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2.  Enhanced photovoltaic property by forming p-i-n structures containing Si quantum dots/SiC multilayers 
Nanoscale Research Letters  2014;9(1):634.
Si quantum dots (Si QDs)/SiC multilayers were fabricated by annealing hydrogenated amorphous Si/SiC multilayers prepared in a plasma-enhanced chemical vapor deposition system. The thickness of amorphous Si layer was designed to be 4 nm, and the thickness of amorphous SiC layer was kept at 2 nm. Transmission electron microscopy observation revealed the formation of Si QDs after 900°C annealing. The optical properties of the Si QDs/SiC multilayers were studied, and the optical band gap deduced from the optical absorption coefficient result is 1.48 eV. Moreover, the p-i-n structure with n-a-Si/i-(Si QDs/SiC multilayers)/p-Si was fabricated, and the carrier transportation mechanism was investigated. The p-i-n structure was used in a solar cell device. The cell had the open circuit voltage of 532 mV and the power conversion efficiency (PCE) of 6.28%.
PACS
81.07.Ta; 78.67.Pt; 88.40.jj
doi:10.1186/1556-276X-9-634
PMCID: PMC4256967  PMID: 25489285
Si quantum dots (Si QDs); Silicon carbide; Multilayers; Solar cell
3.  Fruit and vegetable intake and risk of type 2 diabetes mellitus: meta-analysis of prospective cohort studies 
BMJ Open  2014;4(11):e005497.
Objective
To clarify and quantify the potential dose–response association between the intake of fruit and vegetables and risk of type 2 diabetes.
Design
Meta-analysis and systematic review of prospective cohort studies.
Data source
Studies published before February 2014 identified through electronic searches using PubMed and Embase.
Eligibility criteria for selecting studies
Prospective cohort studies with relative risks and 95% CIs for type 2 diabetes according to the intake of fruit, vegetables, or fruit and vegetables.
Results
A total of 10 articles including 13 comparisons with 24 013 cases of type 2 diabetes and 434 342 participants were included in the meta-analysis. Evidence of curve linear associations was seen between fruit and green leafy vegetables consumption and risk of type 2 diabetes (p=0.059 and p=0.036 for non-linearity, respectively). The summary relative risk of type 2 diabetes for an increase of 1 serving fruit consumed/day was 0.93 (95% CI 0.88 to 0.99) without heterogeneity among studies (p=0.477, I2=0%). For vegetables, the combined relative risk of type 2 diabetes for an increase of 1 serving consumed/day was 0.90 (95% CI 0.80 to 1.01) with moderate heterogeneity among studies (p=0.002, I2=66.5%). For green leafy vegetables, the summary relative risk of type 2 diabetes for an increase of 0.2 serving consumed/day was 0.87 (95% CI 0.81 to 0.93) without heterogeneity among studies (p=0.496, I2=0%). The combined estimates showed no significant benefits of increasing the consumption of fruit and vegetables combined.
Conclusions
Higher fruit or green leafy vegetables intake is associated with a significantly reduced risk of type 2 diabetes.
doi:10.1136/bmjopen-2014-005497
PMCID: PMC4225228  PMID: 25377009
4.  MUC1 gene polymorphism rs4072037 and susceptibility to gastric cancer: a meta-analysis 
SpringerPlus  2014;3:599.
The association between MUC1 polymorphism rs4072037 and the risk of gastric cancer has been described in several studies. However, these studies yielded inconsistent results, especially in different pathological type of gastric cancer. Therefore, we performed this meta-analysis to evaluate the relationship between MUC1 gene polymorphism and gastric cancer susceptibility. A comprehensive database search was performed to identify eligible studies. Odds ratios with 95% confidence intervals were calculated to assess the strength of the association between MUC1 rs4072037 and risk of gastric cancer. Subgroup analyses, publication bias, and sensitivity analyses were also conducted. PubMed, EMBASE, Web of Science and CNKI databases were systematically searched to identify relevant studies. A total of 9 studies (12 datasets) were included in the meta-analysis including 10,410 cases and 11,437 controls. Overall, the G allele at rs4072037 of MUC1 gene was associated with a significant decreased gastric cancer risk (OR=0.70, 95% CI: 0.64–0.76). The association was significant in both anatomic location and pathological subtype subgroup analyses. However, the association was detected in Asian rather than Caucasian. Our findings demonstrate that the presence of the G allele at rs4072037 of the MUC1 gene may contribute to protection against gastric cancer in Asian. Further large studies of multiethnic groups are needed to validate these findings.
