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1.  Evaluation of voltage-dependent calcium channel γ gene families identified several novel potential susceptible genes to schizophrenia 
Scientific Reports  2016;6:24914.
Voltage-gated L-type calcium channels (VLCC) are distributed widely throughout the brain. Among the genes involved in schizophrenia (SCZ), genes encoding VLCC subunits have attracted widespread attention. Among the four subunits comprising the VLCC (α − 1, α −2/δ, β, and γ), the γ subunit that comprises an eight-member protein family is the least well understood. In our study, to further investigate the risk susceptibility by the γ subunit gene family to SCZ, we conducted a large-scale association study in Han Chinese individuals. The SNP rs17645023 located in the intergenic region of CACNG4 and CACNG5 was identified to be significantly associated with SCZ (OR = 0.856, P = 5.43 × 10−5). Similar results were obtained in the meta-analysis with the current SCZ PGC data (OR = 0.8853). We also identified a two-SNP haplotype (rs10420331-rs11084307, P = 1.4 × 10−6) covering the intronic region of CACNG8 to be significantly associated with SCZ. Epistasis analyses were conducted, and significant statistical interaction (OR = 0.622, P = 2.93 × 10−6, Pperm < 0.001) was observed between rs192808 (CACNG6) and rs2048137 (CACNG5). Our results indicate that CACNG4, CACNG5, CACNG6 and CACNG8 may contribute to the risk of SCZ. The statistical epistasis identified between CACNG5 and CACNG6 suggests that there may be an underlying biological interaction between the two genes.
doi:10.1038/srep24914
PMCID: PMC4840350  PMID: 27102562
2.  Synthetic antibodies and peptides recognizing progressive multifocal leukoencephalopathy-specific point mutations in polyomavirus JC capsid viral protein 1 
mAbs  2015;7(4):681-692.
Polyomavirus JC (JCV) is the causative agent of progressive multifocal leukoencephalopathy (PML), a rare and frequently fatal brain disease that afflicts a small fraction of the immune-compromised population, including those affected by AIDS and transplantation recipients on immunosuppressive drug therapy. Currently there is no specific therapy for PML. The major capsid viral protein 1 (VP1) involved in binding to sialic acid cell receptors is believed to be a key player in pathogenesis. PML-specific mutations in JCV VP1 sequences present at the binding pocket of sialic acid cell receptors, such as L55F and S269F, abolish sialic acid recognition and might favor PML onset. Early diagnosis of these PML-specific mutations may help identify patients at high risk of PML, thus reducing the risks associated with immunosuppressive therapy. As a first step in the development of such early diagnostic tools, we report identification and characterization of affinity reagents that specifically recognize PML-specific mutations in VP1 variants using phage display technology. We first identified 2 peptides targeting wild type VP1 with moderate specificity. Fine-tuning via selection of biased libraries designed based on 2 parental peptides yielded peptides with different, yet still moderate, bindinspecificities. In contrast, we had great success in identifying synthetic antibodies that recognize one of the PML-specific mutations (L55F) with high specificity from the phage-displayed libraries. These peptides and synthetic antibodies represent potential candidates for developing tailored immune-based assays for PML risk stratification in addition to complementing affinity reagents currently available for the study of PML and JCV.
doi:10.1080/19420862.2015.1038447
PMCID: PMC4623438  PMID: 25879139
phage display; synthetic antibody; protein engineering; JC virus; virus-like particle
3.  EphA1 activation promotes the homing of endothelial progenitor cells to hepatocellular carcinoma for tumor neovascularization through the SDF-1/CXCR4 signaling pathway 
Background
Endothelial progenitor cells (EPCs) can migrate to the tumor tissue and enhance the angiogenesis of hepatocellular carcinoma (HCC); thus, they are associated with a poor prognosis. However, the specific molecular mechanism underlying the homing of EPCs to the HCC neovasculature remains unrevealed.
Methods
Co-culture experiments of endothelial progenitor cells with HCC cells with modulation of EphA1 were performed in vitro. Using EPCs as angiogenic promoters by injecting them into HCC xenograft-bearing nude mice via their tail veins to test homing ability of EPCs changed according to different EphA1 level in HCC xenograft.
Results
In this study, we found that the up-regulation of EphA1 expression in HCC cells could affect not only the chemotaxis of EPCs to tumor cells and endothelial cells (ECs) but also the tube formation ability of EPCs in a paracrine fashion. Further, we revealed that the increased expression of EphA1 in HCC cells led to an increased SDF-1 concentration in the tumor microenvironment, which in turn activated the SDF-1/CXCR4 axis and enhanced the recruitment of EPCs to HCC. In addition, the EphA1-activated SDF-1 expression and secretion was partially mediated by the PI3K and mTOR pathways. In vivo experiments demonstrated that blocking EphA1/SDF-1/CXCR4 signaling significantly inhibited the growth of HCC xenografts. Using immunohistochemistry and immunofluorescence assays, we verified that the inhibition of tumor angiogenesis was at least partially caused by the decreased number of EPCs homing to tumor tissue.
