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1.  WASH complex regulates Arp2/3 complex for actin-based polar body extrusion in mouse oocytes 
Scientific Reports  2014;4:5596.
Prior to their fertilization, oocytes undergo asymmetric division, which is regulated by actin filaments. Recently, WASH complex were identified as actin nucleation promoting factors (NPF) that activated Arp2/3 complex. However, the roles of WASH complex remain uncertain, particularly for oocyte polarization and asymmetric division. Here, we examined the functions of two important subunits of a WASH complex, WASH1 and Strumpellin, during mouse oocyte meiosis. Depleting WASH1 or disrupting Strumpellin activity by WASH1 morpholino (MO) injection or Strumpellin antibody injection decreased polar body extrusion and caused oocyte symmetric division, and this may have been due to spindle formation and migration defects. Time lapse microscopy showed that actin filaments distribution and relative amount at the membrane and in the cytoplasm of oocytes was significantly decreased after disrupting WASH complex. In addition, Arp2/3 complex expression was reduced after WASH1 depletion. Thus, our data indicated that WASH complex regulated Arp2/3 complex and were required for cytokinesis and following polar body extrusion during mouse oocyte meiotic maturation.
doi:10.1038/srep05596
PMCID: PMC4083260  PMID: 24998208
2.  Modulation of the Epithelial Sodium Channel (ENaC) by Bacterial Metalloproteases and Protease Inhibitors 
PLoS ONE  2014;9(6):e100313.
The serralysin family of metalloproteases is associated with the virulence of multiple gram-negative human pathogens, including Pseudomonas aeruginosa and Serratia marcescens. The serralysin proteases share highly conserved catalytic domains and show evolutionary similarity to the mammalian matrix metalloproteases. Our previous studies demonstrated that alkaline protease (AP) from Pseudomonas aeruginosa is capable of activating the epithelial sodium channel (ENaC), leading to an increase in sodium absorption in airway epithelia. The serralysin proteases are often co-expressed with endogenous, intracellular or periplasmic inhibitors, which putatively protect the bacterium from unwanted or unregulated protease activities. To evaluate the potential use of these small protein inhibitors in regulating the serralysin induced activation of ENaC, proteases from Pseudomonas aeruginosa and Serratia marcescens were purified for characterization along with a high affinity inhibitor from Pseudomonas. Both proteases showed activity against in vitro substrates and could be blocked by near stoichiometric concentrations of the inhibitor. In addition, both proteases were capable of activating ENaC when added to the apical surfaces of multiple epithelial cells with similar slow activation kinetics. The high-affinity periplasmic inhibitor from Pseudomonas effectively blocked this activation. These data suggest that multiple metalloproteases are capable of activating ENaC. Further, the endogenous, periplasmic bacterial inhibitors may be useful for modulating the downstream effects of the serralysin virulence factors under physiological conditions.
doi:10.1371/journal.pone.0100313
PMCID: PMC4070987  PMID: 24963801
3.  Glutamate and Lipid Metabolic Perturbation in the Hippocampi of Asymptomatic Borna Disease Virus-Infected Horses 
PLoS ONE  2014;9(6):e99752.
Borna disease virus (BDV) is a neurotropic, enveloped, non-segmented, negative-stranded RNA virus that infects a wide variety of vertebrate species from birds to humans across a broad global geographic distribution. Animal symptomatology range from asymptomatic infection to behavioral abnormalities to acute meningoencephalitis. Asymptomatic BDV infection has been shown to be more frequent than conventionally estimated. However, the molecular mechanism(s) underyling asymptomatic BDV infection remain largely unknown. Here, based on real-time quantitative PCR and Western blotting, a total of 18 horse hippocampi were divided into BDV-infected (n = 8) and non-infected control (n = 10) groups. A gas chromatography coupled with mass spectrometry (GC-MS) metabolomic approach, in conjunction with multivariate statistical analysis, was used to characterize the hippocampal metabolic changes associated with asymptomatic BDV infection. Multivariate statistical analysis showed a significant discrimination between the BDV-infected and control groups. BDV-infected hippocampi were characterized by lower levels of D-myo-inositol-1-phosphate, glutamate, phosphoethanolamine, heptadecanoic acid, and linoleic acid in combination with a higher level of ammonia. These differential metabolites are primarily involved in glutamate and lipid metabolism. These finding provide an improved understanding of hippocampal changes associated with asymptomatic BDV infection.
doi:10.1371/journal.pone.0099752
PMCID: PMC4067290  PMID: 24956478
4.  SAR Based Optimization of a 4-Quinoline Carboxylic Acid Analog with Potent Anti-Viral Activity 
ACS medicinal chemistry letters  2013;4(6):517-521.
