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1.  Behavioral and metabolic characterization of heterozygous and homozygous POLG mutator mice 
Mitochondrion  2013;13(4):282-291.
The mitochondrial DNA (mtDNA) polymerase γ (POLG) mutator mice provide the first experimental evidence that high levels of somatic mtDNA mutations can be functionally significant. Here we report that older homozygous, but not heterozygous, POLG mice show significant reductions in striatal dopaminergic terminals as well as deficits in motor function. However, resting oxygen consumption, heat production, mtDNA content and mitochondrial electron transport chain activities are significantly decreased at older ages in both homozygous and heterozygous mice. These results indicate that high levels of somatic mtDNA mutations can contribute to dopaminergic dysfunction and to behavioral and metabolic deficits.
PMCID: PMC3682692  PMID: 23542163
mtDNA polymerase γ; mtDNA mutation; Parkinson’s disease; dopamine; behavioral deficits; metabolic deficits
2.  A Dual Chicken IgY Against Rotavirus and Norovirus 
Antiviral research  2012;97(3):293-300.
Rotavirus (RV) and norovirus (NoV) are the two most important causes of viral gastroenteritis. While vaccine remains an effective prophylactic strategy, development of other approaches, such as passive immunization to control and treat clinical infection and illness of the two pathogens, is necessary. Previously we demonstrated that high titers of NoV-specific IgY were readily developed by immunization of chickens with the NoV P particles. In this study, we developed a dual IgY against both RV and NoV through immunization of chickens with a divalent vaccine comprising neutralizing antigens of both RV and NoV. This divalent vaccine, named P-VP8* particle, is made of the NoV P particle as a carrier with the RV spike protein VP8* as a surface insertion. Approximately 45 mg of IgY were readily obtained from each yolk with high titers of anti-P particle and anti-VP8* antibodies detected by ELISA, Western blot, HBGA blocking (NoV and RV) and neutralization (RV) assays. Reductions of RV replication were observed with viruses treated with the IgY before and after inoculation into cells, suggesting an application of the IgY as both prophylactic and a therapeutic treatment. Collectively, our data suggested that the P-VP8* based IgY could serve as a practical approach against both NoV and RV.
PMCID: PMC3995418  PMID: 23267830
rotavirus; norovirus; diarrhea; immunoglobulin Y (IgY); passive immunization
3.  Noble-metal-free plasmonic photocatalyst: hydrogen doped semiconductors 
Scientific Reports  2014;4:3986.
The unique capacity of localized surface plasmon resonance (LSPR) offers a new opportunity to overcome the limited efficiency of semiconductor photocatalyst. Here we unravel that LSPR, which usually occurs in noble metal nanoparticles, can be realized by hydrogen doping in noble-metal-free semiconductor using TiO2 as a model photocatalyst. Moreover, its LSPR is located in infrared region, which supplements that of noble metal whose LSPR is generally in the visible region, making it possible to extend the light response of photocatalyst to infrared region. The near field enhancement is shown to be comparable with that of noble-metal nanoparticles, indicating that highly enhanced light absorption rate can be expected. The present work can provide a key guideline for the creation of highly efficient noble-metal-free plasmonic photocatalysts and have a much wider impact in infrared bioimaging and spectroscopy where infrared LSPR is essential.
PMCID: PMC3913932  PMID: 24496400
4.  Evaluation of anti-norovirus IgY from egg yolk of chickens immunized with norovirus P particles 
Journal of virological methods  2012;186(1-2):126-131.
Noroviruses (NoVs) are a leading cause of epidemic acute gastroenteritis affecting millions of people worldwide. Understanding of NoV remains limited due to the lack of a cell culture system and small animal models. Currently, there are no available vaccines or antivirals against NoVs. In this study, an approach for large-scale production of anti-NoV antibodies for use as a potential treatment for NoV disease using passive immunization was evaluated. NoV-specific immunoglobulins (IgY) were produced by immunizing chickens with NoV P particles. The birds continuously produced high titers of antibodies in their eggs for at least 3 months, in which NoV-specific antibody levels reached 4.7-9.2 mg/egg yolk. The egg yolk antibodies strongly reacted with NoV P particles by both ELISA and Western blot and blocked NoV virus-like particle (VLP) and P particle binding to the histo-blood group antigen (HBGA) receptors with a BT50 of about 1:800. The blocking activity of the chicken IgY remained after an incubation at 70°C for 30 min or treatment at pH 4 to 9 for 3 h. These data suggested that chicken IgY could be a practical strategy for large-scale production of anti-NoV antibodies for potential use as passive immunization against NoV infection, as well as for diagnostic purposes.