Electronic supplementary material
The online version of this article (doi:10.1186/2193-1801-3-599) contains supplementary material, which is available to authorized users.
doi:10.1186/2193-1801-3-599
PMCID: PMC4198476  PMID: 25332893
MUC1; Polymorphism; Genetic; Stomach neoplasms; Meta-analysis
5.  Prognostic Value of FGFR Gene Amplification in Patients with Different Types of Cancer: A Systematic Review and Meta-Analysis 
PLoS ONE  2014;9(8):e105524.
Background
Fibroblast growth factor receptor (FGFR) gene amplification has been reported in different types of cancer. We performed an up-to-date meta-analysis to further characterize the prognostic value of FGFR gene amplification in patients with cancer.
Methods
A search of several databases, including MEDLINE (PubMed), EMBASE, Web of Science, and China National Knowledge Infrastructure, was conducted to identify studies examining the association between FGFR gene amplification and cancer. A total of 24 studies met the inclusion criteria, and overall incidence rates, hazard risk (HR), overall survival, disease-free survival, and 95% confidence intervals (CIs) were calculated employing fixed- or random-effects models depending on the heterogeneity of the included studies.
Results
In the meta-analysis of 24 studies, the prevalence of FGFR gene amplification was FGFR1: 0.11 (95% CI: 0.08–0.13) and FGFR2: 0.04 (95% CI: 0.02–0.06). Overall survival was significantly worse among patients with FGFR gene amplification: FGFR1 [HR 1.57 (95% CI: 1.23–1.99); p = 0.0002] and FGFR2 [HR 2.27 (95% CI: 1.73–3.00); p<0.00001].
Conclusions
Current evidence supports the conclusion that the outcomes of patients with FGFR gene amplified cancers is worse than for those with non-FGFR gene amplified cancers.
doi:10.1371/journal.pone.0105524
PMCID: PMC4149366  PMID: 25171497
6.  In vivo imaging of protein–protein and RNA–protein interactions using novel far-red fluorescence complementation systems 
Nucleic Acids Research  2014;42(13):e103.
Imaging of protein–protein and RNA–protein interactions in vivo, especially in live animals, is still challenging. Here we developed far-red mNeptune-based bimolecular fluorescence complementation (BiFC) and trimolecular fluorescence complementation (TriFC) systems with excitation and emission above 600 nm in the ‘tissue optical window’ for imaging of protein–protein and RNA–protein interactions in live cells and mice. The far-red mNeptune BiFC was first built by selecting appropriate split mNeptune fragments, and then the mNeptune-TriFC system was built based on the mNeptune-BiFC system. The newly constructed mNeptune BiFC and TriFC systems were verified as useful tools for imaging protein–protein and mRNA–protein interactions, respectively, in live cells and mice. We then used the new mNeptune-TriFC system to investigate the interactions between human polypyrimidine-tract-binding protein (PTB) and HIV-1 mRNA elements as PTB may participate in HIV mRNA processing in HIV activation from latency. An interaction between PTB and the 3′long terminal repeat region of HIV-1 mRNAs was found and imaged in live cells and mice, implying a role for PTB in regulating HIV-1 mRNA processing. The study provides new tools for in vivo imaging of RNA–protein and protein–protein interactions, and adds new insight into the mechanism of HIV-1 mRNA processing.
doi:10.1093/nar/gku408
PMCID: PMC4117741  PMID: 24813442
7.  Human Astrocytic Cells Support Persistent Coxsackievirus B3 Infection 
Journal of Virology  2013;87(22):12407-12421.
Enteroviruses can frequently target the human central nervous system to induce a variety of neurological diseases. Although enteroviruses are highly cytolytic, emerging evidence has shown that these viruses can establish persistent infections both in vivo and in vitro. Here, we investigated the susceptibility of three human brain cell lines, CCF-STTG1, T98G, and SK-N-SH, to infection with three enterovirus serotypes: coxsackievirus B3 (CVB3), enterovirus 71, and coxsackievirus A9. Persistent infection was observed in CVB3-infected CCF-STTG1 cells, as evidenced by prolonged detection of infectious virions, viral RNA, and viral antigens. Of note, infected CCF-STTG1 cells expressed the nonfunctional canonical viral receptors coxsackievirus-adenovirus receptor and decay-accelerating factor, while removal of cell surface chondroitin sulfate from CCF-STTG1 cells inhibited the replication of CVB3, suggesting that receptor usage was one of the major limiting factors in CVB3 persistence. In addition, CVB3 curtailed the induction of beta interferon in infected CCF-STTG1 cells, which likely contributed to the initiation of persistence. Furthermore, proinflammatory chemokines and cytokines, such as vascular cell adhesion molecule 1, interleukin-8 (IL-8), and IL-6, were upregulated in CVB3-infected CCF-STTG1 cells and human progenitor-derived astrocytes. Our data together demonstrate the potential of CCF-STTG1 cells to be a novel cell model for studying CVB3-central nervous system interactions, providing the basis toward a better understanding of CVB3-induced chronic neuropathogenesis.
doi:10.1128/JVI.02090-13
PMCID: PMC3807905  PMID: 24027313
8.  let-7-repressesed Shc translation delays replicative senescence 
Aging Cell  2013;13(1):185-192.
