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1.  One-Pot Synthesis of Graphene-Supported Monodisperse Pd Nanoparticles as Catalyst for Formic Acid Electro-oxidation 
Scientific Reports  2014;4:4501.
To synthesize monodisperse palladium nanoparticles dispersed on reduced graphene oxide (RGO) sheets, we have developed an easy and scalable solvothermal reduction method from an organic solution system. The RGO-supported palladium nanoparticles with a diameter of 3.8 nm are synthesized in N-methyl-2-pyrrolidone (NMP) and in the presence of oleylamine and trioctylphosphine, which facilitates simultaneous reduction of graphene oxide and formation of Pd nanocrystals. So-produced Pd/RGO was tested for potential use as electrocatalyst for the electro-oxidation of formic acid. Pd/RGO catalyzes formic acid oxidation very well compared to Pd/Vulcan XC-72 catalyst. This synthesis method is a new way to prepare excellent electrocatalysts, which is of great significance in energy-related catalysis.
doi:10.1038/srep04501
PMCID: PMC3968451  PMID: 24675779
2.  Trichostatin A Targets the Mitochondrial Respiratory Chain, Increasing Mitochondrial Reactive Oxygen Species Production to Trigger Apoptosis in Human Breast Cancer Cells 
PLoS ONE  2014;9(3):e91610.
Aim
Histone deacetylase inhibitors (HDACIs)-based therapies have stimulated interest via their anti-tumor activities, including apoptosis induction, cell cycle arrest, cell differentiation, and autophagy. However, the mechanisms of HDACI-associated anti-tumor activity are not yet clearly defined. The aim of this study was to explore the key events of Trichostatin A (TSA), a classic HDACI agent, against breast cancer cells.
Methods
The MCF-7, MDA-MB-231 and MCF-10A cell lines were evaluated with colony-forming and cell viability assays. Apoptosis and cell cycle distribution were detected by flow cytometry. Mitochondrial function was measured with biochemical assays, flow cytometry and transmission electron microscopy.
Results
TSA inhibited breast cancer cell viability and proliferation, without affecting MCF-10A cell. TSA-induced breast cancer cell apoptosis was initiated by G2-M arrest and depended on mitochondrial reactive oxygen species (ROS) produced subsequent to reduced mitochondrial respiratory chain activity. The enhanced mitochondrial ROS production and apoptosis in cancer cells were markedly attenuated by antioxidants, such as N-acetyl cysteine (NAC), reduced glutathione (GSH) and Vitamin C.
Conclusion
The present study demonstrated that TSA-induced cell death by arresting cell cycle in G2-M phase and was dependent on production of mitochondria-derived ROS, which was derived from impaired mitochondrial respiratory chain.
doi:10.1371/journal.pone.0091610
PMCID: PMC3953478  PMID: 24626188
3.  Influence of stress in GaN crystals grown by HVPE on MOCVD-GaN/6H-SiC substrate 
Scientific Reports  2014;4:4179.
GaN crystals without cracks were successfully grown on a MOCVD-GaN/6H-SiC (MGS) substrate with a low V/III ratio of 20 at initial growth. With a high V/III ratio of 80 at initial growth, opaque GaN polycrystals were obtained. The structural analysis and optical characterization reveal that stress has a great influence on the growth of the epitaxial films. An atomic level model is used to explain these phenomena during crystal growth. It is found that atomic mobility is retarded by compressive stress and enhanced by tensile stress.
doi:10.1038/srep04179
PMCID: PMC3935196  PMID: 24569601
4.  Genetic Diversity Analysis of Genotype 2 Porcine Reproductive and Respiratory Syndrome Viruses Emerging in Recent Years in China 
BioMed Research International  2014;2014:748068.
Porcine reproductive and respiratory syndrome virus (PRRSV) is characterized by its extensive genetic diversity. Here we analyzed 101 sequences of NSP2 hypervariable region, 123 ORF3 sequences, and 118 ORF5 sequences from 128 PRRSV-positive clinical samples collected in different areas of China during 2008–early 2012. The results indicated that the amino acid identities of the three genes among these sequences were 87.6%–100%, 92.5%–100%, and 77%–100%, respectively. Meanwhile, 4 novel patterns of deletion and insertion in NSP2 region or GP5 were first found. The phylogenetic analysis on these 3 genes revealed that the Chinese PRRSV strains could be divided into three subgroups; majority of genes analyzed here were clustered in subgroup 3 with multiple branches; the strains with 30-aa deletion in NSP2-coding region were still the dominant virus in the field. Further phylogenetic analysis on four obtained complete genomic sequences showed that they were clustered into different branches with the Chinese corresponding representative strains. Our analyses suggest that the genetic diversity of genotype 2 PRRSV in the field displays a tendency of increasing in recent years in China, and the 30-aa deletion in NSP2-coding region should be no longer defined as the molecular marker of the Chinese HP-PRRSV.