It is established that drugs targeting viral proteins are at risk of generating resistant strains. However, drugs targeting host factors can potentially avoid this problem. Herein we report structure-activity relationship studies leading to the discovery of a very potent lead compound 6-fluoro-2-(5-isopropyl-2-methyl-4-phenoxyphenyl)quinoline-4-carboxylic acid (C44) that inhibits human dihydroorotate dehydrogenase (DHODH) with an IC50 of 1 nM, and viral replication of VSV and WSN-Influenza with an EC50 of 2 nM and 41 nM. We also solved the X-ray structure of human DHODH bound to C44, providing structural insight into the potent inhibition of biaryl ether analogs of brequinar.
doi:10.1021/ml300464h
PMCID: PMC3733392  PMID: 23930152
high-throughput screening; structure-activity relationship; anti-viral; human DHODH inhibitor
5.  SAR-Based Optimization of a 4-Quinoline Carboxylic Acid Analogue with Potent Antiviral Activity 
ACS Medicinal Chemistry Letters  2013;4(6):517-521.
It is established that drugs targeting viral proteins are at risk of generating resistant strains. However, drugs targeting host factors can potentially avoid this problem. Herein, we report structure–activity relationship studies leading to the discovery of a very potent lead compound 6-fluoro-2-(5-isopropyl-2-methyl-4-phenoxyphenyl)quinoline-4-carboxylic acid (C44) that inhibits human dihydroorotate dehydrogenase (DHODH) with an IC50 of 1 nM and viral replication of VSV and WSN-Influenza with an EC50 of 2 nM and 41 nM. We also solved the X-ray structure of human DHODH bound to C44, providing structural insight into the potent inhibition of biaryl ether analogues of brequinar.
doi:10.1021/ml300464h
PMCID: PMC3733392  PMID: 23930152
High-throughput screening; structure−activity relationship; antiviral; human DHODH inhibitor
6.  Lenalidomide in relapsed or refractory mantle cell lymphoma: overview and perspective 
Lenalidomide, a novel immunomodulatory agent, was approved by the US Food and Drug Administration for the treatment of myelodysplastic syndrome and relapsed multiple myeloma. Data from preclinical studies paved the way for clinical trials of lenalidomide in mantle cell lymphoma (MCL). Initial phase I and II clinical trials of lenalidomide alone and as part of combination regimens in patients with relapsed/refractory MCL have shown promising results. Its immunomodulatory, T cell costimulatory, anti-inflammatory and anti-angiogenic actions working together in the tumor cell microenvironment seem to be responsible for its enhanced antitumor efficacy. Lenalidomide’s nature of action and safety profile favor it over other agents studied in relapsed/refractory MCL. This review summarizes the data from preclinical and clinical studies of lenalidomide in relapsed/refractory MCL and compares the results with those of other novel agents being used for relapsed/refractory MCL.
doi:10.1177/2040620714532124
PMCID: PMC4031905  PMID: 24883181
immunomodulatory agents; lenalidomide; mantle cell lymphoma
7.  Association of Myeloid Cells of Triggering Receptor-1 with Left Ventricular Systolic Dysfunction in BALB/c Mice with Sepsis 
Mediators of Inflammation  2014;2014:391492.
Objective. To investigate the correlation between TREM-1 and LPS-induced left ventricular systolic dysfunction in BALB/c mice. Methods. Male BALB/c mice were randomly divided into 3 groups: LPS, LPS/TREM-1, and control groups which were injected intraperitoneally with 25 mg/kg LPS, 5 μg TREM-1mAb 1 h after LPS challenge, and sterilized normal saline, respectively. Left ventricular systolic function was monitored by echocardiography at 6 h, 12 h, and 24 h. Meanwhile, TNF-α, IL-1β, and sTREM-1 in serum and myocardium were determined by ELISA or real-time PCR; at last left ventricles were taken for light microscopy examination. Results. FS and EF in LPS/mAbTREM-1 group, significantly declined compared with LPS and control group at 12 h, were accompanied with a markedly increase in serum IL-1β (at 6 h) and sTREM-1 (at 12 h and 24 h) expression. Myocardium TNF-α (at 6 h and 24 h) and sTREM-1 (at 6 h) were significantly higher in LPS/mAbTrem-1-treated mice than in time-matched LPS-treated mice; meanwhile myocardium TNF-α mRNA were markedly increased in comparison with LPS-treated or saline-treated mice at 24 h. Besides, mAbTREM-1 aggravated LPS-induced myocardial damage was observed. Conclusions. Our results suggest that TREM-1 is significantly associated with LPS-induced left ventricular systolic dysfunction in BALB/c mice.