The p66Shc adaptor protein is an important regulator of lifespan in mammals, but the mechanisms responsible are still unclear. Here, we show that expression of p66Shc, p52Shc, and p46Shc is regulated at the post-transcriptional level by the microRNA let-7a. The levels of let-7a correlated inversely with the levels of Shc proteins without affecting Shc mRNA levels. We identified ‘seedless’ let-7a interaction elements in the coding region of Shc mRNA; mutation of the ‘seedless’ interaction sites abolished the regulation of Shc by let-7a. Our results further revealed that repression of Shc expression by let-7a delays senescence of human diploid fibroblasts (HDFs). In sum, our findings link let-7a abundance to the expression of p66Shc, which in turn controls the replicative lifespan of HDFs.
doi:10.1111/acel.12176
PMCID: PMC3947057  PMID: 24165399
cellular lifespan; let-7a; p66Shc; replicative senescence; translational regulation
9.  Tunable nonlinear optical properties in nanocrystalline Si/SiO2 multilayers under femtosecond excitation 
The nonlinear optical properties of nanocrystalline-Si/SiO2 (nc-Si/SiO2) multilayers have been investigated through Z-scan technique by using a Ti-sapphire laser with 50-fs pulse duration at 800 nm as a pump laser. It is interesting to note that with increasing the annealing temperature to make the sample change from amorphous phase to nanocrystalline state, the nonlinear absorption turns the reverse saturation absorption into saturation absorption while the nonlinear optical refraction is also changed simultaneously from self-defocusing to self-focusing. We propose that the localized states at the nc-Si/SiO2 interfaces play the key role in the observed switching behaviors. Our results demonstrate that the tunable optical nonlinearities can be achieved by controlling the microstructures of nc-Si, which can be used as engineering different nonlinear optical devices.
doi:10.1186/1556-276X-9-28
PMCID: PMC3896739  PMID: 24423198
Optical nonlinearities; Nanocrystalline Si; Multilayers; Interface state; 42.65.-k; 42.65.Jx; 42.65.Pc
10.  The Combination of RAD001 and MK-2206 Exerts Synergistic Cytotoxic Effects against PTEN Mutant Gastric Cancer Cells: Involvement of MAPK-Dependent Autophagic, but Not Apoptotic Cell Death Pathway 
PLoS ONE  2014;9(1):e85116.
In the current study, we showed that the combination of mammalian target of rapamycin (mTOR) inhibitor RAD001 (everolimus) and Akt inhibitor MK-2206 exerted synergistic cytotoxic effects against low-phosphatase and tensin homolog (PTEN) gastric cancer cells (HGC-27 and SNU-601 lines). In HGC-27 cells, RAD001 and MK-2206 synergistically induced G1/S cell cycle arrest, growth inhibition, cell death but not apoptosis. RAD001 and MK-2206 synergistically induced light chain 3B (LC3B) and beclin-1 expression, two important autophagy indicators. Meanwhile, the autophagy inhibitor 3-methyladenine (3-MA) and chloroquine inhibited the cytotoxic effects by RAD001 and MK-2206, suggesting that autophagic, but not apoptotic cell death was important for the cytotoxic effects by the co-administration. We observed that the combination of RAD001 and MK-2206 exerted enhanced effects on Akt/mTOR inhibition, cyclin D1 down-regulation and ERK/MAPK(extracellular signal-regulated kinase/mitogen-activated protein kinases) activation. Intriguingly, MEK/ERK inhibitors PD98059 and U0126 suppressed RAD001 plus MK-2206-induced beclin-1 expression, autophagy induction and cytotoxicity in HGC-27 cells. In conclusion, these results suggested that the synergistic anti-gastric cancer cells ability by RAD001 and MK-2206 involves ERK-dependent autophagic cell death pathway.
doi:10.1371/journal.pone.0085116
PMCID: PMC3887024  PMID: 24416349
11.  Clinicopathologic significance of claudin-6, occludin, and matrix metalloproteinases −2 expression in ovarian carcinoma 
Diagnostic Pathology  2013;8:190.