doi:10.1155/2014/748068
PMCID: PMC3955690  PMID: 24719885
5.  Determination of 16 Selected Trace Elements in Children Plasma from China Economical Developed Rural Areas Using High Resolution Magnetic Sector Inductively Coupled Mass Spectrometry 
A rapid, accurate, and high performance method of high resolution sector field inductively coupled plasma mass spectrometry (HR-ICP-MS) combined with a small-size sample (0.1 mL) preparation was established. The method was validated and applied for the determination of 16 selected plasma trace elements (Fe, Cu, Zn, Rb, B, Al, Se, Sr, V, Cr, Mn, Co, As, Mo, Cd, and Pb). The linear working ranges were over three intervals, 0-1 μg/L, 0–10 μg/L and 0–100 μg/L. Correlation coefficients (R2) ranged from 0.9957 to 0.9999 and the limits of quantification (LOQ) ranged from 0.02 μg/L (Rb) to 1.89 μg/L (Se). The trueness (or recovery) spanned from 89.82% (Al) to 119.15% (Se) and precision expressed by the relative standard deviation (RSD %) for intra-day ranging from 1.1% (Zn) to 9.0% (Se), while ranged from 3.7% (Fe) to 12.7% (Al) for interday. A total of 440 plasma samples were collected from Chinese National Nutrition and Health Survey Project 2002 (CNNHS 2002), which represented the status of plasma trace elements for the children aged 3–12 years from China economical developed rural areas. The concentrations of 16 trace elements were summarized and compared by age groups and gender, which can be used as one of the basic components for the formulation of the baseline reference values of trace elements for the children in 2002.
doi:10.1155/2014/975820
PMCID: PMC3950582
6.  Characterization of disease-associated N-linked glycoproteins 
Proteomics  2013;13(0):10.1002/pmic.201200333.
N-linked glycoproteins play important roles in biological processes, including cell-to-cell recognition, growth, differentiation, and programmed cell death. Specific N-linked glycoprotein changes are associated with disease progression and identification of these N-linked glycoproteins has potential for use in disease diagnosis, prognosis, and prediction of treatments. In this review, we summarize common strategies for N-linked glycoprotein characterization and applications of these strategies to identification of glycoprotein changes associated with disease states. We also review the N-linked glycoproteins altered in diseases such as breast cancer, lung cancer, and prostate cancer. Although assays for these glycoproteins have potential clinical utility, research is needed to translate these glycoproteins to clinical biomarkers.
doi:10.1002/pmic.201200333
PMCID: PMC3733363  PMID: 23255236
Disease association; Glycoproteomics; N-linked glycoproteins
7.  Ubiquitin B in Cervical Cancer: Critical for the Maintenance of Cancer Stem-Like Cell Characters 
PLoS ONE  2013;8(12):e84457.
Cervical cancer cells exhibit an increased requirement for ubiquitin-dependent protein degradation associated with an elevated metabolic turnover rate. Ubiquitin, which is a small, highly conserved protein expressed in all eukaryotic cells, can be covalently linked to certain target proteins to mark them for degradation by the ubiquitin-proteasome system. Previous studies highlight the essential role of Ubiquitin B (UbB) and UbB-dependent proteasomal protein degradation in histone deacetylase inhibitor (HDACi) -induced tumor selectivity. We hypothesized that UbB plays a critical role in the function of cervical cancer stem cells. We measured endogenous UbB levels in mammospheres in vitro by real-time PCR and Western blotting. The function of UbB in cancer stem-like cells was assessed after knockdown of UbB expression in prolonged Trichostatin A-selected HeLa cells (HeLa/TSA) by measuring in vitro cell proliferation, cell apoptosis, invasion, and chemotherapy resistance as well as by measuring in vivo growth in an orthotopic model of cervical cancer. We also assessed the cancer stem cell frequency, tumorsphere formation, and in vivo growth of human cervical cancer xenografts after UbB silencing. We found that HeLa/TSA were resistant to chemotherapy, highly expressed the UbB gene and the stem cell markers Sox2, Oct4 and Nanog. These cells also displayed induced differentiation abilities, including enhanced migration/invasion/malignancy capabilities in vitro and in vivo. Furthermore, an elevated expression of UbB was shown in the tumor samples of chemotherapy patients. Silencing of UbB inhibited tumorsphere formation, lowered the expression of stem cell markers and decreased cervical xenograft growth. Our results demonstrate that UbB was significantly increased in prolonged Trichostatin A-selected HeLa cells and it played a key role in the maintenance of cervical cancer stem-like cells.
doi:10.1371/journal.pone.0084457
PMCID: PMC3867485  PMID: 24367661
8.  Targeting of Histone Deacetylases to Reactivate Tumour Suppressor Genes and Its Therapeutic Potential in a Human Cervical Cancer Xenograft Model 
PLoS ONE  2013;8(11):e80657.