Conclusions
Our findings indicate that targeting the EphA1/SDF-1 signaling pathway might be a therapeutic anti-angiogenesis approach for treating HCC.
Electronic supplementary material
The online version of this article (doi:10.1186/s13046-016-0339-6) contains supplementary material, which is available to authorized users.
doi:10.1186/s13046-016-0339-6
PMCID: PMC4827226  PMID: 27066828
EphA1; SDF-1/CXCR4; Endothelial progenitor cells; Hepatocellular carcinoma; Neovascularization
4.  Lipoxin A4 inhibits microglial activation and reduces neuroinflammation and neuropathic pain after spinal cord hemisection 
Background
Spinal cord injury (SCI) is a severe neurological disorder with many disabling consequences, including persistent neuropathic pain, which develops in about 40 % of SCI patients and is induced and sustained by excessive and uncontrolled spinal neuroinflammation. Here, we have evaluated the effects of lipoxin A4 (LXA4), a member of a unique class of endogenous lipid mediators with both anti-inflammatory and analgesic properties, on spinal neuroinflammation and chronic pain in an experimental model of SCI.
Methods
Spinal hemisection at T10 was carried out in adult male CD1 mice and Wistar rats. To test if LXA4 can reduce neuroinflammation and neuropathic pain, each animal received two intrathecal injections of LXA4 (300 pmol) or vehicle at 4 and 24 h after SCI. Sensitivity to mechanical stimulation of the hind paws was evaluated using von Frey monofilaments, and neuroinflammation was tested by measuring the mRNA and/or protein expression levels of glial markers and cytokines in the spinal cord samples after SCI. Also, microglia cultures prepared from murine cortical tissue were used to assess the direct effects of LXA4 on microglial activation and release of pro-inflammatory TNF-α.
Results
LXA4 treatment caused significant reductions in the intensity of mechanical pain hypersensitivity and spinal expression levels of microglial markers and pro-inflammatory cytokines induced by SCI, when compared to rodents receiving control vehicle injections. Notably, the increased expressions of the microglial marker IBA-1 and of the pro-inflammatory cytokine TNF-α were the most affected by the LXA4 treatment. Furthermore, cortical microglial cultures expressed ALX/FPR2 receptors for LXA4 and displayed potentially anti-inflammatory responses upon challenge with LXA4.
Conclusions
Collectively, our results suggest that LXA4 can effectively modulate microglial activation and TNF-α release through ALX/FPR2 receptors, ultimately reducing neuropathic pain in rodents after spinal cord hemisection. The dual anti-inflammatory and analgesic properties of LXA4, allied to its endogenous nature and safety profile, may render this lipid mediator as new therapeutic approach for treating various neuroinflammatory disorders and chronic pain with only limited side effects.
Electronic supplementary material
The online version of this article (doi:10.1186/s12974-016-0540-8) contains supplementary material, which is available to authorized users.
doi:10.1186/s12974-016-0540-8
PMCID: PMC4826542  PMID: 27059991
Lipoxin; Microglia; Neuroinflammation; Chronic pain; Spinal cord injury
5.  Activation of the TGFβ/SMAD Transcriptional Pathway Underlies a Novel Tumor Promoting Role of Sulfatase1 in Hepatocellular Carcinoma* 
Hepatology (Baltimore, Md.)  2015;61(4):1269-1283.
In vitro studies have proposed a tumor suppressor role for Sulfatase1 (SULF1) in hepatocellular carcinoma (HCC), however high expression in human HCC has been associated with poor prognosis. The reason underlying this paradoxical observation remains to be explored. Using a transgenic (Tg) mouse model overexpressing Sulf1 (Sulf1-Tg) we assessed the effects of SULF1 on the diethylnitrosamine (DEN) model of liver carcinogenesis. Sulf1-Tg mice show higher incidence of large and multifocal tumors with DEN injection compared to wild type (WT) mice. Lung metastases were found in 75% of Sulf1-Tg mice but not in WT mice. Immunohistochemistry (IHC), immunoblotting and reporter assays all show a significant activation of the TGFβ/SMAD transcriptional pathway by SULF1 both in vitro and in vivo. This effect of SULF1 on TGFβ/SMAD pathway is functional; overexpression of SULF1 promotes TGFβ-induced gene expression and epithelial-mesenchymal-transition (EMT), and enhances cell migration/invasiveness. Mechanistic analyses demonstrate that inactivating mutation of the catalytic site of SULF1 impairs the above actions of SULF1 and diminishes the release of TGFβ from the cell surface. And we also show that SULF1expression decreases the interaction between TGF-β1 and its HSPG sequestration receptor TGFβR3. Finally, using gene expression from human HCCs, we show that patients with high SULF1 expression have poorer recurrence-free survival (HR 4.1 (1.9–8.3); p=0.002) compared to patients with low SULF1. We also found strong correlations of SULF1 expression with TGFβ expression and with several TGFβ-related EMT genes in human HCC.
