sites in the genome for all individuals in the genetic mapping population. The RAD-seq data were used to construct a genetic linkage map containing 440 single nucleotide polymorphism markers. Quantitative trait locus (QTL) analysis identified a new disease-resistant QTL specific to Pi733 on chromosome 2. The Ph-3 gene located on chromosome 9 could be detected whichever isolates were used. This study demonstrated the feasibility and efficiency of RAD-Seq technology for conducting a QTL mapping experiment using an F2:3 mapping population, which allowed the identification of a new late blight resistant QTL in tomato.
doi:10.1371/journal.pone.0096417
PMCID: PMC4008630  PMID: 24788810
15.  Generating Better Medicines for Cancer 
ACS macro letters  2013;2(5):393-397.
The complexity of tumor biology warrants tailored drug delivery for overcoming the major challenges faced by cancer therapies. The versatility of the PRINT® (Particle Replication In Non-wetting Templates) process has enabled the preparation of shape- and size-specific particles with a wide range of chemical compositions and therapeutic cargos. Different particle matrices and drugs may be combined in a plug-and-play approach, such that physico-chemical characteristics of delivery vectors may be optimized for biocompatibility, cargo stability and release, circulation half-life, and efficacy. Thus, the engineering of particles for cancer therapy with specific biophysical behaviors and cellular responses has been demonstrated via the PRINT process.
doi:10.1021/mz400116a
PMCID: PMC3680140  PMID: 23772351
PRINT; soft lithography; nanoparticle; cancer; medicine; drug delivery
16.  The Influence of BMX Gene Polymorphisms on Clinical Symptoms after Mild Traumatic Brain Injury 
BioMed Research International  2014;2014:293687.
Mild traumatic brain injury (mTBI) is one of the most common neurological disorders. Most patients diagnosed with mTBI could fully recover, but 15% of patients suffer from persistent symptoms. In recent studies, genetic factors were found to be associated with recovery and clinical outcomes after TBI. In addition, results from our previous research have demonstrated that the bone marrow tyrosine kinase gene in chromosome X (BMX), a member of the Tec family of kinases, is highly expressed in rats with TBI. Therefore, our aim in this study was to identify the association between genetic polymorphisms of BMX and clinical symptoms following mTBI. Four tagging single nucleotide polymorphisms (tSNPs) of BMX with minimum allele frequency (MAF) >1% were selected from the HapMap Han Chinese database. Among these polymorphisms, rs16979956 was found to be associated with the Beck anxiety inventory (BAI) and dizziness handicap inventory (DHI) scores within the first week after head injury. Additionally, another SNP, rs35697037, showed a significant correlation with dizziness symptoms. These findings suggested that polymorphisms of the BMX gene could be a potential predictor of clinical symptoms following mTBI.
doi:10.1155/2014/293687
PMCID: PMC4016905  PMID: 24860816
17.  All-Arthroscopic versus Mini-Open Repair of Small to Large Sized Rotator Cuff Tears: A Meta-Analysis of Clinical Outcomes 
PLoS ONE  2014;9(4):e94421.
Purpose
The purpose of this study was to compare clinical outcomes of patients with full-thickness small to large sized tears undergoing all-arthroscopic versus mini-open rotator cuff repair.
Method
A literature search for electronic databases and references for eligible studies was conducted through Medline, Embase and Cochrane library between 1969 and 2013.
Results
A total of 12 comparative studies (n = 770 patients) were included. Pooled results showed: there were no differences in function outcome, pain scores, retear rate or the incidence of adhesive capsulitis between all arthroscopic and mini-open repair groups.
Conclusions
There were no differences in outcomes between the arthroscopic and mini-open rotator cuff repair techniques, they should be considered alternative treatment options.
Level of Evidence
Level IV, Meta analysis.
doi:10.1371/journal.pone.0094421
PMCID: PMC3984182  PMID: 24728326
18.  HSV-2 Increases TLR4-Dependent Phosphorylated IRFs and IFN-β Induction in Cervical Epithelial Cells 
PLoS ONE  2014;9(4):e94806.
Our previous studies demonstrated that HSV-2 infection up-regulates TLR4 expression and induces NF-kB activity, thereby facilitating innate immune response in human cervical epithelial cells. This process requires involvement of TLR4 adaptors, Mal and MyD88. In the current study, we found that HSV-2 infection increases levels of phosphoryalted IRF3 and IRF7, then regulating expression of type I IFN. As expected, these changes induced by HSV-2 infection depended upon TLR4. Knockdown of TRIF and/or TRAM by siRNAs indicated that TRIF/TRAM might be involved in expression of IFN-β. Our results demonstrate for the first time that IRF3 and IRF7 are both involved in inducing TLR4-dependent IFN-β expression in response to HSV-2 in its primary infected genital epithelial cells. Thus, TLR4-Mal/MyD88 and TLR4-TRIF/TRAM signaling may synergize and/or cooperate in innate immune response of cervical epithelial cells to HSV-2 infection.
doi:10.1371/journal.pone.0094806
PMCID: PMC3983257  PMID: 24722640
19.  Epithelioid angiosarcoma of the spine: A case report of a rare bone tumor 
Oncology Letters  2014;7(6):2170-2174.