Aberrant histone acetylation plays an essential role in the neoplastic process via the epigenetic silencing of tumour suppressor genes (TSGs); therefore, the inhibition of histone deacetylases (HDAC) has become a promising target in cancer therapeutics. To investigate the correlation of histone acetylation with clinicopathological features and TSG expression, we examined the expression of acetylated H3 (AcH3), RARβ2, E-cadherin, and β-catenin by immunohistochemistry in 65 cervical squamous cell carcinoma patients. The results revealed that the absence of AcH3 was directly associated with poor histological differentiation and nodal metastasis as well as reduced/negative expression of RARβ2, E-cadherin, and β-catenin in clinical tumour samples. We further demonstrated that the clinically available HDAC inhibitors valproic acid (VPA) and suberoylanilide hydroxamic acid (SAHA), in combination with all-trans retinoic acid (ATRA), can overcome the epigenetic barriers to transcription of RARβ2 in human cervical cancer cells. Chromatin immunoprecipitation analysis showed that the combination treatment increased the enrichment of acetylated histone in the RARβ2-RARE promoter region. In view of these findings, we evaluated the antitumor effects induced by combined VPA and ATRA treatment in a xenograft model implanted with poorly differentiated human squamous cell carcinoma. Notably, VPA restored RARβ2 expression via epigenetic modulation. Additive antitumour effects were produced in tumour xenografts by combining VPA with ATRA treatment. Mechanistically, the combination treatment reactivated the expression of TSGs RARβ2, E-cadherin, P21CIP1, and P53 and reduced the level of p-Stat3. Sequentially, upregulation of involucrin and loricrin, which indicate terminal differentiation, strongly contributed to tumour growth inhibition along with partial apoptosis. In conclusion, targeted therapy with HDAC inhibitors and RARβ2 agonists may represent a novel therapeutic approach for patients with cervical squamous cell carcinoma.
doi:10.1371/journal.pone.0080657
PMCID: PMC3834007  PMID: 24260446
9.  Proteomic Analysis of Chinese Hamster Ovary Cells 
Journal of proteome research  2012;11(11):5265-5276.
In order to complement the recent genomic sequencing of Chinese hamster ovary (CHO) cells, proteomic analysis was performed on CHO including the cellular proteome, secretome, and glycoproteome using tandem mass spectrometry (MS/MS) of multiple fractions obtained from gel electrophoresis, multi-dimensional liquid chromatography, and solid phase extraction of glycopeptides (SPEG). From the 120 different mass spectrometry analyses generating 682,097 MS/MS spectra, 93,548 unique peptide sequences were identified with at most a 0.02 false discovery rate (FDR). A total of 6164 grouped proteins were identified from both glycoproteome and proteome analysis, representing an 8-fold increase in the number of proteins currently identified in the CHO proteome. Furthermore, this is the first proteomic study done using CHO genome exclusively which provides for more accurate identification of proteins. From this analysis, the CHO codon frequency was determined and found to be distinct from humans, which will facilitate expression of human proteins in CHO cells. Analysis of the combined proteomic and mRNA data sets indicated the enrichment of a number of pathways including protein processing and apoptosis but depletion of proteins involved in steroid hormone and glycosphingolipid metabolism. 504 of the detected proteins included N-acetylation modifications and 1292 different proteins were observed to be N-glycosylated. This first large-scale proteomic analysis will enhance the knowledge base about CHO capabilities for recombinant expression and provide information useful in cell engineering efforts aimed at modifying CHO cellular functions.
doi:10.1021/pr300476w
PMCID: PMC3772721  PMID: 22971049
10.  Organic Matter and Water Addition Enhance Soil Respiration in an Arid Region 
PLoS ONE  2013;8(10):e77659.
Climate change is generally predicted to increase net primary production, which could lead to additional C input to soil. In arid central Asia, precipitation has increased and is predicted to increase further. To assess the combined effects of these changes on soil CO2 efflux in arid land, a two factorial manipulation experiment in the shrubland of an arid region in northwest China was conducted. The experiment used a nested design with fresh organic matter and water as the two controlled parameters. It was found that both fresh organic matter and water enhanced soil respiration, and there was a synergistic effect of these two treatments on soil respiration increase. Water addition not only enhanced soil C emission, but also regulated soil C sequestration by fresh organic matter addition. The results indicated that the soil CO2 flux of the shrubland is likely to increase with climate change, and precipitation played a dominant role in regulating soil C balance in the shrubland of an arid region.
doi:10.1371/journal.pone.0077659
PMCID: PMC3799695  PMID: 24204907
11.  Reduced Vancomycin Susceptibility Found in Methicillin-Resistant and Methicillin-Sensitive Staphylococcus aureus Clinical Isolates in Northeast China 
PLoS ONE  2013;8(9):e73300.