CONCLUSION
In summary, our study proposes a novel role of SULF1 in HCC tumor progression through augmentation of the TGFβ pathway, thus defining SULF1 as a potential biomarker for tumor progression and a novel target for drug development for HCC.
doi:10.1002/hep.27658
PMCID: PMC4376661  PMID: 25503294
HCC; TGF beta; tumor progression; SULF1; Heparin Sulfate
6.  The Fifth Domain of Beta 2 Glycoprotein I Protects from Natural IgM Mediated Cardiac Ischaemia Reperfusion Injury 
PLoS ONE  2016;11(3):e0152681.
Reperfusion after a period of ischemia results in reperfusion injury (IRI) which involves activation of the inflammatory cascade. In cardiac IRI, IgM natural antibodies (NAb) play a prominent role through binding to altered neoepitopes expressed on damaged cells. Beta 2 Glycoprotein I (β2GPI) is a plasma protein that binds to neoepitopes on damaged cells including anionic phospholipids through its highly conserved Domain V. Domain I of β2GPI binds circulating IgM NAbs and may provide a link between the innate immune system, IgM NAb binding and cardiac IRI. This study was undertaken to investigate the role of Β2GPI and its Domain V in cardiac IRI using wild-type (WT), Rag-1 -/- and β2GPI deficient mice. Compared with control, treatment with Domain V prior to cardiac IRI prevented binding of endogenous β2GPI to post-ischemic myocardium and resulted in smaller myocardial infarction size in both WT and β2GPI deficient mice. Domain V treatment in WT mice also resulted in less neutrophil infiltration, less apoptosis and improved ejection fraction at 24 h. Rag-1 -/- antibody deficient mice reconstituted with IgM NAbs confirmed that Domain V prevented IgM NAb induced cardiac IRI. Domain V remained equally effective when delivered at the time of reperfusion which has therapeutic clinical relevance.Based upon this study Domain V may function as a universal inhibitor of IgM NAb binding in the setting of cardiac IRI, which offers promise as a new therapeutic strategy in the treatment of cardiac IRI.
doi:10.1371/journal.pone.0152681
PMCID: PMC4816326  PMID: 27031114
7.  Pramipexole-Induced Hypothermia Reduces Early Brain Injury via PI3K/AKT/GSK3β pathway in Subarachnoid Hemorrhage rats 
Scientific Reports  2016;6:23817.
Previous studies have shown neuroprotective effects of hypothermia. However, its effects on subarachnoid hemorrhage (SAH)-induced early brain injury (EBI) remain unclear. In this study, a SAH rat model was employed to study the effects and mechanisms of pramipexole-induced hypothermia on EBI after SAH. Dose-response experiments were performed to select the appropriate pramipexole concentration and frequency of administration for induction of mild hypothermia (33–36 °C). Western blot, neurobehavioral evaluation, Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) and Fluoro-Jade B (FJB) staining were used to detect the effects of pramipexole-induced hypothermia on SAH-induced EBI, as well as to study whether controlled rewarming could attenuate these effects. Inhibitors targeting the PI3K/AKT/GSK3β pathway were administered to determine whether the neuroprotective effect of pramipexole-induced hypothermia was mediated by PI3K/AKT/GSK3β signaling pathway. The results showed that intraperitoneal injection of pramipexole at 0.25 mg/kg body weight once per 8 hours was found to successfully and safely maintain rats at mild hypothermia. Pramipexole-induced hypothermia ameliorated SAH-induced brain cell death, blood-brain barrier damage and neurobehavioral deficits in a PI3K/AKT/GSK3β signaling-dependent manner. Therefore, we may conclude that pramipexole-induced hypothermia could effectively inhibit EBI after SAH in rats via PI3K/AKT/GSK3β signaling pathway.
doi:10.1038/srep23817
PMCID: PMC4812308  PMID: 27026509
8.  Clinicopathological significance of STAT4 in hepatocellular carcinoma and its effect on cell growth and apoptosis 
OncoTargets and therapy  2016;9:1721-1734.
Background
Recent studies showed that signal transducer and activator of transcription 4 (STAT4) was downregulated in hepatocellular carcinoma (HCC) tissues. However, the role of STAT4 in HCC is still unknown. The aim of this study is to explore the association between STAT4 expression and other clinicopathological features in HCC and to test the effect of STAT4 on cell growth and apoptosis in vitro.
Methods
STAT4 was evaluated by immunohistochemistry in 171 HCC and corresponding paraneoplastic liver, 37 cirrhosis, and 33 normal liver tissues. Association between STAT4 and clinicopathological parameters was analyzed. Meta-analysis on STAT4 in cancer was performed. The effect of STAT4 small interfering RNA (siRNA) on cell growth and cell apoptosis was also detected.