Epithelioid angiosarcoma (EA) is an extremely rare subtype of angiosarcoma, which is characterized by large cells with an epithelioid morphology. EA typically arises in deep soft tissues, including the adrenal gland, skin and thyroid, however, EA rarely arises in the spine. The current study presents a case of osteolytic lesions involving the fourth lumbar (L4) level of the spine. Preoperatively, the patient was misdiagnosed with metastatic carcinoma, however, a radiological examination detected the presence of osteolytic or destructive lesions in the vertebrae, which extended into the pedicles. Histopathological and immunohistochemical evaluations were performed on the tumor tissue obtained from a decompression specimen of the L4 vertebra. A bone lesion composed of sheet-like malignant cells exhibiting atypical epithelioid morphology with vascular formation was observed. The presence of anastomosing vascular channels lined by epithelioid endothelial cells also indicated that focal endothelial differentiation had occurred. In addition, immunohistochemistry assays revealed that the lesion was positive for the endothelial cell markers, CD31, CD34 and vimentin. The tumor was treated with decompression of the L4 vertebra, followed by posterior stabilization. The patient subsequently refused chemotherapy and radiotherapy but completed six months of follow-up. At the time of writing, the tumor remains under control and the patient is asymptomatic. This case highlights the difficulty of diagnosing EA, which requires careful pathological examination and immunophenotype labeling. At present, CD31 is the most sensitive marker for detecting EA.
doi:10.3892/ol.2014.2055
PMCID: PMC4049740  PMID: 24932310
epithelioid angiosarcoma; CD31; vertebral tumor; factor VIII-related antigen; spine
20.  Affibody Modified and Radiolabeled Gold-Iron Oxide Hetero-nanostructures for Tumor PET, Optical and MR Imaging 
Biomaterials  2013;34(11):2796-2806.
A highly monodispersed hetero-nanostructure with two different functional nanomaterials (gold (Au) and iron oxide (Fe3O4, IO)) within one structure was successfully developed as Affibody based trimodality nanoprobe (positron emission tomography, PET; optical imaging; and magnetic resonance imaging, MRI) for imaging of epidermal growth factor receptor (EGFR) positive tumors. Unlike other regular nanostructures with a single component, the Au-IO hetero-nanostructures (Au-IONPs) with unique chemical and physical properties have capability to combine several imaging modalities together to provide complementary information. The IO component within hetero-nanostructures serve as a T2 reporter for MRI; and gold component serve as both optical and PET reporters. Moreover, such hetero-nanoprobes could provide a robust nano-platform for surface-specific modification with both targeting molecules (anti-EGFR Affibody protein) and PET imaging reporters (radiometal 64Cu chelators) in highly efficient and reliable manner. In vitro and in vivo study showed that the resultant nanoprobe provided high specificity, sensitivity, and excellent tumor contrast for both PET and MRI imaging in the human EGFR-expressing cells and tumors. Our study data also highlighted the EGFR targeting efficiency of hetero-nanoparticles and the feasibility for their further theranostic applications.
doi:10.1016/j.biomaterials.2013.01.014
PMCID: PMC3563754  PMID: 23343632
Au-Fe3O4; Hetero-nanoparticles; Affibody; EGFR; PET; MRI; Optical
21.  Glomus tumor in the stomach: A case report and review of the literature 
Oncology Letters  2014;7(6):1790-1792.
This study reports a rare case of a 47-year-old female with a gastric glomus tumor who was admitted with epigastralgia. Endoscopic ultrasound revealed a protrusion on the posterior wall of the gastric antrum. Enhanced computed tomography confirmed the presence of a 10-mm mass. The tumor was resected, and immunohistochemistry revealed the tumor to be positive for smooth muscle actin and collagen type IV, and negative for synaptophysin, chromogranin A, laminin, S-100, cluster of differentiation (CD)34, CD31, CD99, cytokeratin (AE1/AE3), desmin and epithelial membrane antigen. The proliferation marker Ki-67 was positive in <5% of tumor cell nuclei. The clinical procedures with a review of the literature are reported.
doi:10.3892/ol.2014.1986
PMCID: PMC4049669  PMID: 24932234
gastric glomus tumor; immunohistochemistry; diagnosis; treatment
22.  Psychotic-affective symptoms and multiple system atrophy expand phenotypes of spinocerebellar ataxia type 2 
BMJ Case Reports  2012;2012:bcr1020115061.