Background
Strains of Staphylococcus aureus with an intermediate level of resistance to vancomycin (vancomycin-intermediate S. aureus, or VISA) or which contain subpopulations of mixed susceptibility (heterogeneous VISA, or hVISA) have been reported worldwide. However, the prevalence of VISA and hVISA infections in Northeast China is unknown. From 2007 through 2010, we surveyed the vancomycin susceptibility of methicillin-resistant and methicillin-sensitive S. aureus (MRSA and MSSA, respectively) clinical isolates in Northeast China.
Methods
S. aureus clinical isolates (369 MRSA and 388 MSSA) were screened for hVISA and VISA on brain heart infusion agar containing 3 μg/mL vancomycin, and their identity confirmed using a modified population analysis profile-area under the curve method and broth microdilution. All hVISA and VISA isolates were characterized genotypically and phenotypically.
Results
Ten percent and 0.5 percent of the isolates were hVISA and VISA, respectively. The proportion of hVISA among MSSA isolates for the entire study period was 4.1%, but increased significantly year-by-year, from 1.2% in 2007 to 7.2% in 2010. The predominant sources of hVISA and VISA isolates were sputum (56.3%), pus (18.8%), and blood (8.8%). Molecular typing of hVISA and VISA strains revealed that, taken together, 80% contained the accessory gene regulator (agr) group II, and of these, 85.7% of the MR-hVISA and MR-VISA strains were staphylococcal cassette chromosome mec (SCCmec) type II. The adherence ability of all hVISA and VISA strains was reduced compared with that of vancomycin-susceptible strains, shown by biofilm assay.
Conclusions
The percentage of hVISA strains was high and increased each year. The proportion of hVISA among MSSA specifically also increased significantly each year. In isolates collected from diverse infection sites, hVISA and VISA strains were found predominantly in sputum, pus, and blood, in descending order. Testing for vancomycin susceptibility should include both MRSA and MSSA isolates collected from different clinical sites.
doi:10.1371/journal.pone.0073300
PMCID: PMC3772004  PMID: 24069184
12.  Interlaboratory Reproducibility of Selective Reaction Monitoring Assays Using Multiple Upfront Analyte Enrichment Strategies 
Journal of proteome research  2012;11(8):3986-3995.
Over the past few years, mass spectrometry has emerged as a technology to complement and potentially replace standard immunoassays in routine clinical core laboratories. Application of mass spectrometry to protein and peptide measurement can provide advantages including high sensitivity, the ability to multiplex analytes, and high specificity at the amino acid sequence level. In our previous study, we demonstrated excellent reproducibility of mass spectrometry-selective reaction monitoring (MS-SRM) assays when applying standardized standard operating procedures (SOPs) to measure synthetic peptides in a complex sample, as lack of reproducibility has been a frequent criticism leveled at the use of mass spectrometers in the clinical laboratory compared to immunoassays. Furthermore, an important caveat of SRM-based assays for proteins is that many low-abundance analytes require some type of enrichment before detection with MS. This adds a level of complexity to the procedure and the potential for irreproducibility increases, especially across different laboratories with different operators. The purpose of this study was to test the interlaboratory reproducibility of SRM assays with various upfront enrichment strategies and different types of clinical samples (representing real-world body fluids commonly encountered in routine clinical laboratories). Three different, previously published enrichment strategies for low-abundance analytes and a no-enrichment strategy for high-abundance analytes were tested across four different laboratories using different liquid chromatography-SRM (LC-SRM) platforms and previously developed SOPs. The results demonstrated that these assays were indeed reproducible with coefficients of variation of less than 30% for the measurement of important clinical proteins across all four laboratories in real world samples.
doi:10.1021/pr300014s
PMCID: PMC3761372  PMID: 22639787
SRM assay; mass spectrometry; proteomics; clinical assay
13.  Molecular Mechanism for p202-mediated Specific Inhibition of AIM2 Inflammasome Activation 
Cell reports  2013;4(2):327-339.