PMCID: PMC3496071  PMID: 22867844
Norovirus; Immunoglobulin; IgY; Chicken; Norovirus P particle; Diarrhea
5.  Identification of Breast Cancer Prognosis Markers via Integrative Analysis 
In breast cancer research, it is of great interest to identify genomic markers associated with prognosis. Multiple gene profiling studies have been conducted for such a purpose. Genomic markers identified from the analysis of single datasets often do not have satisfactory reproducibility. Among the multiple possible reasons, the most important one is the small sample sizes of individual studies. A cost-effective solution is to pool data from multiple comparable studies and conduct integrative analysis. In this study, we collect four breast cancer prognosis studies with gene expression measurements. We describe the relationship between prognosis and gene expressions using the accelerated failure time (AFT) models. We adopt a 2-norm group bridge penalization approach for marker identification. This integrative analysis approach can effectively identify markers with consistent effects across multiple datasets and naturally accommodate the heterogeneity among studies. Statistical and simulation studies demonstrate satisfactory performance of this approach. Breast cancer prognosis markers identified using this approach have sound biological implications and satisfactory prediction performance.
PMCID: PMC3389801  PMID: 22773869
Breast cancer prognosis; Gene expression; Marker identification; Integrative analysis; 2-norm group bridge
6.  Activation of the JAK-STAT pathway is necessary for desensitization of 5-HT2A receptor-stimulated phospholipase C signaling by olanzapine, clozapine and MDL100907 
We previously demonstrated that olanzapine-induced desensitization of 5-HT2A receptor-stimulated phospholipase C (PLC) activity is associated with increases in RGS7 protein levels both in vivo and in cells in culture, and the increase in RGS7 is dependent on activation of the JAK-STAT pathway in cells in culture (Muma, et al., 2007;Singh, et al., 2007). In the current study, we found that desensitization of 5-HT2A receptor-stimulated PLC activity induced by olanzapine is dependent on activation of the JAK-STAT pathway. Similar to olanzapine, clozapine-induced desensitization of 5-HT2A receptor signaling is accompanied by increases in RGS7 and activation of JAK2. Treatment with the selective 5-HT2A receptor antagonist MDL100907 also increased RGS7 protein levels and JAK2 activation. Using a JAK2 inhibitor AG490, we found that clozapine and MDL100907-induced increases in RGS7 are dependent on activation of the JAK-STAT pathway. Olanzapine, clozapine, and MDL100907 treatment increased mRNA levels of RGS7. Using a chromatin immunoprecipitation assay we found STAT3 binding to the putative RGS7 promoter region. Taken together, olanzapine-induced activation of the JAK-STAT pathway, and STAT3 binding to the RGS7 gene could underlie the increase in RGS7 mRNA which could subsequently increase protein expression. Furthermore, the increase in RGS7 protein could play a role in the desensitization of 5-HT2A receptor signaling by terminating the activated Gαq/11 proteins more rapidly. Overall, our data suggest that the complete desensitization of 5-HT2A receptor-stimulated PLC activity by olanzapine, clozapine and MDL100,907 requires activation of the JAK-STAT pathway, which in turn increases RGS7 expression likely by direct transcriptional activity of STAT3.
PMCID: PMC3733235  PMID: 18976543
JAK-STAT; 5-HT2A receptor; Clozapine; Olanzapine; Desensitization
7.  Ephexin1 is required for structural maturation and neurotransmission at the neuromuscular junction 
Neuron  2010;65(2):204-216.