Results
Positive rate of STAT4 was 29.2% (50/171) in HCC tissues, 53.2% (91/171) in paraneoplastic liver tissues, 64.9% (24/37) in cirrhosis tissues, and 72.7% (24/33) in normal liver tissues. STAT4 was upregulated in younger patients who were female, with single tumor node, early TNM stage, without portal vein tumor embolus, and α-fetoprotein (AFP)-positive tumors compared with the groups comprising older patients, males, and those with multiple tumor nodes, advanced TNM stage, with portal vein tumor embolus, and AFP negative tumors. Meta-analysis showed STAT4 was correlated with TNM stage (OR =0.50, 95% CI =0.30, 0.83, P=0.008) and age (OR =0.58, 95% CI =0.38, 0.95, P=0.032) in malignant tissues, and with AFP level (OR =1.76, 95% CI =1.06, 2.94, P=0.03) in HCC. STAT4 siRNA promoted growth and suppressed apoptosis of HepG2 cells.
Conclusion
STAT4 might play a vital role in development of HCC, via influencing cell growth and apoptosis, as a tumor suppressor.
doi:10.2147/OTT.S100040
PMCID: PMC4807935  PMID: 27051307
hepatocellular carcinoma; HCC; signal transducers and activators of transcription 4; STAT4; clinicopathological features; immunohistochemistry; meta-analysis; in vitro
9.  PD-L1 Deficiency within Islets Reduces Allograft Survival in Mice 
PLoS ONE  2016;11(3):e0152087.
Background
Islet transplantation may potentially cure type 1 diabetes mellitus (T1DM). However, immune rejection, especially that induced by the alloreactive T-cell response, remains a restraining factor for the long-term survival of grafted islets. Programmed death ligand-1 (PD-L1) is a negative costimulatory molecule. PD-L1 deficiency within the donor heart accelerates allograft rejection. Here, we investigate whether PD-L1 deficiency in donor islets reduces allograft survival time.
Methods
Glucose Stimulation Assays were performed to evaluate whether PD-L1 deficiency has detrimental effects on islet function. Islets isolated from PDL1-deficient mice or wild- type (WT) mice (C57BL/6j) were implanted beneath the renal capsule of streptozotocin (STZ)-induced diabetic BALB/c mice. Blood glucose levels and graft survival time after transplantation were monitored. Moreover, we analyzed the residual islets, infiltrating immune cells and alloreactive cells from the recipients.
Results
PD-L1 deficiency within islets does not affect islet function. However, islet PD-L1 deficiency increased allograft rejection and was associated with enhanced inflammatory cell infiltration and recipient T-cell alloreactivity.
Conclusions
This is the first report to demonstrate that PD-L1 deficiency accelerated islet allograft rejection and regulated recipient alloimmune responses.
doi:10.1371/journal.pone.0152087
PMCID: PMC4798758  PMID: 26990974
10.  CD117+ Dendritic and Mast Cells Are Dependent on RasGRP4 to Function as Accessory Cells for Optimal Natural Killer Cell-Mediated Responses to Lipopolysaccharide 
PLoS ONE  2016;11(3):e0151638.
Ras guanine nucleotide-releasing protein-4 (RasGRP4) is an evolutionarily conserved calcium-regulated, guanine nucleotide exchange factor and diacylglycerol/phorbol ester receptor. While an important intracellular signaling protein for CD117+ mast cells (MCs), its roles in other immune cells is less clear. In this study, we identified a subset of in vivo-differentiated splenic CD117+ dendritic cells (DCs) in wild-type (WT) C57BL/6 mice that unexpectedly contained RasGRP4 mRNA and protein. In regard to the biologic significance of these data to innate immunity, LPS-treated splenic CD117+ DCs from WT mice induced natural killer (NK) cells to produce much more interferon-γ (IFN-γ) than comparable DCs from RasGRP4-null mice. The ability of LPS-responsive MCs to cause NK cells to increase their expression of IFN-γ was also dependent on this intracellular signaling protein. The discovery that RasGRP4 is required for CD117+ MCs and DCs to optimally induce acute NK cell-dependent immune responses to LPS helps explain why this signaling protein has been conserved in evolution.
doi:10.1371/journal.pone.0151638
PMCID: PMC4794117  PMID: 26982501
11.  Using an in vitro xenoantibody-mediated complement-dependent cytotoxicity model to evaluate the complement inhibitory activity of the peptidic C3 inhibitor Cp40 
Simple and reliable methods for evaluating the inhibitory effects of drug candidates on complement activation are essential for preclinical development. Here, using an immortalized porcine aortic endothelial cell line (iPEC) as target, we evaluated the feasibility and effectiveness of an in vitro xenoantibody-mediated complement-dependent cytotoxicity (CDC) model for evaluating the complement inhibitory activity of Cp40, a potent analog of the peptidic C3 inhibitor compstatin. The binding of human xenoantibodies to iPECs led to serum dilution-dependent cell death. Pretreatment of the human serum with Cp40 almost completely inhibited the deposition of C3 fragments and C5b-9 on the cells, resulting in a dose-dependent inhibition of CDC against the iPECs. Using the same method to compare the effects of Cp40 on complement activation in humans, rhesus and cynomolgus monkeys, we found that the inhibitory patterns were similar overall. Thus, the in vitro xenoantibody-mediated CDC assay may have considerable potential for future clinical use.
doi:10.1016/j.clim.2015.11.002
PMCID: PMC4784679  PMID: 26548839
SV40-immortalized porcine aortic endothelial; cell; Complement inhibitor; Cp40; Nonhuman primate
12.  Increased frequency of thymic T follicular helper cells in myasthenia gravis patients with thymoma 
Journal of Thoracic Disease  2016;8(3):314-322.