Background
Tight junctions (TJs) are mainly composed of claudins, occludin, and tight junction adhesion molecules (JAM). The invasive and metastatic phenotype of highly invasive cancer cells has been related to abnormal structure and function of TJs, and with expression of activated matrix metalloproteinases (MMPs). The relevance of these mechanisms responsible for the invasion and metastasis of ovarian carcinoma is unclear. Similarly, it is not known if the expression of claudin-6, occludin and MMP2 is related with the clinical properties of these tumors.
Methods
Expression of claudin-6, occludin, and MMP2 was detected in samples of human ovarian cancer tissues by immunohistochemistry and correlated with the clinical properties of the tumors.
Results
The positive expression rates of claudin-6 and MMP-2 were higher in ovarian papillary serous carcinomas than n ovarian serous adenomas (P < 0.05). There were no differences in the expression of occludin (P > 0.05). The expression of claudin-6 and occludin in ovarian cancer was not correlated with patient age, pathological grade, clinical stage, and metastasis (P > 0.05). MMP-2 expression was enhanced with increased clinical stage and metastasis (P < 0.05), but was unrelated to patient age or tumor grade (P > 0.05). There were no apparent correlations between expression of claudin-6, occludin and MMP-2 in ovarian cancer tissue (P > 0.05).
Conclusions
Our data suggest, for the first time, that the claudin-6 and MMP-2 are up-regulated in ovarian papillary serous carcinomas, MMP-2 expression was enhanced with increased clinical stage and metastasis. Claudin-6 and MMP-2 may play a positive role in the invasion and metastasis of ovarian cancer.
Virtual slides
The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1775628454106511.
doi:10.1186/1746-1596-8-190
PMCID: PMC3866569  PMID: 24245968
Tight junctions; Ovarian cancer; Claudin-6; Occludin; MMP-2
12.  Differential reconstructed gene interaction networks for deriving toxicity threshold in chemical risk assessment 
BMC Bioinformatics  2013;14(Suppl 14):S3.
Background
Pathway alterations reflected as changes in gene expression regulation and gene interaction can result from cellular exposure to toxicants. Such information is often used to elucidate toxicological modes of action. From a risk assessment perspective, alterations in biological pathways are a rich resource for setting toxicant thresholds, which may be more sensitive and mechanism-informed than traditional toxicity endpoints. Here we developed a novel differential networks (DNs) approach to connect pathway perturbation with toxicity threshold setting.
Methods
Our DNs approach consists of 6 steps: time-series gene expression data collection, identification of altered genes, gene interaction network reconstruction, differential edge inference, mapping of genes with differential edges to pathways, and establishment of causal relationships between chemical concentration and perturbed pathways. A one-sample Gaussian process model and a linear regression model were used to identify genes that exhibited significant profile changes across an entire time course and between treatments, respectively. Interaction networks of differentially expressed (DE) genes were reconstructed for different treatments using a state space model and then compared to infer differential edges/interactions. DE genes possessing differential edges were mapped to biological pathways in databases such as KEGG pathways.
Results
Using the DNs approach, we analyzed a time-series Escherichia coli live cell gene expression dataset consisting of 4 treatments (control, 10, 100, 1000 mg/L naphthenic acids, NAs) and 18 time points. Through comparison of reconstructed networks and construction of differential networks, 80 genes were identified as DE genes with a significant number of differential edges, and 22 KEGG pathways were altered in a concentration-dependent manner. Some of these pathways were perturbed to a degree as high as 70% even at the lowest exposure concentration, implying a high sensitivity of our DNs approach.
Conclusions
Findings from this proof-of-concept study suggest that our approach has a great potential in providing a novel and sensitive tool for threshold setting in chemical risk assessment. In future work, we plan to analyze more time-series datasets with a full spectrum of concentrations and sufficient replications per treatment. The pathway alteration-derived thresholds will also be compared with those derived from apical endpoints such as cell growth rate.
doi:10.1186/1471-2105-14-S14-S3
PMCID: PMC3851258  PMID: 24268022
13.  HBP1-Mediated Transcriptional Regulation of DNA Methyltransferase 1 and Its Impact on Cell Senescence 
Molecular and Cellular Biology  2013;33(5):887-903.