The maturation of neuromuscular junctions (NMJs) requires the topological transformation of postsynaptic acetylcholine receptor (AChR)-containing structures from a simple plaque to an elaborate structure composed of pretzel-like branches. This maturation process results in the precise apposition of the pre- and postsynaptic specializations. However, little is known about the molecular mechanisms underlying the plaque-to-pretzel transition of AChR clusters. In this study, we identify an essential role for the RhoGEF ephexin1 in the maturation of AChR clusters. Adult ephexin1−/− mice exhibit severe muscle weakness and impaired synaptic transmission at the NMJ. Intriguingly, when ephexin1 expression is deficient in vivo, the NMJ fails to differentiate into the pretzel-like shape, and such abnormalities can be rescued by re-expression of ephexin1. We further demonstrate that ephexin1 regulates the stability of AChR clusters in a RhoA-dependent manner. Taken together, our findings reveal an indispensible role for ephexin1 in regulating the structural maturation and neurotransmission of NMJs.
PMCID: PMC3718047  PMID: 20152127
synapse; ephrin; EphA4; Rho GTPase; AChR
8.  Inhibition of Histo-blood Group Antigen Binding as a Novel Strategy to Block Norovirus Infections 
PLoS ONE  2013;8(7):e69379.
Noroviruses (NoVs) are the most important viral pathogens that cause epidemic acute gastroenteritis. NoVs recognize human histo-blood group antigens (HBGAs) as receptors or attachment factors. The elucidation of crystal structures of the HBGA-binding interfaces of a number of human NoVs representing different HBGA binding patterns opens a new strategy for the development of antiviral compounds against NoVs through rational drug design and computer-aided virtual screening methods. In this study, docking simulations and virtual screening were used to identify hit compounds targeting the A and B antigens binding sites on the surface of the capsid P protein of a GII.4 NoV (VA387). Following validation by re-docking of the A and B ligands, these structural models and AutoDock suite of programs were used to screen a large drug-like compound library (derived from ZINC library) for inhibitors blocking GII.4 binding to HBGAs. After screening >2 million compounds using multistage protocol, 160 hit compounds with best predicted binding affinities and representing a number of distinct chemical classes have been selected for subsequent experimental validation. Twenty of the 160 compounds were found to be able to block the VA387 P dimers binding to the A and/or B HBGAs at an IC50<40.0 µM, with top 5 compounds blocking the HBGA binding at an IC50<10.0 µM in both oligosaccharide- and saliva-based blocking assays. Interestingly, 4 of the top-5 compounds shared the basic structure of cyclopenta [a] dimethyl phenanthren, indicating a promising structural template for further improvement by rational design.
PMCID: PMC3716607  PMID: 23894462
9.  Variable selection for semiparametric regression models with iterated penalization 
Semiparametric regression models with multiple covariates are commonly encountered. When there are covariates not associated with response variable, variable selection may lead to sparser models, more lucid interpretations and more accurate estimation. In this study, we adopt a sieve approach for the estimation of nonparametric covariate effects in semiparametric regression models. We adopt a two-step iterated penalization approach for variable selection. In the first step, a mixture of the Lasso and group Lasso penalties are employed to conduct the first-round variable selection and obtain the initial estimate. In the second step, a mixture of the weighted Lasso and weighted group Lasso penalties, with weights constructed using the initial estimate, are employed for variable selection. We show that the proposed iterated approach has the variable selection consistency property, even when number of unknown parameters diverges with sample size. Numerical studies, including simulation and analysis of a diabetes dataset, show satisfactory performance of the proposed approach.
PMCID: PMC3367330  PMID: 22685376
Iterated penalization; Variable selection; Semiparametric regression
10.  Expression of a Functional Recombinant Human Basic Fibroblast Growth Factor from Transgenic Rice Seeds 
Basic fibroblast growth factor (FGF-2) is an important member of the FGF gene family. It is widely used in clinical applications for scald and wound healing in order to stimulate cell proliferation. Further it is applied for inhibiting stem cell differentiation in cultures. Due to a shortage of plasma and low expression levels of recombinant rbFGF in conventional gene expression systems, we explored the production of recombinant rbFGF in rice grains (Oryza sativa bFGF, OsrbFGF). An expression level of up to 185.66 mg/kg in brown rice was obtained. A simple purification protocol was established with final recovery of 4.49% and resulting in a yield of OsrbFGF reaching up to 8.33 mg/kg OsrbFGF. The functional assay of OsrbFGF indicated that the stimulating cell proliferation activity on NIH/3T3 was the same as with commercialized rbFGF. Wound healing in vivo of OsrbFGF is equivalent to commercialized rbFGF. Our results indicate that rice endosperm is capable of expressing small molecular mass proteins, such as bFGF. This again demonstrates that rice endosperm is a promising system to express various biopharmaceutical proteins.