SUMMARY
Mouse p202 containing two HIN domains antagonizes AIM2 inflammasome signaling and potentially modifies lupus susceptibility. We found only HIN1 of p202 binds dsDNA, while HIN2 forms a homo-tetramer. Crystal structures of HIN1 revealed that dsDNA is bound on the opposite face to the site used in AIM2 and IFI16. The structure of HIN2 revealed a dimer of dimers, with the face analogous to the HIN1 dsDNA binding site being a dimerization interface. Electron microscopy imaging showed that HIN1 is flexibly linked to HIN2 in p202, and tetramerization provided enhanced avidity for dsDNA. Surprisingly, HIN2 of p202 interacts with AIM HIN domain. We propose this results in spatial separation of AIM2 pyrin domains, and indeed p202 prevented dsDNA-dependent clustering of ASC and AIM2 inflammasome activation. We hypothesize that while p202 was evolutionarily selected to limit AIM2-mediated inflammation in some mouse strains, the same mechanism contributes to increased interferon production and lupus susceptibility.
doi:10.1016/j.celrep.2013.06.024
PMCID: PMC3760141  PMID: 23850291
14.  The Effect of Lutein Supplementation on Blood Plasma Levels of Complement Factor D, C5a and C3d 
PLoS ONE  2013;8(8):e73387.
Lutein is selectively taken up by the primate retina and plays an important role as a filter for harmful blue light and as an antioxidant. Recent studies have shown that lutein has systemic anti-inflammatory properties. Dietary lutein has been associated with reduced circulating levels of inflammatory biomarkers such as CRP and sICAM. Whether lutein also affects activation of the complement system has not yet been addressed and was the purpose of the study described here. Seventy-two subjects with signs of early macular degeneration were randomly assigned to receive either a 10 mg lutein supplement or a placebo during one year. EDTA blood samples were collected at 0, 4, 8 and 12 months. Complement factor D (CFD), a rate limiting component of the alternative pathway of complement activation and the complement activation products C5a and C3d were determined in the plasma samples by ELISA. A significant 0.11 µg/ml monthly decrease in plasma CFD concentration was observed in the lutein group (p<0.001), resulting in a 51% decrease from 2.3 µg/ml at baseline to 1.0 µg/ml at 12 months. The C5a concentration showed a significant 0.063ng/ml monthly decrease in the lutein group (p<0.001) resulting in a 36% decrease from 2.2ng/ml at baseline to 1.6ng/ml at 12 months. The C3d concentration showed a significant 0.19µg/ml monthly decrease in the lutein group (p=0.004) that gave rise to a 9% decrease from 15.4µg/ml at baseline to 14.4µg/ml at 12 months. In the placebo group we found a significant 0.04 µg/ml monthly decrease in plasma CFD concentration, whereas no changes were observed for C5a and C3d. Lutein supplementation markedly decreases circulating levels of the complement factors CFD, C5a and C3d levels, which might allow a simple method to control this inflammatory pathway of the innate immune system.
doi:10.1371/journal.pone.0073387
PMCID: PMC3756963  PMID: 24009749
15.  Effects of Added Organic Matter and Water on Soil Carbon Sequestration in an Arid Region 
PLoS ONE  2013;8(7):e70224.
It is generally predicted that global warming will stimulate primary production and lead to more carbon (C) inputs to soil. However, many studies have found that soil C does not necessarily increase with increased plant litter input. Precipitation has increased in arid central Asia, and is predicted to increase more, so we tested the effects of adding fresh organic matter (FOM) and water on soil C sequestration in an arid region in northwest China. The results suggested that added FOM quickly decomposed and had minor effects on the soil organic carbon (SOC) pool to a depth of 30 cm. Both FOM and water addition had significant effects on the soil microbial biomass. The soil microbial biomass increased with added FOM, reached a maximum, and then declined as the FOM decomposed. The FOM had a more significant stimulating effect on microbial biomass with water addition. Under the soil moisture ranges used in this experiment (21.0%–29.7%), FOM input was more important than water addition in the soil C mineralization process. We concluded that short-term FOM input into the belowground soil and water addition do not affect the SOC pool in shrubland in an arid region.
doi:10.1371/journal.pone.0070224
PMCID: PMC3713057  PMID: 23875022
16.  Different Effects of Six Antibiotics and Ten Traditional Chinese Medicines on Shiga Toxin Expression by Escherichia coli O157:H7 
This study compared the effects of ten types of traditional Chinese medicines (TCMs) and six different antibiotics on E. coli O157:H7 Shiga toxin gene (stx2) mRNA expression level based on real-time PCR and the expression level of Stx toxin using an ELISA quantitative assay. We also compared their effects on the induction of the SOS response. The results clearly indicated that all ten TCMs had negative results in the SOS response induction test, while most TCMs did not increase the levels of stx2 mRNA and the Stx toxin. Some TCMs did increase the mRNA levels of the stx2 gene and the Stx toxin level, but their increases were much lower than those caused by antibiotics. With the exception of cefotaxime, the six antibiotics increased the Stx toxin level and increased the stx2 gene mRNA level. With the exceptions of cefotaxime and tetracycline, the antibiotics increased the SOS induction response. These results suggest that TCMs may have advantages compared with antibiotics, when treating E. coli O157:H7; TCMs did not greatly increase Stx toxin production and release.
doi:10.1155/2013/121407
PMCID: PMC3730174  PMID: 23956764
17.  Cyclic di-GMP Sensing via the Innate Immune Signaling Protein STING 
Molecular cell  2012;46(6):735-745.