The activity of DNA methyltransferase 1 (DNMT1) is associated with diverse biological activities, including cell proliferation, senescence, and cancer development. In this study, we demonstrated that the HMG box-containing protein 1 (HBP1) transcription factor is a new repressor of DNMT1 in a complex mechanism during senescence. The DNMT1 gene contains an HBP1-binding site at bp −115 to −134 from the transcriptional start site. HBP1 repressed the endogenous DNMT1 gene through sequence-specific binding, resulting in both gene-specific (e.g., p16INK4) and global DNA hypomethylation changes. The HBP1-mediated repression by DNMT1 contributed to replicative and premature senescence, the latter of which could be induced by Ras and HBP1 itself. A detailed investigation unexpectedly revealed that HBP1 has dual and complex transcriptional functions, both of which contribute to premature senescence. HBP1 both repressed the DNMT1 gene and activated the p16 gene in premature senescence. The opposite transcriptional functions proceeded through different DNA sequences and differential protein acetylation. While intricate, the reciprocal partnership between HBP1 and DNMT1 has exceptional importance, since its abrogation compromises senescence and promotes tumorigenesis. Together, our results suggest that the HBP1 transcription factor orchestrates a complex regulation of key genes during cellular senescence, with an impact on overall DNA methylation state.
doi:10.1128/MCB.00637-12
PMCID: PMC3623086  PMID: 23249948
14.  Correction: Altered Reward Circuitry in the Norepinephrine Transporter Knockout Mouse 
PLoS ONE  2013;8(8):10.1371/annotation/76516adc-5541-4941-b4ff-e80d1c4d769f.
doi:10.1371/annotation/76516adc-5541-4941-b4ff-e80d1c4d769f
PMCID: PMC3747294  PMID: 23976933
15.  The distinct expression patterns of claudin-2, -6, and −11 between human gastric neoplasms and adjacent non-neoplastic tissues 
Diagnostic Pathology  2013;8:133.
Background
Cancers have a multifactorial etiology a part of which is genetic. Recent data indicate that expression of the tight junction claudin proteins is involved in the etiology and progression of cancer.
Methods
To explore the correlations of the tight junction proteins claudin-2,-6, and −11 in the pathogenesis and clinical behavior of gastric cancer, 40 gastric cancer tissues and 28 samples of non-neoplastic tissues adjacent to the tumors were examined for expression of claudin-2,-6, and −11 by streptavidin-perosidase immunohistochemical staining method.
Results
The positive expression rates of claudin-2 in gastric cancer tissues and adjacent tissues were 25% and 68% respectively (P < 0.001). The positive expression rates of claudin-6 in gastric cancer tissues and adjacent tissues were 55% and 79% respectively (P = 0.045 < 0.05). In contrast, the positive expression rates of claudin-11 in gastric cancer tissues and gastric cancer adjacent tissues were 80% and 46% (P = 0.004 < 0.01). Thus in our study, the expression of claudin-2, and claudin-6 was down regulated in gastric cancer tissue while the expression of claudin-11 was up regulated. Correlations between claudin expression and clinical behavior were not observed.
Conclusion
Our study provides the first evidence that claudin-2,-6, and −11 protein expression varies between human gastric cancers and adjacent non-neoplastic tissues.
Virtual slides
The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/5470513569630744
doi:10.1186/1746-1596-8-133
PMCID: PMC3751254  PMID: 23919729
Gastric cancer; Tight junctions; Claudin-2; Claudin-6; Claudin-11; Immunohistochemistry
16.  Loss of CARM1 is linked to reduced HuR function in replicative senescence 
BMC Molecular Biology  2013;14:15.
Background
The co-activator-associated arginine methyltransferase 1 (CARM1) catalyzes the methylation of HuR. However, the functional impact of this modification is not fully understood. Here, we investigated the influence of HuR methylation by CARM1 upon the turnover of HuR target mRNAs encoding senescence-regulatory proteins.
Results
Changing the methylation status of HuR in HeLa cells by either silencing CARM1 or mutating the major methylation site (R217K) greatly diminished the effect of HuR in regulating the turnover of mRNAs encoding cyclin A, cyclin B1, c-fos, SIRT1, and p16. Although knockdown of CARM1 or HuR individually influenced the expression of cyclin A, cyclin B1, c-fos, SIRT1, and p16, joint knockdown of both CARM1 and HuR did not show further effect. Methylation by CARM1 enhanced the association of HuR with the 3′UTR of p16 mRNA, but not with the 3′UTR of cyclin A, cyclin B1, c-fos, or SIRT1 mRNAs. In senescent human diploid fibroblasts (HDFs), reduced CARM1 was accompanied by reduced HuR methylation. In addition, knockdown of CARM1 or mutation of the major methylation site of HuR in HDF markedly impaired the ability of HuR to regulate the expression of cyclin A, cyclin B1, c-fos, SIRT1, and p16 as well to maintain a proliferative phenotype.
Conclusion
CARM1 represses replicative senescence by methylating HuR and thereby enhancing HuR’s ability to regulate the turnover of cyclin A, cyclin B1, c-fos, SIRT1, and p16 mRNAs.
doi:10.1186/1471-2199-14-15
PMCID: PMC3718661  PMID: 23837869
CARM1; HuR methylation; mRNA turnover; Replicative senescence
17.  Loss of the miR-144/451 cluster impairs ischaemic preconditioning-mediated cardioprotection by targeting Rac-1 
Cardiovascular Research  2012;94(2):379-390.