PMCID: PMC3588058  PMID: 23434658
recombinant human bFGF; rice endosperm; protein expression and processing; cell proliferation and wound healing
11.  Realization of tunable Dirac cone and insulating bulk states in topological insulators (Bi1−xSbx)2Te3 
Scientific Reports  2012;2:976.
The bulk-insulating topological insulators with tunable surface states are necessary for applications in spintronics and quantum computation. Here we present theoretical evidence for modulating the topological surface states and achieving the insulating bulk states in solid-solution (Bi1−xSbx)2Te3. Our results reveal that the band inversion occurs in (Bi1−xSbx)2Te3, indicating the non-triviality across the entire composition range, and the Dirac point moves upwards till it lies within the bulk energy gap accompanying the increase of Sb concentration x. In addition, with increasing x, the formation of prominent native defects becomes much more difficult, resulting in the truly insulating bulk. The solid-solution system is a promising way of tuning the properties of topological insulators and designing novel topologically insulating devices.
PMCID: PMC3521154  PMID: 23240080
12.  Characterizing the Effects of VPA, VC and RCCS on Rabbit Keratocytes onto Decellularized Bovine Cornea 
PLoS ONE  2012;7(11):e50114.
To investigate the morphological and growth characteristics of rabbit keratocytes when cultured on decellularized cornea under simulate microgravity (SMG) rotary cell culture system (RCCS) and static culture or in plastic culture supplemented with small molecules of valproic acid (VPA) and vitamin C (VC). Bovine corneas were firstly decellularized with Triton X-100 and NH4OH and through short-term freezing process. Then cell count kit-8 (CCK-8) and flow cytometry were used to test the effects of VPA and VC on the proliferation, cell cycle and apoptosis of rabbit keratocytes. Hematoxylin-eosin (H&E) staining and scanning electron microscopy (SEM) imaging showed that cells were eliminated in the decellularized bovine corneas. The proliferation of cultured keratocytes was promoted by VPA and VC in the cell proliferation assay. VPA and VC moderately decreased the number of apoptotic cells and obviously promoted cell-cycle entrance of keratocytes. Rabbit keratocytes in plastic displayed spindle shape and rare interconnected with or without VPA and VC. Cells revealed dendritic morphology and reticular cellular connections when cultured on the carriers of decellularized corneas supplemented with VPA and VC even in the presence of 10% fetal bovine serum (FBS). When cultured in RCCS supplemented with VPA, VC and 10% FBS, keratocytes displayed round shape with many prominences and were more prone to grow into the pores of carriers with aggregation. Reverse transcription-polymerase chain reaction (RT-PCR) analysis proved that the keratocytes cultured on decellularized bovine cornea under SMG with VPA and VC expressed keratocan and lumican. Keratocytes cultured on plastic expressed lumican but not keratocan. Immunofluorescence identification revealed that cells in all groups were positively immunostained for vimentin. Keratocytes on decellularized bovine cornea under SMG or in static culture were positively immunostained for keratocan and lumican. Thus, we reasonably made a conclusion that the combination of VPA, VC, RCCS and decellularized corneal carriers provide a good condition for keratocytes to well grow. Keratocytes can be manipulated to be aggregates or physiological morphological growth in vitro, which are important for the research of corneal stem cells and corneal tissue engineering.
PMCID: PMC3510233  PMID: 23209652
13.  Pgc-1α Overexpression Downregulates Pitx3 and Increases Susceptibility to MPTP Toxicity Associated with Decreased Bdnf 
PLoS ONE  2012;7(11):e48925.