Background
To investigate the presence of T follicular helper (TFH) cells and their associated molecules in myasthenia gravis (MG) patients with thymoma.
Methods
TFH cells are detected in thymus around the thymoma region of 50 patients and atrophic thymus in 10 patients as control. The percentage of TFH cells among CD4+ T cells and the expression level of surface markers CXC chemokine receptor 5 (CXCR5), inducible co-stimulator (ICOS), programmed cell death 1 and the cytoplasmic marker B cell lymphoma 6 (Bcl-6) were analyzed by immunohistochemistry (IHC) staining, immunofluorescence (IF) and western blotting (WB).
Results
Higher percentage of thymic TFH cells was found in MG patients with thymoma compared with both thymoma patients without MG and control group. The expression levels of the four markers in thymoma of MG patients were significantly higher than thymoma patients without MG and control group. No significant difference was found in the levels of programmed cell death 1 (PD-1) and Bcl-6 between thymoma patients without MG and the control, while the levels of CXCR5 and ICOS in thymoma patients without MG were higher than control group.
Conclusions
These results suggested thymic TFH cells might involve in the pathogenesis of MG with thymoma. However, it needs further study to test if the inhibition of the function of TFH cells could effectively alleviate the severity of MG.
doi:10.21037/jtd.2016.03.03
PMCID: PMC4805840  PMID: 27076925
Myasthenia gravis (MG); thymoma; T follicular helper cells (TFH cells); program death 1 (PD-1)
13.  Posterolateral ankle ligament injuries affect ankle stability: a finite element study 
Background
We have already discovered 23 patients during the work of the outpatient department and operations whose unstable signs on the posterolateral ankle. The anterior drawer test demonstrated normal during the physical examinations while the spaces of the posterior tibiotalar joints increased in stress X-ray plain films. ATFL intact and posterolateral ligaments lax were found during operations too. It is important to make existence claims and illuminate the mechanism of posterolateral ankle instability.
Methods
A finite element model of the ankle was established for simulating to cut off posterolateral ligaments in turn. Ankle movements with tibia rotation under load on five forefoot positions were simulated as well.
Results
The difference values with tibia external rotation were negative, and the positive results occurred with tibia internal rotation. The tibia-talus difference values in some forefoot positions were 2 ~ 3 mm after PTFL together with CFL or/and PITFL were cut off. The tibula-talus difference values were 2.21 ~ 2.76 mm after both PTFL and CFL were cut off. The tibia-fibula difference values were small. The difference values increased by 2 ~ 5 mm after cutting off the PITFL.
Conclusions
Posterolateral ankle ligaments, especially CFL and PITFL, play a significant role in maintaining ankle stability. The serious injuries of both CFL and PITFL would affect posterolateral ankle stabilities. PITFL was important to subtalar joint stability.
doi:10.1186/s12891-016-0954-6
PMCID: PMC4765156  PMID: 26905722
Posterolateral ankle ligaments; Posterolateral ankle instability; Finite element (FE); PTFL; CFL; PITFL
14.  Heme oxygenase-1 induction attenuates imiquimod-induced psoriasiform inflammation by negative regulation of Stat3 signaling 
Scientific Reports  2016;6:21132.
Heme oxygenase-1 (HO-1), a stress-inducible protein with a potential anti-inflammatory effect, plays an important role in skin injury and wound healing. However, the function of HO-1 in cutaneous inflammatory diseases, such as psoriasis, remains unknown. The abnormal activation of Stat3, a known transcription factor that induces inflammation and regulates cell differentiation, is directly involved in the pathogenesis and development of psoriasis. Hence, targeting Stat3 is potentially beneficial in the treatment of psoriasis. In this study, HO-1 activation significantly alleviated the disease-related pathogenesis abnormality. To determine the mechanism by which HO-1 exerts immune protection on Th17-related cytokines, IL6/IL22-induced Stat3 activation was significantly suppressed, accompanied by decreased cell proliferation and reversed abnormal cell proliferation. Importantly, HO-1-induced Stat3 suppression was mediated through the activation of protein tyrosine phosphatase SHP-1. Overall, our study provides direct evidence indicating that HO-1 might be a useful therapeutic target for psoriasis. SHP-1-mediated suppression of Stat3 activation after HO-1 activation is a unique molecular mechanism for the regulation of Stat3 activation.
doi:10.1038/srep21132
PMCID: PMC4759695  PMID: 26893174
15.  Silicene nanomeshes: bandgap opening by bond symmetry breaking and uniaxial strain 
Scientific Reports  2016;6:20971.