SUMMARY
Detection of foreign materials is the first step of successful immune responses. Stimulator of interferon genes (STING) was shown to directly bind cyclic diguanylate monophosphate (c-di-GMP), a bacterial second messenger, and to elicit strong interferon responses. Here we elucidate the structural features of the cytosolic c-di-GMP binding domain (CBD) of STING and its complex with c-di-GMP. The CBD exhibits an α + β fold and is a dimer in the crystal and in solution. Surprisingly, one c-di-GMP molecule binds to the central crevice of a STING dimer, using a series of stacking and hydrogen bonding interactions. We show that STING is autoinhibited by an intramolecular interaction between the CBD and the C-terminal tail (CTT) and that c-di-GMP releases STING from this autoinhibition by displacing the CTT. The structures provide a remarkable example of pathogen-host interactions in which a unique microbial molecule directly engages the innate immune system.
doi:10.1016/j.molcel.2012.05.029
PMCID: PMC3697849  PMID: 22705373
18.  A SAGE study of apolipoprotein E3/3, E3/4 and E4/4 allele-specific gene expression in hippocampus in Alzheimer disease 
APOE4 allele is a major risk factor for late-onset Alzheimer disease (AD). The mechanism of action of APOE in AD remains unclear. To study the effects of APOE alleles on gene expression in AD, we have analyzed the gene transcription patterns of human hippocampus from APOE3/3, APOE3/4, APOE4/4 AD patients and normal control using Serial Analysis of Gene Expression (SAGE). Using SAGE, we found gene expression patterns in hippocampus of APOE3/4 and APOE4/4 AD patients differ substantially from those of APOE3/3 AD patients. APOE3/4 and APOE4/4 allele expression may activate similar genes or gene pools with associated functions. APOE4 AD alleles activate multiple tumor suppressors, tumor inducers and negative regulator of cell growth or repressors that may lead to increased cell arrest, senescence and apoptosis. In contrast, there is decreased expression of large clusters of genes associated with synaptic plasticity, synaptic vesicle docking and fusing and axonal/neuronal outgrowth. In addition, reduction of neurotransmitter receptors and Ca++ homeostasis, disruption of multiple signal transduction pathways, loss of cell protection, and perhaps most notably, mitochondrial oxidative phosphorylation/energy metabolism are associated with APOE3/4 and APOE4/4 AD alleles. These findings may help define the mechanisms that APOE4 contribute increased risk for AD and identify new candidate genes conferring susceptibility to AD.
doi:10.1016/j.mcn.2007.06.009
PMCID: PMC3625967  PMID: 17822919
Apolipoprotein E; Alzheimer disease; Serial Analysis of Gene Expression (SAGE); apoptosis; signal pathways
19.  Transcriptomic Analysis of Autistic Brain Reveals Convergent Molecular Pathology 
Nature  2011;474(7351):380-384.
Autism spectrum disorder (ASD) is a common, highly heritable neuro-developmental condition characterized by marked genetic heterogeneity1–3. Thus, a fundamental question is whether autism represents an etiologically heterogeneous disorder in which the myriad genetic or environmental risk factors perturb common underlying molecular pathways in the brain4. Here, we demonstrate consistent differences in transcriptome organization between autistic and normal brain by gene co-expression network analysis. Remarkably, regional patterns of gene expression that typically distinguish frontal and temporal cortex are significantly attenuated in the ASD brain, suggesting abnormalities in cortical patterning. We further identify discrete modules of co-expressed genes associated with autism: a neuronal module enriched for known autism susceptibility genes, including the neuronal specific splicing factor A2BP1/FOX1, and a module enriched for immune genes and glial markers. Using high-throughput RNA-sequencing we demonstrate dysregulated splicing of A2BP1-dependent alternative exons in ASD brain. Moreover, using a published autism GWAS dataset, we show that the neuronal module is enriched for genetically associated variants, providing independent support for the causal involvement of these genes in autism. In contrast, the immune-glial module showed no enrichment for autism GWAS signals, indicating a non-genetic etiology for this process. Collectively, our results provide strong evidence for convergent molecular abnormalities in ASD, and implicate transcriptional and splicing dysregulation as underlying mechanisms of neuronal dysfunction in this disorder.
doi:10.1038/nature10110
PMCID: PMC3607626  PMID: 21614001
20.  Quantitative Analysis of Pancreatic Polypeptide Cell Distribution in the Human Pancreas 
PLoS ONE  2013;8(1):e55501.