doi:10.1155/2014/391492
PMCID: PMC4052473  PMID: 24959004
8.  Identification of a novel potential antitumor activity of gossypol as an APE1/Ref-1 inhibitor 
The human apurinic/apyrimidinic endonuclease 1/redox enhancing factor-1 (APE1/Ref-1), an essential multifunctional protein involved in the repair of oxidative deoxyribonucleic acid (DNA) damage and transcriptional regulation, is often overexpressed in tumor tissues and cancer cells. Moreover, APE1/Ref-1 (APE1) overexpression has been linked to chemoresistance in human tumors. Thus, inhibiting APE1 function in cancer cells is considered a promising strategy to overcome resistance to therapeutic agents. Gossypol is a Bcl-2 homology 3 (BH3)-mimetic agent and is able to bind to the BH3 domain of B-cell lymphoma 2 (Bcl-2) family members. Other studies demonstrated that Bcl-2 directly interacted with APE1 via its BH domains. Using apurinic/apyrimidinic (AP) endonuclease assays, we found that gossypol inhibits the repair activity of APE1. Electrophoretic mobility shift assays and dual luciferase assays showed that gossypol could also inhibit the redox function of APE1. Using dual polarization interferometry technology, we show that gossypol can directly interact with APE1. Furthermore, addition of gossypol, in conjunction with APE1 overexpression, leads to cancer cell death. The addition of gossypol also enhances the cell killing effect of the laboratory alkylating agent methyl methanesulfonate and the clinical agent cisplatin (DDP). Administration of gossypol significantly inhibited the growth of xenografts. Furthermore, the combined treatment of gossypol and DDP resulted in a statistically higher antitumor activity compared with DDP alone in vivo. In conclusion, we have demonstrated that gossypol effectively inhibits the repair and redox activity of APE1 through a direct interaction.
doi:10.2147/DDDT.S62963
PMCID: PMC4026309  PMID: 24872679
cancer; oxidative DNA damage; BH3-mimetic
9.  Electroacupuncture for thalidomide/bortezomib-induced peripheral neuropathy in multiple myeloma: a feasibility study 
Background
This single-arm study evaluated feasibility, safety, and initial efficacy of electroacupuncture for thalidomide/bortezomib-induced peripheral neuropathy (PN) in cancer patients with multiple myeloma.
Methods
Patients with neuropathy ≥ grade 2 received 20 acupuncture treatments over 9 weeks.
Results
For the 19 evaluable patients, Functional Assessment of Cancer Therapy/Gynecological Oncology Group-Neurotoxicity (FACT/GOG/NTX) mean (SD) scores improved significantly between baseline and week 13 (20.8 [9.6] vs 13.2 [8.5], p = 0.0002). Moderate effect size differences began on week 4, with the largest effect size differences found at week 9 for FACT/GOG/NTX scores, worst pain in the last 24 hours, and pain severity (Cohen’s d = 1.43, 1.19, and 1.08, respectively) and continuing through week 13 (Cohen’s d = 0.86, 0.88, and 0.90, respectively). From baseline to week 13, additional significant improvements were seen as follows: postural stability (1.0 [0.6] vs 0.8 [0.4], p = 0.02); coin test (10.0 [7.4] vs 5.6 [1.9], p < 0.0001); button test (96.1 [144.4] vs 54.9 [47.3], p < 0.0001); and walking test (21.6 [10.0] vs 17.2 [7.7], p = 0.0003). No significant changes were seen with NCS.
Conclusions
Acupuncture may help patients experiencing thalidomide- or bortezomib-induced PN. Larger, randomized, clinical trials are needed.
Trial registration
ClinicalTrials.gov Identifier: NCT00891618.
doi:10.1186/1756-8722-7-41
PMCID: PMC4038108  PMID: 24886772
Acupuncture; Myeloma; Chemotherapy; Peripheral neuropathy; Integrative medicine
10.  Arabidopsis ABA Receptor RCAR1/PYL9 Interacts with an R2R3-Type MYB Transcription Factor, AtMYB44 
Abscisic acid (ABA) signaling plays important roles in plant growth, development and adaptation to various stresses. RCAR1/PYL9 has been known as a cytoplasm and nuclear ABA receptor in Arabidopsis. To obtain further insight into the regulatory mechanism of RCAR1/PYL9, a yeast two-hybrid approach was performed to screen for RCAR1/PYL9-interacting proteins and an R2R3-type MYB transcription factor, AtMYB44, was identified. The interaction between RCAR1/PYL9 and AtMYB44 was further confirmed by glutathione S-transferase (GST) pull-down and bimolecular fluorescence complementation (BiFC) assays. Gene expression analysis showed that AtMYB44 negatively regulated the expression of ABA-responsive gene RAB18, in contrast to the opposite role reported for RCAR1/PYL9. Competitive GST pull-down assay and analysis of phosphatase activity demonstrated that AtMYB44 and ABI1 competed for binding to RCAR1/PYL9 and thereby reduced the inhibitory effect of RCAR1/PYL9 on ABI1 phosphatase activity in the presence of ABA in vitro. Furthermore, transient activation assay in protoplasts revealed AtMYB44 probably also decreased RCAR1/PYL9-mediated inhibition of ABI1 activity in vivo. Taken together, our work provides a reasonable molecular mechanism of AtMYB44 in ABA signaling.
doi:10.3390/ijms15058473
PMCID: PMC4057743  PMID: 24828206
ABA; signaling; RCAR1/PYL9; receptor; AtMYB44; ABI1
11.  Regulating hippocampal hyperexcitability through GABAB Receptors 
Physiological Reports  2014;2(4):e00278.