Based on the first-principles calculations, we have investigated in detail the bandgap opening of silicene nanomeshes. Different to the mechanism of bandgap opening induced by the sublattice equivalence breaking, the method of degenerate perturbation through breaking the bond symmetry could split the π-like bands in the inversion symmetry preserved silicene nanomeshes, resulting into the πa1 − πa2 and πz1 − πz2 band sets with sizable energy intervals. Besides the bandgap opening in the nanomeshes with Dirac point being folded to Γ point, the split energy intervals are however apart away from Fermi level to leave the semimetal nature unchanged for the other nanomeshes with Dirac points located at opposite sides of Γ point as opposite pseudo spin wave valleys. A mass bandgap could be then opened at the aid of uniaxial strain to transfer the nanomesh to be semiconducting, whose width could be continuously enlarged until reaching its maximum Emax. Moreover, the Emax could also be tuned by controlling the defect density in silicene nanomeshes. These studies could contribute to the understanding of the bandgap engineering of silicene-based nanomaterials to call for further investigations on both theory and experiment.
doi:10.1038/srep20971
PMCID: PMC4748269  PMID: 26860967
16.  An immunohistochemical study of cyclin-dependent kinase 5 (CDK5) expression in non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC): a possible prognostic biomarker 
Background
Cyclin-dependent kinase 5 (CDK5) is an atypical CDK which plays a vital role in several cancers via regulating migration and motility of cancer cells. However, the clinicopathological impact and function of CDK5 in lung cancer remain poorly understood. The present study was aimed at exploring expression and clinicopathological significance of CDK5 in lung cancer.
Methods
There were 395 samples of lung tissue including 365 lung tumors (339 non-small cell lung cancers and 26 small cell lung cancers) and 30 samples of normal lung. CDK5 expression was detected by immunohistochemistry on lung tissue microarrays.
Results
Over expression was detected in lung cancer compared with normal lung tissues (P = 0.001). Furthermore, area under curve (AUC) of receiver operating characteristic (ROC) of CDK5 was 0.685 (95 % CI 0.564~0.751, P = 0.004). In lung cancer, we also discovered close correlations between CDK5 and pathological grading (r = 0.310, P < 0.001), TNM stage (r = 0.155, P = 0.003), and lymph node metastasis (r = 0.279, P < 0.001) by using Spearman analysis. In two subgroups of non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), the expression of CDK5 was also higher than that of normal lung tissue, respectively (P = 0.001 and P = 0.004). Moreover, in NSCLCs, Spearman analysis revealed that expression of CDK5 was correlated with TNM stages (r = 0.129, P = 0.017), lymph node metastasis (r = 0.365, P < 0.001), and pathological grading (r = 0.307, P < 0.001), respectively. The significant correlation was also found between CDK5 expression and TNM stages (r = 0.415, P = 0.049) and lymphatic metastasis (r = 0.469, P = 0.024) in SCLCs.
Conclusions
The results of this present study suggest that the CDK5 expression is associated with several clinicopathological factors linked with poorer prognosis.
doi:10.1186/s12957-016-0787-7
PMCID: PMC4746778  PMID: 26860827
Lung neoplasms; Cyclin-dependent kinase 5; Immunohistochemistry; Tissue array analysis; Neoplasm metastasis
17.  BOLD data representing activation and connectivity for rare no-go versus frequent go cues 
Data in Brief  2016;7:66-70.
The neural circuitry underlying response control is often studied using go/no-go tasks, in which participants are required to respond as fast as possible to go cues and withhold from responding to no-go stimuli. In the current task, response control was studied using a fully counterbalanced design in which blocks with a low frequency of no-go cues (75% go, 25% no-go) were alternated with blocks with a low frequency of go cues (25% go, 75% no-go); see also “Segregating attention from response control when performing a motor inhibition task: Segregating attention from response control” [1]. We applied a whole brain corrected, paired t-test to the data assessing for regions differentially activated by low frequency no-go cues relative to high frequency go cues. In addition, we conducted a generalized psychophysiological interaction analysis on the data using a right inferior frontal gyrus seed region. This region was identified through the BOLD response t-test and was chosen because right inferior gyrus is highly implicated in response inhibition.
doi:10.1016/j.dib.2016.02.011
PMCID: PMC4761693  PMID: 26955650
Cognitive control; Go/No-go; fMRI; Generalized psychophysiological interactions; Inhibition
18.  Electric Control of the Hall effect in Pt/Bi0.9La0.1FeO3 bilayers 
Scientific Reports  2016;6:20330.
Platinum metal, being nonmagnetic and with a strong spin-orbit coupling interaction, has been deposited on weak ferromagnetic Bi0.9La0.1FeO3 thin films. The Hall effect is studied as a function of the polarization direction of multiferroic Bi0.9La0.1FeO3 thin films, as well as magnetic field (H) and temperature (T). For the two polarization directions, besides the obvious difference of the anomalous Hall resistance RAH, it increases sharply with decreasing temperature, and even changes sign, thus violating the conventional expression. This observations indicate local magnetic moments in Pt caused by the local electric fields at the interface of Bi0.9La0.1FeO3 films. Also, possible proximity effects and induced magnetic ordering in Pt on weak ferromagnetic Bi0.9La0.1FeO3 thin films of both upward and downward polarization states may exist and their contribution to the spin-related measurements should not be neglected.
doi:10.1038/srep20330
PMCID: PMC4738251  PMID: 26837911
19.  Enzymatic Synthesis of Modified Oligonucleotides by PEAR Using Phusion and KOD DNA Polymerases 
Nucleic Acid Therapeutics  2015;25(1):27-34.