Multiple mechanisms likely contribute to neuronal death in Parkinson’s disease (PD), including mitochondrial dysfunction and oxidative stress. Peroxisome proliferator-activated receptor gamma co-activator-1 alpha (PGC-1α) positively regulates the expression of genes required for mitochondrial biogenesis and the cell’s antioxidant responses. Also, expression of PGC-1α-regulated genes is low in substantia nigra (SN) neurons in early PD. Thus upregulation of PGC-1α is a candidate neuroprotective strategy in PD. Here, an adeno-associated virus (AAV) was used to induce unilateral overexpression of Pgc-1α, or a control gene, in the SN of wild-type C57BL/6CR mice. Three weeks after AAV administration, mice were treated with saline or MPTP. Overexpression of Pgc-1α in the SN induced expression of target genes, but unexpectedly it also greatly reduced the expression of tyrosine hydroxylase (Th) and other markers of the dopaminergic phenotype with resultant severe loss of striatal dopamine. Reduced Th expression was associated with loss of Pitx3, a transcription factor that is critical for the development and maintenance of dopaminergic cells. Expression of the neurotrophic factor Bdnf, which also is regulated by Pitx3, similarly was reduced. Overexpression of Pgc-1α also led to increased sensitivity to MPTP-induced death of Th+ neurons. Pgc-1α overexpression alone, in the absence of MPTP treatment, did not lead to cell loss in the SN or to loss of dopaminergic terminals. These data demonstrate that overexpression of Pgc-1α results in dopamine depletion associated with lower levels of Pitx3 and enhances susceptibility to MPTP. These data may have ramifications for neuroprotective strategies targeting overexpression of PGC-1α in PD.
PMCID: PMC3492133  PMID: 23145024
14.  Risk Factors of Non-Hodgkin Lymphoma 
Despite decades of intensive research, Non-Hodgkin Lymphoma (NHL) remains poorly understood and is largely incurable. NHL is a heterogeneous group of malignancies with multiple subtypes, each of which has distinct morphologic, immunophenotypic, and clinical features. Identifying the risk factors for NHL may improve our understanding of the underlying biological mechanisms and have an impact on clinical practice.
Areas covered
This article provides a review of several aspects of NHL, including epidemiology and subtype classification, clinical, environmental, genetic, and genomic risk factors identified for etiology and prognosis, and available statistical and bioinformatics tools for identification of genetic and genomic risk factors from the analysis of high-throughput studies.
Expert opinion
Multiple clinical and environmental risk factors have been identified. However, they have failed to provide practically effective prediction. Genetic and genomic risk factors identified from high-throughput studies have suffered a lack of reproducibility. The identification of genetic/genomic risk factors demands innovative statistical and bioinformatics tools. Although multiple analysis methods have been developed, there is still room for improvement. There is a critical need for well-designed, prospective, large-scale pangenomic studies.
PMCID: PMC3205981  PMID: 22059093
NHL; etiology; prognosis; risk factors; bioinformatics analysis
15.  Principal component analysis based methods in bioinformatics studies 
Briefings in Bioinformatics  2011;12(6):714-722.
In analysis of bioinformatics data, a unique challenge arises from the high dimensionality of measurements. Without loss of generality, we use genomic study with gene expression measurements as a representative example but note that analysis techniques discussed in this article are also applicable to other types of bioinformatics studies. Principal component analysis (PCA) is a classic dimension reduction approach. It constructs linear combinations of gene expressions, called principal components (PCs). The PCs are orthogonal to each other, can effectively explain variation of gene expressions, and may have a much lower dimensionality. PCA is computationally simple and can be realized using many existing software packages. This article consists of the following parts. First, we review the standard PCA technique and their applications in bioinformatics data analysis. Second, we describe recent ‘non-standard’ applications of PCA, including accommodating interactions among genes, pathways and network modules and conducting PCA with estimating equations as opposed to gene expressions. Third, we introduce several recently proposed PCA-based techniques, including the supervised PCA, sparse PCA and functional PCA. The supervised PCA and sparse PCA have been shown to have better empirical performance than the standard PCA. The functional PCA can analyze time-course gene expression data. Last, we raise the awareness of several critical but unsolved problems related to PCA. The goal of this article is to make bioinformatics researchers aware of the PCA technique and more importantly its most recent development, so that this simple yet effective dimension reduction technique can be better employed in bioinformatics data analysis.