Spinocerebellar ataxia type 2 (SCA2) is a progressive neurodegenerative disorder, characterised by ataxic gait, slow saccades and peripheral neuropathy. Levodopa-responsive parkinsonism could be a clinical phenotype of SCA2, especially those of Chinese origin. In addition to these motor symptoms, SCA2 has been associated with depression and cognitive dysfunction, with only rare reports of psychosis. The authors report the presence of severe psychosis, major depression and multiple system atrophy in affected subjects of a Taiwanese family with intermediate CAG repeats within the ATXN2 gene. The identification of this rare and distinctive SCA2 phenotype expands the current knowledge of the phenotypic variability of SCA2 and suggests that modifier genes could influence the clinical phenotype of SCA2.
doi:10.1136/bcr.10.2011.5061
PMCID: PMC3316827  PMID: 22605703
23.  Monodispersed bimetallic PdAg nanoparticles with twinned structures: Formation and enhancement for the methanol oxidation 
Scientific Reports  2014;4:4288.
Monodispersed bimetallic PdAg nanoparticles can be fabricated through the emulsion-assisted ethylene glycol (EG) ternary system. Different compositions of bimetallic PdAg nanoparticles, Pd80Ag20, Pd65Ag35 and Pd46Ag54 can be obtained via adjusting the reaction parameters. For the formation process of the bimetallic PdAg nanoparticles, there have two-stage growth processes: firstly, nucleation and growth of the primary nanoclusters; secondly, formation of the secondary nanoparticles with the size-selection and relax process via the coalescence or aggregation of the primary nanoclusters. The as-prepared PdAg can be supported on the carbon black without any post-treatment, which exhibited high electro-oxidation activity towards methanol oxidation under alkaline media. More importantly, carbon-supported Pd80Ag20 nanoparticles reveal distinctly superior activities for the methanol oxidation, even if compared with commercial Pt/C electro-catalyst. It is concluded that the enhanced activity is dependant on the unique twinning structure with heterogeneous phase due to the dominating coalescence growth in EG ternary system.
doi:10.1038/srep04288
PMCID: PMC3948072  PMID: 24608736
24.  ArdA proteins from different mobile genetic elements can bind to the EcoKI Type I DNA methyltransferase of E. coli K12☆ 
Biochimica et Biophysica Acta  2014;1844(3):505-511.
Anti-restriction and anti-modification (anti-RM) is the ability to prevent cleavage by DNA restriction–modification (RM) systems of foreign DNA entering a new bacterial host. The evolutionary consequence of anti-RM is the enhanced dissemination of mobile genetic elements. Homologues of ArdA anti-RM proteins are encoded by genes present in many mobile genetic elements such as conjugative plasmids and transposons within bacterial genomes. The ArdA proteins cause anti-RM by mimicking the DNA structure bound by Type I RM enzymes. We have investigated ArdA proteins from the genomes of Enterococcus faecalis V583, Staphylococcus aureus Mu50 and Bacteroides fragilis NCTC 9343, and compared them to the ArdA protein expressed by the conjugative transposon Tn916. We find that despite having very different structural stability and secondary structure content, they can all bind to the EcoKI methyltransferase, a core component of the EcoKI Type I RM system. This finding indicates that the less structured ArdA proteins become fully folded upon binding. The ability of ArdA from diverse mobile elements to inhibit Type I RM systems from other bacteria suggests that they are an advantage for transfer not only between closely-related bacteria but also between more distantly related bacterial species.
Highlights
•Diverse ArdA proteins all target the EcoKI Type I DNA modification enzyme.•ArdA proteins have variable secondary structure content.•ArdA all bind equally well to EcoKI despite stability variations.
doi:10.1016/j.bbapap.2013.12.008
PMCID: PMC3969726  PMID: 24368349
RM, restriction–modification; anti-RM, antirestriction/antimodification; MGE, mobile genetic element; MTase, modification methyltransferase; M subunit, modification subunit; S subunit, sequence specificity subunit; Orf, open reading frame; CD, circular dichroism; GuCl, guanidinium chloride; 2-ME, 2-mercaptoethanol; SEC, size exclusion chromatography; Kd, dissociation constant; DNA methyltransferase; ArdA protein; DNA mimic; Horizontal gene transfer
25.  An Investigation of Factors Affecting Elementary School Students' BMI Values Based on the System Dynamics Modeling 
This study used system dynamics method to investigate the factors affecting elementary school students' BMI values. The construction of the dynamic model is divided into the qualitative causal loop and the quantitative system dynamics modeling. According to the system dynamics modeling, this study consisted of research on the four dimensions: student's personal life style, diet-relevant parenting behaviors, advocacy and implementation of school nutrition education, and students' peer interaction. The results of this study showed that students with more adequate health concepts usually have better eating behaviors and consequently have less chance of becoming obese. In addition, this study also verified that educational attainment and socioeconomic status of parents have a positive correlation with students' amounts of physical activity, and nutrition education has a prominent influence on changing students' high-calorie diets.
doi:10.1155/2014/575424
PMCID: PMC3950593  PMID: 24701250

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