Antisense synthetic oligonucleotides have been developed as potential gene-targeted therapeutics. We previously reported polymerase–endonuclease amplification reaction (PEAR) for amplification of natural and 5′-O-(1-thiotriphosphate) (S)-modified oligonucleotides. Here, we extended the PEAR technique for enzymatic preparation of 2′-deoxy-2′-fluoro-(2′-F) and 2′-F/S double-modified oligonucleotides. The result showed that KOD and Phusion DNA polymerase could synthesize oligonucleotides with one or two modified nucleotides, and KOD DNA polymerase is more suitable than Phusion DNA polymerase for PEAR amplification of 2′-F and 2′-F/S double modified oligonucleotides. The composition of PEAR products were analyzed by electrospray ionization liquid chromatography mass spectrometry (ESI/LC/MS) detection and showed that the sequence of the PEAR products are maintained at an extremely high accuracy (>99.9%), and after digestion the area percent of full-length modified oligonucleotides reaches 89.24%. PEAR is suitable for synthesis of modified oligonucleotides efficiently and with high purity.
doi:10.1089/nat.2014.0513
PMCID: PMC4296748  PMID: 25517220
20.  NADPH Oxidase: A Potential Target for Treatment of Stroke 
Stroke is the third leading cause of death in industrialized nations. Oxidative stress is involved in the pathogenesis of stroke, and excessive generation of reactive oxygen species (ROS) by mitochondria is thought to be the main cause of oxidative stress. NADPH oxidase (NOX) enzymes have recently been identified and studied as important producers of ROS in brain tissues after stroke. Several reports have shown that knockout or deletion of NOX exerts a neuroprotective effect in three major experimental stroke models. Recent studies also confirmed that NOX inhibitors ameliorate brain injury and improve neurological outcome after stroke. However, the physiological and pathophysiological roles of NOX enzymes in the central nervous system (CNS) are not known well. In this review, we provide a comprehensive summary of our current understanding about expression and physiological function of NOX enzymes in the CNS and its pathophysiological roles in the three major types of stroke: ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage.
doi:10.1155/2016/5026984
PMCID: PMC4752995  PMID: 26941888
21.  Long Noncoding RNA MALAT-1 Can Predict Poor Prognosis: A Meta-Analysis 
Background
MALAT-1 is a highly conserved nuclear long non-coding RNA (lncRNA). The overexpression of MALAT-1 has been reported in several types of cancers. This meta-analysis was conducted to further investigate its potential role as a prognostic indicator in various cancers.
Material/Methods
The meta-analysis was performed by use of systematic search terms in 13 databases for qualified papers on prognosis in cancer from inception to June 30, 2015. The combined hazard ratios (HRs) with 95% confidence interval (95% CI) were computed to demonstrate the effect of MALAT-1 on prognosis of cancers.
Results
A total of 590 papers were initially identified, and 17 studies were finally included in this paper. Meta-analysis was accomplished with a total of 1626 patients. Combined HRs and 95% CI were calculated by fixed-effects or random-effects models. The quality assessment of included studies was performed by the Newcastle-Ottawa scale (NOS). High expression of MALAT-1 was found to be an indicator of poor prognosis in overall survival (OS) (HR=1.84, 95% CI: 1.27–2.67) and disease-free survival (DFS) (HR=2.37, 95% CI: 1.55–3.62). In subgroups, the associations between MALAT-1 and survival were also apparent, for instance, in country subgroup: China (HR=1.85, 95% CI: 1.14–2.99).
Conclusions
The overexpression of MALAT-1 may be a potential prognostic indicator for various human cancers.
doi:10.12659/MSM.895171
PMCID: PMC4737057  PMID: 26821178
Genes, Neoplasm; Meta-Analysis; Prognosis; RNA, Long Noncoding; Survival
22.  Cigarette Smoke Disturbs the Survival of CD8+ Tc/Tregs Partially through Muscarinic Receptors-Dependent Mechanisms in Chronic Obstructive Pulmonary Disease 
PLoS ONE  2016;11(1):e0147232.
Background
CD8+ T cells (Cytotoxic T cells, Tc) are known to play a critical role in the pathogenesis of smoking related airway inflammation including chronic obstructive pulmonary disease (COPD). However, how cigarette smoke directly impacts systematic CD8+ T cell and regulatory T cell (Treg) subsets, especially by modulating muscarinic acetylcholine receptors (MRs), has yet to be well elucidated.