Abstract
Disturbances of GABAergic inhibition are a major cause of epileptic seizures. GABA exerts its actions via ionotropic GABAA receptors and metabotropic G protein‐coupled GABAB receptors. Malfunction of GABAA inhibition has long been recognized in seizure genesis but the role of GABAB receptors in controlling seizure activity is still not well understood. Here, we examined the anticonvulsive, or inhibitory effects, of GABAB receptors in a mouse model of hippocampal kindling as well as mouse hippocampal slices through the use of GS 39783, a positive allosteric GABAB receptor modulator, and CGP 55845, a selective GABAB receptor antagonist. When administered via intraperitoneal injections in kindled mice, GS 39783 (5 mg/kg) did not attenuate hippocampal EEG discharges, but did reduce aberrant hippocampal spikes, whereas CGP 55845 (10 mg/kg) prolonged hippocampal discharges and increased spike incidences. When examined in hippocampal slices, neither GS 39783 at 5 μmol/L nor the GABAB receptor agonist baclofen at 0.1 μmol/L alone significantly altered repetitive excitatory field potentials, but GS 39783 and baclofen together reversibly abolished these field potentials. In contrast, CGP 55845 at 1 μmol/L facilitated induction and incidence of these field potentials. In addition, CGP 55845 attenuated the paired pulse depression of CA3 population spikes and increased the frequency of EPSCs in individual CA3 pyramidal neurons. Collectively, these data suggest that GABABB receptors regulate hippocampal hyperexcitability by inhibiting CA3 glutamatergic synapses. We postulate that positive allosteric modulation of GABAB receptors may be effective in reducing seizure‐related hyperexcitability.
GABAB positive modulator GS 39783 attenuated, whereas GABAB antagonist CGP55845 facilitated hippocampal EEG spikes in kindled mice and excitatory field potentials in hippocampal slices. We postulate that GABAB receptors may inhibit CA3 glutamate synapses and hence regulate hippocampal hyperexcitability.
doi:10.1002/phy2.278
PMCID: PMC4001873  PMID: 24771688
Allosteric; EEG; epilepsy; hippocampus; kindling; mice; seizure; slices
12.  Transcription Factor ZBED6 Mediates IGF2 Gene Expression by Regulating Promoter Activity and DNA Methylation in Myoblasts 
Scientific Reports  2014;4:4570.
Zinc finger, BED-type containing 6 (ZBED6) is an important transcription factor in placental mammals, affecting development, cell proliferation and growth. In this study, we found that the expression of the ZBED6 and IGF2 were upregulated during C2C12 differentiation. The IGF2 expression levels were negatively associated with the methylation status in beef cattle (P < 0.05). A luciferase assay for the IGF2 intron 3 and P3 promoter showed that the mutant-type 439 A-SNP-pGL3 in driving reporter gene transcription is significantly higher than that of the wild-type 439 G-SNP-pGL3 construct (P < 0.05). An over-expression assay revealed that ZBED6 regulate IGF2 expression and promote myoblast differentiation. Furthermore, knockdown of ZBED6 led to IGF2 expression change in vitro. Taken together, these results suggest that ZBED6 inhibits IGF2 activity and expression via a G to A transition disrupts the interaction. Thus, we propose that ZBED6 plays a critical role in myogenic differentiation.
doi:10.1038/srep04570
PMCID: PMC3972505  PMID: 24691566
13.  Integrated care: a comprehensive bibliometric analysis and literature review 
Introduction
Integrated care could not only fix up fragmented health care but also improve the continuity of care and the quality of life. Despite the volume and variety of publications, little is known about how ‘integrated care’ has developed. There is a need for a systematic bibliometric analysis on studying the important features of the integrated care literature.
Aim
To investigate the growth pattern, core journals and jurisdictions and identify the key research domains of integrated care.
Methods
We searched Medline/PubMed using the search strategy ‘(delivery of health care, integrated [MeSH Terms]) OR integrated care [Title/Abstract]’ without time and language limits. Second, we extracted the publishing year, journals, jurisdictions and keywords of the retrieved articles. Finally, descriptive statistical analysis by the Bibliographic Item Co-occurrence Matrix Builder and hierarchical clustering by SPSS were used.