The pancreatic islet is mainly composed of beta-, alpha- and delta-cells with small numbers of pancreatic polypeptide (PP) and epsilon cells. It is known that there is a region in the head of the pancreas that is rich in PP-cells. In the present study, we examined the distribution of PP-cells, and assessed the influence of the PP-cell rich region to quantify the total islet mass. Pancreatic tissues were collected from donors with no history of diabetes or pancreatic diseases (n = 12). A stereological approach with a computer-assisted large-scale analysis of whole pancreatic sections was applied to quantify the entire distribution of endocrine cells within a given section. The initial whole pancreas analysis showed that a PP-cell rich region was largely restricted to the uncinate process with a clear boundary. The distinct distribution of PP-cells includes irregularly shaped clusters composed solely of PP-cells. Furthermore, in the PP-cell rich region, beta- and alpha-cell mass is significantly reduced compared to surrounding PP-cell poor regions. The results suggest that the analysis of the head region should distinguish the PP-cell rich region, which is best examined separately. This study presents an important implication for the regional selection and interpretation of the results.
doi:10.1371/journal.pone.0055501
PMCID: PMC3561199  PMID: 23383206
21.  EFFECTS OF PHASE CANCELLATION AND RECEIVER APERTURE SIZE ON BROADBAND ULTRASONIC ATTENUATION FOR TRABECULAR BONE IN VITRO 
Ultrasound in medicine & biology  2011;37(12):2116-2125.
Phase cancellation in ultrasound due to large receiver size has been proposed as a contributing factor to the inaccuracy of estimating broadband ultrasound attenuation (BUA), which is used to characterize bone quality. Transducers with aperture size ranging from 2 to 5 mm have been used in previous attempts to study the effect of phase cancellation. However, these receivers themselves are susceptible to phase cancellation because aperture size is close to one center wavelength (about 3 mm at 500 KHz in water). This study uses an ultra small receiver (aperture size: 0.2mm) in conjunction with a newly developed 2-D synthetic array system to investigate the effects of phase cancellation and receiver aperture size on BUA estimations of bone tissue. In vitro ultrasound measurements were conducted on 54 trabecular bone samples (harvested from sheep femurs) in a confocal configuration with a focused transmitter and synthesized focused receivers of different aperture sizes. Phase sensitive (PS) and phase insensitive (PI) detections were performed. The results show that phase cancellation does have a significant effect on BUA. The normalized BUA (nBUA) with PS is 8.1% higher than PI nBUA while PI BUA is well correlated with PS BUA. Receiver aperture size also influences the BUA reading for both PI and PS detection and smaller receiver aperture tends to result in higher BUA readings. The results also indicate that the receiver aperture size used in the confocal configuration with PI detection should at least equal the aperture of the transmitter to capture most of the energy redistributed by the interference and diffraction from the trabecular bone.
doi:10.1016/j.ultrasmedbio.2011.08.009
PMCID: PMC3223273  PMID: 22033134
Phase cancellation; Broadband ultrasound attenuation; Synthetic array; Trabecular bone; Bone quality assessment; Osteoporosis; Osteopenia
22.  Identification of glycoproteins associated with different histological subtypes of ovarian tumors using quantitative glycoproteomics 
Proteomics  2011;11(24):4677-4687.
Ovarian cancer is the most lethal gynecologic malignancy in adult women. The origin of epithelial ovarian tumors is both morphologically and biologically heterogeneous, and different subtypes of ovarian tumors have different clinical outcomes. In spite of the heterogeneous nature of ovarian carcinoma, the current biomarkers and treatments for this disease are not subtype-specific. To discover the molecular basis of the ovarian tumor subtypes, we analyzed extracellular glycoproteins of seven common subtypes and normal ovary tissues using quantitative glycoproteomic analysis. Glycoproteins for different ovarian tumor subtypes were identified by liquid chromatography-tandem mass spectrometry and quantitated by spectral counting and then verified by iTRAQ labeling and Western blotting. Glycoproteins uniquely expressed in different subtypes of ovarian tumors or commonly expressed in most subtypes were identified. Using Western blots, we verified that mesothelin was overexpressed in serous carcinoma and transitional-cell carcinoma, CEA5 and CEA6 were overexpressed only in mucinous carcinoma, while versican and periostin were overexpressed in most subtypes of ovarian tumors. This study represents the first proteomic characterization of different ovarian tumor subtypes. The identified glycoproteins for histological subtypes of ovarian tumors will facilitate the understanding of the molecular basis, diagnosis of ovarian tumor subtypes, and predictions for treatment responses to therapeutic agents.
doi:10.1002/pmic.201000811
PMCID: PMC3426283  PMID: 22113853
ovarian tumor; histological subtypes; quantitative glycoproteomics; mass spectrometry; Western blot
23.  Cone-beam computed tomography study of root and canal morphology of mandibular premolars in a western Chinese population 
BMC Medical Imaging  2012;12:18.