PMCID: PMC3220871  PMID: 21242203
principal component analysis; dimension reduction; bioinformatics methodologies; gene expression
16.  Phospholipase C, Ca2+, and calmodulin signaling are required for 5-HT2A receptor-mediated transamidation of Rac1 by transglutaminase 
Psychopharmacology  2010;213(2-3):403-412.
Serotonin and especially serotonin 2A (5-HT2A) receptor signaling are important in the etiology and treatment of schizophrenia and affective disorders. We previously reported a novel 5-HT2A receptor effector, increased transglutaminase (TGase)-catalyzed transamidation, and activation of the small G protein Rac1 in A1A1v cells, a rat embryonic cortical cell line.
In this study, we explore the signaling pathway involved in 5-HT2A receptor-mediated Rac1 transamidation.
A1A1v cells were pretreated with pharmacological inhibitors of phospholipase C (PLC) or calmodulin (CaM), and then stimulated by the 5-HT2A receptor agonist, 2,5-dimethoxy-4-iodoamphetamine (DOI). Intracellular Ca2+ concentration and TGase-modified Rac1 transamidation were monitored. The effect of manipulation of intracellular Ca2+ by a Ca2+ ionophore or a chelating agent on Rac1 transamidation was also evaluated.
In cells pretreated with a PLC inhibitor U73122, DOI-stimulated increases in the intracellular Ca2+ concentration and TGase-modified Rac1 were significantly attenuated as compared to those pretreated with U73343, an inactive analog. The membrane-permeant Ca2+ chelator, BAPTA-AM strongly reduced TGase-catalyzed Rac1 transamidation upon DOI stimulation. Conversely, the Ca2+ ionophore ionomycin, at a concentration that induced an elevation of cytosolic Ca2+ to a level comparable to cells treated with DOI, produced an increase in TGase-modified Rac1 without 5-HT2A receptor activation. Moreover, the CaM inhibitor W-7, significantly decreased Rac1 transamidation in a dose-dependent manner in DOI-treated cells.
These results indicate that 5-HT2A receptorcoupled PLC activation and subsequent Ca2+ and CaM signaling are necessary for TGase-catalyzed Rac1 transamidation, and an increase in intracellular Ca2+ is sufficient to induce Rac1 transamidation.
PMCID: PMC3033764  PMID: 20717650
5-HT2A receptor; Rac1; Transglutaminase; Transamidation; Phospholipase C; Calcium; Calmodulin; Serotonin; Small G proteins; A1A1v cells; Serotonylation
17.  Estradiol-induced desensitization of 5-HT1A receptor signaling in the paraventricular nucleus of the hypothalamus is independent of estrogen receptor-beta 
Psychoneuroendocrinology  2010;35(7):1023-1033.
Estradiol regulates serotonin 1A(5-HT1A) receptor signaling. Since desensitization of 5-HT1A receptors may be an underlying mechanism by which selective serotonin reuptake inhibitors (SSRIs) mediate their therapeutic effects and combining estradiol with SSRIs enhances the efficacy of the SSRIs, it is important to determine which estrogen receptors are capable of desensitizating 5-HT1A receptor function. We previously demonstrated that selective activation of the estrogen receptor, GPR30, desensitizes 5-HT1A receptor signaling in rat hypothalamic paraventricular nucleus(PVN). However, since estrogen receptor beta(ERβ), is highly expressed in the PVN, we investigated the role of ERβ in estradiol-induced desensitization of 5-HT1A receptor signaling. We first showed that a selective ERβ agonist, diarylpropionitrile(DPN) has a 100-fold lower binding affinity than estradiol for GPR30. Administration of DPN did not desensitize 5-HT1A receptor signaling in rat PVN as demonstrated by agonist-stimulated hormone release. Second, we used a recombinant adenovirus containing ERβ siRNAs to decrease ERβ expression in the PVN. Reductions in ERβ did not alter the estradiol-induced desensitization of 5-HT1A receptor signaling in oxytocin cells. In contrast, in animals with reduced ERβ, estradiol administration, instead of producing desensitization, augmented the ACTH response to a 5-HT1A agonist. Combined with the results from the DPN treatment experiments, desensitization of 5-HT1A receptor signaling does not appear to be mediated by ERβ in oxytocin cells, but that ERβ, together with GPR30, may play a complex role in central regulation of 5-HT1A-mediated ACTH release. Determining the mechanisms by which estrogens induce desensitization may aid in the development of better treatments for mood disorders.