Aims
While a wealth of data has uncovered distinct microRNA (miR) expression alterations in hypertrophic and ischaemic/reperfused (I/R) hearts, little is known about miR regulation and response to ischaemic preconditioning (IPC).
Methods and results
We analysed miRs in murine hearts preconditioned with six cycles of 4 min ischaemia via coronary artery occlusion, followed by 4 min reperfusion in vivo. Both miRs within the miR-144/451 cluster were the most elevated among a cohort of 21 dysregulated miRs in preconditioned hearts, compared with shams. To investigate the significance of this finding, we examined IPC-mediated cardioprotection within a miR-144/451-knockout (KO) mouse model. Wild-type (WT) hearts exposed to IPC followed by I/R (30 min/24 h) showed a smaller infarction size compared with mice treated with I/R alone. In contrast, IPC failed to protect miR-144/451-KO hearts against infarct caused by I/R treatment. Thus, the miR-144/451 cluster is required for IPC-elicited cardioprotection. Rac-1, a key component of NADPH oxidase, was mostly up-regulated in KO hearts among three bona fide targets (Rac-1, 14-3-3ζ, and CUGBP2) for both miR-144 and miR-451. Accordingly, reactive oxygen species (ROS) levels were markedly increased in KO hearts upon IPC, compared with IPC-WT hearts. Pre-treatment of KO hearts with a Rac-1 inhibitor NSC23766 (20 mg/kg, ip) reduced IPC-triggered ROS levels and restored IPC-elicited cardioprotection. Using antagomiRs, we showed that miR-451 was largely responsible for IPC-mediated cardioprotection.
Conclusion
Loss of the miR-144/451 cluster limits IPC cardioprotection by up-regulating Rac-1-mediated oxidative stress signalling.
doi:10.1093/cvr/cvs096
PMCID: PMC3331614  PMID: 22354898
MicroRNA-144; MicroRNA-451; Ischaemic preconditioning; Myocardial ischaemia/reperfusion; Rac-1; Oxidative stress
18.  Deficits in axonal transport in hippocampal-based circuitry and the visual pathway in APP knock-out animals witnessed by manganese enhanced MRI 
Neuroimage  2012;60(3):1856-1866.
Mounting evidence implicates axonal transport defects, typified by the presence of axonal varicosities with aberrant accumulations of cargo, as an early event in Alzheimer’s disease (AD) pathogenesis. Work identifying amyloid precursor protein (APP) as a vesicular motor receptor for anterograde axonal transport further implicates axonal transport in AD. Manganese-enhanced MRI (MEMRI) detects axonal transport dynamics in preclinical studies. Here we pursue an understanding of the role of APP in axonal transport in the central nervous system by applying MEMRI to hippocampal circuitry and to the visual pathway in living mice homozygous for either wild type or a deletion in the APP gene (n = 12 for each genotype). Following intra-ocular or stereotaxic hippocampal injection, we performed time-lapse MRI to detect Mn2+ transport. Three dimensional whole brain datasets were compared on a voxel-wise basis using within-group pair-wise analysis. Quantification of transport to structures connected to injection sites via axonal fiber tracts was also performed. Histology confirmed consistent placement of hippocampal injections and no observable difference in glial-response to the injections. APP −/− mice had significantly reduced transport from the hippocampus to the septal nuclei and amygdala after 7 hours and reduced transport to the contralateral hippocampus after 25 hours; axonal transport deficits in the APP −/− animals were also identified in the visual pathway. These data support a system-wide role for APP in axonal transport within the central nervous system and demonstrate the power of MEMRI for assessing neuronal circuitry involved in memory and learning.
doi:10.1016/j.neuroimage.2012.01.132
PMCID: PMC3328142  PMID: 22500926
Amyloid precursor protein; Manganese enhanced MRI (MEMRI); Alzheimer’s disease; axonal transport; statistical parametric mapping; optic tract; synaptic transmission; hippocampus; visual pathway
19.  Association of Dyslipidemia with Renal Cell Carcinoma: A 1∶2 Matched Case-Control Study 
PLoS ONE  2013;8(3):e59796.