Background
Traditional radiography is limited in its ability to give reliable information on the number and morphology of root canals. The application of cone-beam computed tomography (CBCT) provides a non-invasive three-dimensional confirmatory diagnosis as a complement to conventional radiography. The aim of this study was to evaluate the root and canal morphology of mandibular premolars in a western Chinese population using CBCT scanning.
Methods
The sample included 149 CBCT images comprising 178 mandibular first premolars and 178 second premolars. The tooth position, number of roots and canals, and canal configuration according to Vertucci’s classification were recorded.
Results
The results showed that 98% of mandibular first premolars had one root and 2% had two roots; 87.1% had one canal, 11.2% had two canals and 0.6% had three canals. The prevalence of C-shaped canals was 1.1%. All mandibular second premolars had one root; 97.2% had one canal and 2.2% had two canals. The prevalence of C-shaped canals was 0.6%.
Conclusions
The prevalence of multiple canals in mandibular first premolars was mainly of Type V, and mandibular second premolars had a low rate of canal variation in this western Chinese population. Root canal bifurcation occurred at the middle or apical third in most bicanal mandibular premolars. CBCT scanning can be used in the management of mandibular premolars with complex canal morphology.
doi:10.1186/1471-2342-12-18
PMCID: PMC3412166  PMID: 22817397
Cone-beam computed tomography; Mandibular premolar; Morphology; Root canal configuration
24.  Multilevel-3D Bit Patterned Magnetic Media with 8 Signal Levels Per Nanocolumn 
PLoS ONE  2012;7(7):e40134.
This letter presents an experimental study that shows that a 3rd physical dimension may be used to further increase information packing density in magnetic storage devices. We demonstrate the feasibility of at least quadrupling the magnetic states of magnetic-based data storage devices by recording and reading information from nanopillars with three magnetically-decoupled layers. Magneto-optical Kerr effect microscopy and magnetic force microscopy analysis show that both continuous (thin film) and patterned triple-stack magnetic media can generate eight magnetically-stable states. This is in comparison to only two states in conventional magnetic recording. Our work further reveals that ferromagnetic interaction between magnetic layers can be reduced by combining Co/Pt and Co/Pd multilayers media. Finally, we are showing for the first time an MFM image of multilevel-3D bit patterned media with 8 discrete signal levels.
doi:10.1371/journal.pone.0040134
PMCID: PMC3393742  PMID: 22808105
25.  GlycoFish: A Database of Zebrafish N-linked Glycoproteins Identified Using SPEG Method Coupled with LC/MS 
Analytical chemistry  2011;83(13):5296-5303.
Zebrafish (Danio rerio) is a model organism to study the mechanisms and pathways of human disorders. Many dysfunctions in neurological, development and neuromuscular systems are due to glycosylation deficiencies, but the glycoproteins involved in zebrafish embryonic development have not been established. In this study, a mass spectrometry-based glycoproteomic characterization of zebrafish embryos was performed to identify the N-linked glycoproteins and N-linked glycosylation sites. To increase the number of glycopeptides, proteins from zebrafish were digested with two different proteases, chymotrypsin and trypsin, into peptides of different length. The N-glycosylated peptides of zebrafish were then captured by the solid phase extraction of N-linked glycopeptides (SPEG) method and the peptides were identified with an LTQ OrbiTrap Velos mass spectrometer. From 265 unique glycopeptides, including 269 consensus NXT/S glycosites, we identified 169 different N-glycosylated proteins. The identified glycoproteins were highly abundant in proteins belonging to the transporter, cell adhesion, and ion channel/ion binding categories which are important to embryonic, organ, and central nervous system development. This proteomics data will expand our knowledge about glycoproteins in zebrafish and may be used to elucidate the role glycosylation plays in cellular processes and disease. The glycoprotein data are available through the GlycoFish database (http://betenbaugh.jhu.edu/GlycoFish) introduced in this paper.
doi:10.1021/ac200726q
PMCID: PMC3128545  PMID: 21591763
N-linked glycoproteins; glycosylation; glycomics; glycoproteomics; proteomics; zebrafish (Danio rerio) embryos; Solid Phase Extraction of N-linked glycopeptides (SPEG); Mass spectrometry (MS); GlycoFish

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