Results
As many as 9090 articles were retrieved. Results included: (1) the cumulative numbers of the publications on integrated care rose perpendicularly after 1993; (2) all documents were recorded by 1646 kinds of journals. There were 28 core journals; (3) the USA is the predominant publishing country; and (4) there are six key domains including: the definition/models of integrated care, interdisciplinary patient care team, disease management for chronically ill patients, types of health care organizations and policy, information system integration and legislation/jurisprudence.
Discussion and conclusion
Integrated care literature has been most evident in developed countries. International Journal of Integrated Care is highly recommended in this research area. The bibliometric analysis and identification of publication hotspots provides researchers and practitioners with core target journals, as well as an overview of the field for further research in integrated care.
PMCID: PMC4059213  PMID: 24987322
integrated care; bibliometric analysis; delivery of health care; integrated; literature review
14.  Network Models Predict that Reduced Excitatory Fluctuations Can Give Rise to Hippocampal Network Hyper-Excitability in MeCP2-Null Mice 
PLoS ONE  2014;9(3):e91148.
Rett syndrome is a severe pediatric neurological disorder caused by loss of function mutations within the gene encoding methyl CpG-binding protein 2 (MeCP2). Although MeCP2 is expressed near ubiquitously, the primary pathophysiology of Rett syndrome stems from impairments of nervous system function. One alteration within different regions of the MeCP2-deficient brain is the presence of hyper-excitable network responses. In the hippocampus, such responses exist despite there being an overall decrease in spontaneous excitatory drive within the network. In this study, we generated and used mathematical, neuronal network models to resolve this apparent paradox. We did this by taking advantage of previous mathematical modelling insights that indicated that decreased excitatory fluctuations, but not mean excitatory drive, more critically explain observed changes in hippocampal network oscillations from MeCP2-null mouse slices. Importantly, reduced excitatory fluctuations could also bring about hyper-excitable responses in our network models. Therefore, these results indicate that diminished excitatory fluctuations may be responsible for the hyper-excitable state of MeCP2-deficient hippocampal circuitry.
doi:10.1371/journal.pone.0091148
PMCID: PMC3958347  PMID: 24642514
15.  Rewiring of regenerated axons by combining treadmill training with semaphorin3A inhibition 
Molecular Brain  2014;7:14.
Background
Rats exhibit extremely limited motor function recovery after total transection of the spinal cord (SCT). We previously reported that SM-216289, a semaphorin3A inhibitor, enhanced axon regeneration and motor function recovery in SCT adult rats. However, these effects were limited because most regenerated axons likely do not connect to the right targets. Thus, rebuilding the appropriate connections for regenerated axons may enhance recovery. In this study, we combined semaphorin3A inhibitor treatment with extensive treadmill training to determine whether combined treatment would further enhance the “rewiring” of regenerated axons. In this study, which aimed for clinical applicability, we administered a newly developed, potent semaphorin3A inhibitor, SM-345431 (Vinaxanthone), using a novel drug delivery system that enables continuous drug delivery over the period of the experiment.
Results
Treatment with SM-345431 using this delivery system enhanced axon regeneration and produced significant, but limited, hindlimb motor function recovery. Although extensive treadmill training combined with SM-345431 administration did not further improve axon regeneration, hindlimb motor performance was restored, as evidenced by the significant improvement in the execution of plantar steps on a treadmill. In contrast, control SCT rats could not execute plantar steps at any point during the experimental period. Further analyses suggested that this strategy reinforced the wiring of central pattern generators in lumbar spinal circuits, which, in turn, led to enhanced motor function recovery (especially in extensor muscles).
Conclusions
This study highlights the importance of combining treatments that promote axon regeneration with specific and appropriate rehabilitations that promote rewiring for the treatment of spinal cord injury.
doi:10.1186/1756-6606-7-14
PMCID: PMC4008261  PMID: 24618249
Axonal regeneration; Semaphorin3A; Inhibitor; Rehabilitation; Rewiring; Drug delivery system
16.  Enhancement of Antitumor Immunity Using a DNA-Based Replicon Vaccine Derived from Semliki Forest Virus 
PLoS ONE  2014;9(3):e90551.