Abnormal serum lipid profiles are associated with the risk of some cancers, but the direction and magnitude of the association with renal cell carcinoma is unclear. We explore the relationship between serum lipids and renal cell carcinoma via a matched case-control study. A 1∶2-matched case-control study design was applied, where one renal cell carcinoma patient was matched to two non-renal-cell-carcinoma residents with respect to age (±0 year) and gender. Cases (n = 248) were inpatients with a primary diagnosis of renal cell carcinoma, confirmed by pathology after operations. Controls were sampled from a community survey database matched on age and gender with cases, 2 controls for each case. Stratified Cox proportional hazard regression analysis was used to obtain hazard ratios and corresponding 95% confidence intervals of lipids level and dyslipidemia for the risk of renal cell carcinoma. Elevated serum cholesterol (p<0.001), LDL cholesterol (p<0.001), and HDL cholesterol (p = 0.003) are associated with decreased hazard of renal cell carcinoma, adjusting for obesity, smoke, hypertension and diabetes. However, risk caused by hTG showed no statistical significance (p = 0.263). This study indicates that abnormal lipid profile influences the risk of renal cell carcinoma.
doi:10.1371/journal.pone.0059796
PMCID: PMC3607555  PMID: 23536888
20.  The role of autophagy in Parkinson's disease: rotenone-based modeling 
Background
Autophagy-mediated self-digestion of cytoplasmic inclusions may be protective against neurodegenerative diseases such as Parkinson’s disease (PD). However, excessive autophagic activation evokes autophagic programmed cell death.
Methods
In this study, we aimed at exploring the role of autophagy in the pathogenesis of rotenone-induced cellular and animal models for PD.
Results
Reactive oxygen species over-generation, mitochondrial membrane potential reduction or apoptosis rate elevation occurred in a dose-dependent fashion in rotenone-treated human neuroblastoma cell line SH-SY5Y. The time- and dose-dependent increases in autophagic marker microtubule-associated protein1 light chain 3 (LC3) expression and decreases in autophagic adaptor protein P62 were observed in this cellular model. LC3-positive autophagic vacuoles were colocalized with alpha-synuclein-overexpressed aggregations. Moreover, the number of autophagic vacuoles was increased in rotenone-based PD models in vitro and in vivo.
Conclusions
These data, along with our previous finding showing rotenone-induced toxicity was prevented by the autophagy enhancers and was aggravated by the autophagy inhibitors in SH-SY5Y, suggest that autophagy contributes to the pathogenesis of PD, attenuates the rotenone toxicity and possibly represents a new subcellular target for treating PD.
doi:10.1186/1744-9081-9-13
PMCID: PMC3606411  PMID: 23497442
Autophagy; LC3; Parkinson's Desease; Rotenone; Autophagosome; Pathogenesis
21.  Altered Reward Circuitry in the Norepinephrine Transporter Knockout Mouse 
PLoS ONE  2013;8(3):e57597.
Synaptic levels of the monoamine neurotransmitters dopamine, serotonin, and norepinephrine are modulated by their respective plasma membrane transporters, albeit with a few exceptions. Monoamine transporters remove monoamines from the synaptic cleft and thus influence the degree and duration of signaling. Abnormal concentrations of these neuronal transmitters are implicated in a number of neurological and psychiatric disorders, including addiction, depression, and attention deficit/hyperactivity disorder. This work concentrates on the norepinephrine transporter (NET), using a battery of in vivo magnetic resonance imaging techniques and histological correlates to probe the effects of genetic deletion of the norepinephrine transporter on brain metabolism, anatomy and functional connectivity. MRS recorded in the striatum of NET knockout mice indicated a lower concentration of NAA that correlates with histological observations of subtle dysmorphisms in the striatum and internal capsule. As with DAT and SERT knockout mice, we detected minimal structural alterations in NET knockout mice by tensor-based morphometric analysis. In contrast, longitudinal imaging after stereotaxic prefrontal cortical injection of manganese, an established neuronal circuitry tracer, revealed that the reward circuit in the NET knockout mouse is biased toward anterior portions of the brain. This is similar to previous results observed for the dopamine transporter (DAT) knockout mouse, but dissimilar from work with serotonin transporter (SERT) knockout mice where Mn2+ tracings extended to more posterior structures than in wildtype animals. These observations correlate with behavioral studies indicating that SERT knockout mice display anxiety-like phenotypes, while NET knockouts and to a lesser extent DAT knockout mice display antidepressant-like phenotypic features. Thus, the mainly anterior activity detected with manganese-enhanced MRI in the DAT and NET knockout mice is likely indicative of more robust connectivity in the frontal portion of the reward circuit of the DAT and NET knockout mice compared to the SERT knockout mice.
doi:10.1371/journal.pone.0057597
PMCID: PMC3587643  PMID: 23469209
22.  Effects of oleic acid on cell proliferation through an integrin-linked kinase signaling pathway in 786-O renal cell carcinoma cells 
Oncology Letters  2013;5(4):1395-1399.