Methods
Circulating CD8+ Tc/Tregs in healthy nonsmokers (n = 15), healthy smokers (n = 15) and COPD patients (n = 18) were evaluated by flow cytometry after incubating with anti-CD3, anti-CD8, anti-CD25, anti-Foxp3 antibodies. Peripheral blood T cells (PBT cells) from healthy nonsmokers were cultured in the presence of cigarette smoke extract (CSE) alone or combined with MRs agonist/antagonist for 5 days. Proliferation and apoptosis were evaluated by flow cytometry using Ki-67/Annexin-V antibodies to measure the effects of CSE on the survival of CD8+ Tc/Tregs.
Results
While COPD patients have elevated circulating percentage of CD8+ T cells, healthy smokers have higher frequency of CD8+ Tregs. Elevated percentages of CD8+ T cells correlated inversely with declined FEV1 in COPD. CSE promoted the proliferation and inhibited the apoptosis of CD8+ T cells, while facilitated both the proliferation and apoptosis of CD8+ Tregs. Notably, the effects of CSE on CD8+ Tc/Tregs can be mostly simulated or attenuated by muscarine and atropine, the MR agonist and antagonist, respectively. However, neither muscarine nor atropine influenced the apoptosis of CD8+ Tregs.
Conclusion
The results imply that cigarette smoking likely facilitates a proinflammatory state in smokers, which is partially mediated by MR dysfunction. The MR antagonist may be a beneficial drug candidate for cigarette smoke-induced chronic airway inflammation.
doi:10.1371/journal.pone.0147232
PMCID: PMC4726532  PMID: 26808506
23.  Diversity index of mucosal resident T lymphocyte repertoire predicts clinical prognosis in gastric cancer  
Oncoimmunology  2015;4(4):e1001230.
A characteristic immunopathology of human cancers is the induction of tumor antigen-specific T lymphocyte responses within solid tumor tissues. Current strategies for immune monitoring focus on the quantification of the density and differentiation status of tumor-infiltrating T lymphocytes; however, properties of the TCR repertoire ‒ including antigen specificity, clonality, as well as its prognostic significance ‒ remain elusive. In this study, we enrolled 28 gastric cancer patients and collected tumor tissues, adjacent normal mucosal tissues, and peripheral blood samples to study the landscape and compartmentalization of these patients’ TCR β repertoire by deep sequencing analyses. Our results illustrated antigen-driven expansion within the tumor compartment and the contracted size of shared clonotypes in mucosa and peripheral blood. Most importantly, the diversity of mucosal T lymphocytes could independently predict prognosis, which strongly underscores critical roles of resident mucosal T-cells in executing post-surgery immunosurveillance against tumor relapse.
doi:10.1080/2162402X.2014.1001230
PMCID: PMC4485732  PMID: 26137399
gastric cancer; mucosal-residence; prognosis; repertoire sequencing; T-cell repertoire; TCR, T-cell receptor
24.  STAT3 in arsenic lung carcinogenicity 
Oncoimmunology  2015;4(4):e995566.
We recently found that the chronic sterile inflammation contributes to arsenic lung tumorigenesis which is inhibited by autophagy. STAT3 regulates the interaction between inflammation and autophagy. STAT3 may also play a critical role in mediating the crosstalk between lung epithelial cells and their microenvironment, including immune cells, during arsenic lung carcinogenesis.
doi:10.1080/2162402X.2014.995566
PMCID: PMC4485752  PMID: 26137408
autophagy; arsenic; immunosurveillance; lung tumorigenesis; microenvironment; STAT3
25.  Alcohol drinking as an unfavorable prognostic factor for male patients with nasopharyngeal carcinoma 
Scientific Reports  2016;6:19290.
The relationship between alcohol drinking and the prognosis of nasopharyngeal carcinoma (NPC) is unknown. To investigate the prognostic value of alcohol drinking on NPC, this retrospective study was conducted on 1923 male NPC patients. Patients were classified as current, former and non-drinkers according to their drinking status. Furthermore, they were categorized as heavy drinkers and mild/none drinkers based on the intensity and duration of alcohol drinking. Survival outcomes were compared using Kaplan–Meier analysis and Cox proportional hazards model. We found that current drinkers had significantly lower overall survival (OS) rate (5-year OS: 70.2% vs. 76.4%, P < 0.001) and locoregional recurrence-free survival (LRFS) rate (5-year LRFS: 69.3% vs. 77.5%, P < 0.001) compared with non-drinkers. Drinking ≥14 drinks/week, and drinking ≥20 years were both independent unfavorable prognostic factors for OS (hazard ratio [HR] = 1.38, 95% confidence interval [CI] 1.05–1.81, P = 0.022; HR = 1.38, 95% CI 1.09–1.75, P = 0.007). Stratified analyses further revealed that the negative impacts of alcohol were manifested mainly among older patients and among smokers. In conclusion, alcohol drinking is a useful predictor of prognosis in male NPC patients; drinkers, especially heavy drinkers have poorer prognosis.
doi:10.1038/srep19290
PMCID: PMC4725964  PMID: 26776301

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