A DNA-based replicon vaccine derived from Semliki Forest virus, PSVK-shFcG-GM/B7.1 (Fig. 1a) was designed for tumor immunotherapy as previously constructed. The expression of the fusion tumor antigen (survivin and hCGβ-CTP37) and adjuvant molecular protein (Granulocyte-Macrophage Colony-Stimulating Factor/ GM-CSF/B7.1) genes was confirmed by Immunofluorescence assay in vitro, and immunohistochemistry assay in vivo. In this paper, the immunological effect of this vaccine was determined using immunological assays as well as animal models. The results showed that this DNA vaccine induced both humoral and cellular immune responses in C57BL/6 mice after immunization, as evaluated by the ratio of CD4+/CD8+ cells and the release of IFN-γ. Furthermore, the vaccination of C57BL/6 mice with PSVK-shFcG-GM/B7.1 significantly delayed the in vivo growth of tumors in animal models (survivin+ and hCGβ+ murine melanoma, B16) when compared to vaccination with the empty vector or the other control constructs (Fig. 1b). These data indicate that this type of replicative DNA vaccine could be developed as a promising approach for tumor immunotherapy. Meanwhile, these results provide a basis for further study in vaccine pharmacodynamics and pharmacology, and lay a solid foundation for clinical application.
doi:10.1371/journal.pone.0090551
PMCID: PMC3946523  PMID: 24608380
17.  Energy-Efficient Routing Control Algorithm in Large-Scale WSN for Water Environment Monitoring with Application to Three Gorges Reservoir Area 
The Scientific World Journal  2014;2014:802915.
The typical application backgrounds of large-scale WSN (wireless sensor networks) for the water environment monitoring in the Three Gorges Reservoir are large coverage area and wide distribution. To maximally prolong lifetime of large-scale WSN, a new energy-saving routing algorithm has been proposed, using the method of maximum energy-welfare optimization clustering. Firstly, temporary clusters are formed based on two main parameters, the remaining energy of nodes and the distance between a node and the base station. Secondly, the algorithm adjusts cluster heads and optimizes the clustering according to the maximum energy-welfare of the cluster by the cluster head shifting mechanism. Finally, in order to save node energy efficiently, cluster heads transmit data to the base station in single-hop and multihop way. Theoretical analysis and simulation results show that the proposed algorithm is feasible and advanced. It can efficiently save the node energy, balance the energy dissipation of all nodes, and prolong the network lifetime.
doi:10.1155/2014/802915
PMCID: PMC3967459  PMID: 24741360
18.  CXCR4/CXCL12 mediate autocrine cell cycle progression in NF1-associated malignant peripheral nerve sheath tumors 
Cell  2013;152(5):1077-1090.
Malignant Peripheral Nerve Sheath Tumors (MPNSTs) are soft tissue sarcomas that arise in connective tissue surrounding peripheral nerves. They occur sporadically in a subset of patients with Neurofibromatosis type-1 (NF1). MPNSTs are highly aggressive, therapeutically resistant, and typically fatal. Using comparative transcriptome analysis, we identified CXCR4, a G protein-coupled receptor, as highly expressed in mouse models of NF1-deficient MPNSTs, but not in non-transformed precursor cells. The chemokine receptor CXCR4 and its ligand, CXCL12, promote MPNST growth by stimulating cyclin D1 expression and cell cycle progression through PI3-Kinase (PI3K) and β-catenin signaling. Suppression of CXCR4 activity, either by shRNA or pharmacological inhibition decreases MPNST cell growth in culture and inhibits tumorigenesis in allografts and in spontaneous genetic mouse models of MPNST. We further demonstrate conservation of these activated molecular pathways in human MPNSTs. Our findings indicate a role for CXCR4 in NF1-associated MPNST development, and identify a novel therapeutic target.
doi:10.1016/j.cell.2013.01.053
PMCID: PMC3594500  PMID: 23434321
19.  The Prevalence and Molecular Spectrum of α- and β-Globin Gene Mutations in 14,332 Families of Guangdong Province, China 
PLoS ONE  2014;9(2):e89855.
Objective
To reveal the familial prevalence and molecular variation of α- and β-globin gene mutations in Guangdong Province.
Methods
A total of 40,808 blood samples from 14,332 families were obtained and analyzed for both hematological and molecular parameters.
Results
A high prevalence of α- and β-globin gene mutations was found. Overall, 17.70% of pregnant women, 15.94% of their husbands, 16.03% of neonates, and 16.83% of couples (pregnant women and their husbands) were heterozygous carriers of α- or β-thalassemia. The regions with the highest prevalence were the mountainous and western regions, followed by the Pearl River Delta; the region with the lowest prevalence was Chaoshan. The total familial carrier rate (both spouses were α- or β-thalassemia carriers) was 1.87%, and the individual carrier rates of α- and β-thalassemia were 1.68% and 0.20%, respectively. The total rate of moderate-to-severe fetal thalassemia was 12.78% among couples in which both parents were carriers.
Conclusions
There was a high prevalence of α- and β-thalassemia in Guangdong Province. This study will contribute to the development of thalassemia prevention and control strategies in Guangdong Province.
doi:10.1371/journal.pone.0089855
PMCID: PMC3937408  PMID: 24587075
20.  Genome-wide association study in Han Chinese identifies four new susceptibility loci for coronary artery disease 
Nature genetics  2012;44(8):890-894.