An increased risk of renal cell carcinoma (RCC) has been linked with obesity and metabolic syndrome. However, the mechanisms by which lipid metabolic disorders affect the development of RCC remain unclear and highly controversial. Integrin-linked kinase (ILK) is a serine/threonine protein kinase involved in the regulation of tumor cell growth and angiogenesis. In the present study, the effect of free fatty acids in the promotion of RCC progression was investigated by upregulating ILK. Results of the MTT assay indicated that treatment of 786-O cells with oleic acid induced a concentration-dependent increase in cell viability. Flow cytometry analysis revealed that the effect of oleic acid on cell apoptosis was not significant. Following treatment with oleic acid, the expression of ILK, phospho-Akt and G protein-coupled receptor 40 (GPR40) was increased in 786-O cells. These effects were reversed when the expression of ILK was downregulated using specific small interfering RNA. These results indicate that free fatty acids are associated with the development of renal cell carcinoma via activation of the GPR40/ILK/Akt pathway, revealing a novel mechanism for the correlation between metabolic disturbance and renal carcinoma.
doi:10.3892/ol.2013.1160
PMCID: PMC3629253  PMID: 23599801
oleic acid; renal cell carcinoma; cell proliferation; integrin-linked kinase
23.  Endothelial lipase mediates HDL levels in normal and hyperlipidemic rabbits 
Existing evidence suggests that endothelial lipase (EL) plays an important role in high-density-lipoprotein (HDL) metabolism. Because rabbits are a useful animal model for the study of human lipid metabolism and atherosclerosis, we characterized rabbit tissue EL expression and investigated its relationship with plasma HDL levels in normal and hyperlipidemic rabbits. First, we cloned the rabbit EL (rEL) cDNA and gene. Using Northern blotting, real-time RT-PCR, Western blotting, and in situ hybridization, we revealed that rEL mRNA was highly expressed in the cholesterol synthesis-related organs including the liver, testis, and adrenal along with its expression in the lung, kidney, bone marrow, and small intestine. Interestingly, Watanabe heritable hyperlipidemic (WHHL) rabbits, a model of human familial hypercholesterolemia, had lower plasma levels of HDLs than normal rabbits. The plasma HDL levels in WHHL rabbits were inversely associated with high levels of plasma rEL proteins and hepatic expression of rEL mRNA. Injection of rEL-specific antisense oligonucleotides into rabbits resulted in an elevation of plasma large-sized HDLs. Furthermore, we demonstrated that the rEL mRNA was expressed by both endothelial cells and macrophages in the lesions of aortic atherosclerosis of WHHL rabbits. EL is expressed in multiple tissues and may have many physiological and pathophysiological functions such as in the regulation of cholesterol metabolism and atherosclerosis. Our results suggest that EL is an important regulator of plasma HDL levels in rabbits.
PMCID: PMC3493565  PMID: 22240910
Endothelial lipase; HDL; rabbit; hypercholesterolemia; antisense
24.  Glucocerebrosidase L444P mutation confers genetic risk for Parkinson’s disease in central China 
Background
Mutations of the glucocerebrosidase (GBA) gene have reportedly been associated with Parkinson disease (PD) in various ethnic populations such as Singaporean, Japanese, Formosan, Canadian, American, Portuguese, Greek, Brazilian, British, Italian, Ashkenazi Jewish, southern and southwestern Chinese. The purpose of this study is to determine in central China whether or not the reported GBA mutations remain associated with PD.
Methods
In this project, we conducted a controlled study in a cohort of 208 central Chinese PD patients and 298 controls for three known GBA mutations (L444P, N370S and R120W).
Results
Our data reveals a significantly higher frequency of L444P mutation in GBA gene of PD cases (3.4%) compared with the controls (0.3%) (P = 0.007, OR = 10.34, 95% CI = 1.26 - 84.71). Specifically, the frequency of L444P mutation was higher in the late onset PD (LOPD) cases compared with that in control subjects. The N370S and R120W mutations were detected in neither the PD group nor the control subjects.
Conclusions
Our observations demonstrated that the GBA L444P mutation confers genetic risk for PD, especially LOPD, among the population in the central China area.
doi:10.1186/1744-9081-8-57
PMCID: PMC3538614  PMID: 23227814
Parkinson’s disease; Glucocerebrosidase; L444P; N370S; R120W; Central China
25.  Correction: Toll-Like Receptor (TLR) 2 and TLR4 Differentially Regulate Doxorubicin Induced Cardiomyopathy in Mice 
PLoS ONE  2012;7(10):10.1371/annotation/e82f77a8-3d29-44be-a9ef-7abc6c7e584a.
doi:10.1371/annotation/e82f77a8-3d29-44be-a9ef-7abc6c7e584a
PMCID: PMC3491864

Results 1-25 (59)