We performed a meta-analysis of 2 genome-wide association studies of coronary artery disease comprising 1,515 cases with coronary artery disease and 5,019 controls, followed by de novo replication studies in 15,460 cases and 11,472 controls, all of Chinese Han descent. We successfully identified four new loci for coronary artery disease reaching genome-wide significance (P < 5 × 10−8), which mapped in or near TTC32-WDR35, GUCY1A3, C6orf10-BTNL2 and ATP2B1. We also replicated four loci previously identified in European populations (PHACTR1, TCF21, CDKN2A/B and C12orf51). These findings provide new insights into biological pathways for the susceptibility of coronary artery disease in Chinese Han population.
doi:10.1038/ng.2337
PMCID: PMC3927410  PMID: 22751097
21.  Loss of the TNFα function inhibits Wnt/β-catenin signaling, exacerbates obesity development in adolescent spontaneous obese mice 
Tumor necrosis factor alpha (TNFα) is an adipokine involved in the regulation of cell differentiation and lipid metabolism, but its specific role has not been clearly understood. We validated a hypothesis that loss of TNFα function would inhibit Wnt/β-catenin signaling and accelerate adipogenesis in adolescent genetic obese mice. Epididymal white adipose tissues (eWAT) from TNFα deficient (TNFα−/−), leptin receptor deficient (db/db) and double gene mutant (db/db/TNFα−/−, DT) male mice were used for comparative analysis of key molecules in Wnt/β-catenin signaling and adipogenic markers by qRT-PCR and western blot techniques. Compared with TNFα−/− and WT mice of 28 days old, an obese trait was observed in both db/db and DT mice, while the latter showed more significant body weight gain and eWAT hypertrophy. The mRNA level of key molecules in Wnt/β-catenin pathway was reduced in both obese groups, while the DT group was the lowest. Expression of adipocyte-specific genes was up-regulated during obese development in the two obese groups, while the DT group revealed more correlation than that of db/db group. At the protein level, a down regulation of Wnt10b and β-catenin in obese eWAT showed similar tendency with that of mRNA level. Compared with the lean groups, the levels of adiponectin and PPARγ2 for the obese groups were down-regulated at 21-day-old age, while they were elevated at older age. Our results suggested that deficiency in TNFα inhibited Wnt/β-catenin signaling of the obese eWAT and up-regulated expression of adipokines, and accelerated adipogenesis in genetic obese mice on a chow diet.
Electronic supplementary material
The online version of this article (doi:10.1007/s11010-014-1987-5) contains supplementary material, which is available to authorized users.
doi:10.1007/s11010-014-1987-5
PMCID: PMC4006126  PMID: 24522555
TNFα; Wnt/β-catenin signaling; Leptin receptor; Obesity; Adipocyte
22.  A new technique combining virtual simulation and methylene blue staining for the localization of small peripheral pulmonary lesions 
BMC Cancer  2014;14:79.
Background
Quickly and accurately localizing small peripheral pulmonary lesions can avoid prolonged operative time and unplanned open thoracotomy. In this study, we aimed to introduce and evaluate a new technique combining virtual simulation and methylene blue staining for the localization of small peripheral pulmonary lesions.
Methods
Seventy four (74) patients with 80 peripheral pulmonary lesions <20 mm in size on computer tomography (CT) were virtually punctured using a radiotherapy planning simulator on the day before operation. Under general anaesthesia, methylene blue dye was injected to the virtually identified point according to the surface point, angle and depth previously determined by the simulator. The wedge resection of the marked lesion was performed under video-assisted thoracoscopic surgery (VATS) and the specimens were sent for immediate pathologic examination. According to pathology results, appropriate surgical procedures were decided and undertaken.
Results
The average lesion size was 10.4±3.5 mm (range: 4-17 mm) and the average distance to the pleural surface was 9.4±4.9 mm. Our preoperative localization procedure was successful in 75 of 80 (94%) lesions. Histological examination showed 28 benign lesions and 52 lung cancers. The shortest distance between the edges of the stain and lesion was 5.1±3.1 mm. Localization time was 17.4±2.3 min. All patients with malignant lesions subsequently underwent lobectomy and systematic lymph node dissection. No complications were observed in all participants.
Conclusions
The novel technique combining the preoperative virtual simulation and methylene blue staining techniques has a high success rate for localizing small peripheral pulmonary lesions, particularly for those tiny lesions which are difficult to visualise and palpate during VATS.
doi:10.1186/1471-2407-14-79
PMCID: PMC3926337  PMID: 24512571
Lung cancer; Pulmonary lesions; Thoracoscopy; Localization; Simulation; Methylene blue
23.  Induction of Specific Humoral and Cellular Immune Responses in a Mouse Model following Gene Fusion of HSP70C and Hantaan Virus Gn and S0.7 in an Adenoviral Vector 
PLoS ONE  2014;9(2):e88183.
Heat shock proteins (HSPs) display adjuvant functions when given as fusion proteins to enhance vaccination efficiency. To evaluate enhanced potency of Hantaan virus (HTNV) glycoprotein (GP) and nucleocapsid protein (NP) immunogenicity by heat shock protein 70 (HSP70), a recombinant adenovirus rAd-GnS0.7-pCAG-HSP70C expression vector was developed by genetically linking the HSP70 C-terminal gene (HSP70 359–610 aa, HSP70C) to the Gn and 0.7 kb fragment of the NP (aa1–274-S0.7). C57BL/6 mice were immunized with these recombinant adenoviral vectors. A series of immunological assays determined the immunogenicity of the recombinant adenoviral vectors. The results showed that rAd-GnS0.7-pCAG-HSP70C induced a stronger humoral and cellular immune response than other recombinant adenoviruses (rAd-GnS0.7-pCAG and rAd-GnS0.7) and the HFRS vaccine control. Animal protection experiments showed that rAd-GnS0.7-pCAG-HSP70C was effective at protecting C57BL/6 mice from HTNV infection. The results of the immunological experiments showed that HSP70C lead to enhanced vaccine potency, and suggested significant potential in the development of genetically engineered vaccines against HTNV.
doi:10.1371/journal.pone.0088183
PMCID: PMC3913774  PMID: 24505421
24.  Induction of Apoptosis in Human Multiple Myeloma Cell Lines by Ebselen via Enhancing the Endogenous Reactive Oxygen Species Production 
BioMed Research International  2014;2014:696107.
Ebselen a selenoorganic compound showing glutathione peroxidase like activity is an anti-inflammatory and antioxidative agent. Its cytoprotective activity has been investigated in recent years. However, experimental evidence also shows that ebselen causes cell death in several cancer cell types whose mechanism has not yet been elucidated. In this study, we examined the effect of ebselen on multiple myeloma (MM) cell lines in vitro. The results showed that ebselen significantly enhanced the production of reactive oxygen species (ROS) accompanied by cell viability decrease and apoptosis rate increase. Further studies revealed that ebselen can induce Bax redistribution from the cytosol to mitochondria leading to mitochondrial membrane potential ΔΨm changes and cytochrome C release from the mitochondria to cytosol. Furtherly, we found that exogenous addition of N-acetyl cysteine (NAC) completely diminished the cell damage induced by ebselen. This result suggests that relatively high concentration of ebselen can induce MM cells apoptosis in culture by enhancing the production of endogenous ROS and triggering mitochondria mediated apoptotic pathway.
doi:10.1155/2014/696107
PMCID: PMC3921973  PMID: 24587987
25.  Quantitative Assessment of the Influence of TP63 Gene Polymorphisms and Lung Cancer Risk: Evidence Based on 93,751 Subjects 
PLoS ONE  2014;9(1):e87004.
Background
Several genome-wide association studies on lung cancer (LC) have reported similar findings of a new susceptibility locus, 3q28. After that, a number of studies reported that the rs10937405, and rs4488809 polymorphism in chromosome 3q28 has been implicated in LC risk. However, the studies have yielded contradictory results.
Methods
PubMed, ISI web of science, EMBASE and the Chinese National Knowledge Infrastructure databases were systematically searched to identify relevant studies. Data were abstracted independently by two reviewers. A meta-analysis was performed to examine the association between rs10937405, rs4488809 polymorphism at 3q28 and susceptibility to LC. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. Heterogeneity and publication bias were also tested.
Results
A total of 9 studies including 35,961 LC cases and 57,790 controls were involved in this meta-analysis. An overall random-effects per-allele OR of1.19 (95% CI: 1.14–1.25; P<10−5) and 1.19 (95% CI: 1.13–1.25; P<10−5) was found for the rs10937405 and rs4488809 polymorphism respectively. Similar results were also observed using dominant or recessive genetic model. After stratified by ethnicity, significant associations were found among East Asians (per-allele OR = 1.22, 95% CI: 1.17–1.27; P<10−5); whereas no significant associations were found among Caucasians for rs10937405. In the sub-group analysis by sample size, significantly increased risks were found for these polymorphisms in all genetic models. When analyzed according to histological type, the effects of rs10937405, and rs4488809 at 3q28 on the risk of lung cancer were significant mostly for lung adenocarcinoma.
Conclusions
Our findings demonstrated that rs10937405-G allele and rs4488809-G allele might be risk-conferring factors for the development of lung cancer, especially for East Asian populations.
doi:10.1371/journal.pone.0087004
PMCID: PMC3900682  PMID: 24466311

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