PMCID: PMC2891004  PMID: 20138435
estrogen receptors; neuroendocrine responses; siRNA; recombinant adenovirus; serotonin receptors; mood disorders; estradiol
18.  Do Somatic Mitochondrial DNA Mutations Contribute to Parkinson's Disease? 
Parkinson's Disease  2011;2011:659694.
A great deal of evidence supports a role for mitochondrial dysfunction in the pathogenesis of Parkinson's disease (PD), although the origin of the mitochondrial dysfunction in PD remains unclear. Expression of mitochondrial DNA (mtDNA) from PD patients in “cybrid” cell lines recapitulates the mitochondrial defect, implicating a role for mtDNA mutations, but the specific mutations responsible for the mitochondrial dysfunction in PD have been difficult to identify. Somatic mtDNA point mutations and deletions accumulate with age and reach high levels in substantia nigra (SN) neurons. Mutations in mitochondrial DNA polymerase γ (POLG) that lead to the accumulation of mtDNA mutations are associated with a premature aging phenotype in “mutator” mice, although overt parkinsonism has not been reported in these mice, and with parkinsonism in humans. Together these data support, but do not yet prove, the hypothesis that the accumulation of somatic mtDNA mutations in SN neurons contribute to the pathogenesis of PD.
PMCID: PMC3096076  PMID: 21603185
19.  Incorporating higher-order representative features improves prediction in network-based cancer prognosis analysis 
In cancer prognosis studies with gene expression measurements, an important goal is to construct gene signatures with predictive power. In this study, we describe the coordination among genes using the weighted coexpression network, where nodes represent genes and nodes are connected if the corresponding genes have similar expression patterns across samples. There are subsets of nodes, called modules, that are tightly connected to each other. In several published studies, it has been suggested that the first principal components of individual modules, also referred to as "eigengenes", may sufficiently represent the corresponding modules.
In this article, we refer to principal components and their functions as representative features". We investigate higher-order representative features, which include the principal components other than the first ones and second order terms (quadratics and interactions). Two gradient thresholding methods are adopted for regularized estimation and feature selection. Analysis of six prognosis studies on lymphoma and breast cancer shows that incorporating higher-order representative features improves prediction performance over using eigengenes only. Simulation study further shows that prediction performance can be less satisfactory if the representative feature set is not properly chosen.
This study introduces multiple ways of defining the representative features and effective thresholding regularized estimation approaches. It provides convincing evidence that the higher-order representative features may have important implications for the prediction of cancer prognosis.
PMCID: PMC3037289  PMID: 21226928
20.  Synthesis and Characterization of Bowl-Like Single-Crystalline BaTiO3 Nanoparticles 
Nanoscale Research Letters  2010;5(7):1217-1221.
Novel bowl-like single-crystalline BaTiO3 nanoparticles were synthesized by a simple hydrothermal method using Ba(OH)2·8H2O and TiO2 as precursors. The as-prepared products were characterized by XRD, Raman spectroscopy, SEM and TEM. The results show that the bowl-like BaTiO3 nanoparticles are single-crystalline and have a size about 100–200 nm in diameter. Local piezoresponse force measurements indicate that the BaTiO3 nanoparticles have switchable polarization at room temperature. The local effective piezoelectric coefficient \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$ d_{33}^{ * } $$\end{document} is approximately 28 pm/V.
PMCID: PMC2894195  PMID: 20596350
BaTiO3; Bowl-like; Single-crystalline; Piezoelectric properties
21.  Synthesis and Characterization of Bowl-Like Single-Crystalline BaTiO3 Nanoparticles 
Nanoscale Research Letters  2010;5(7):1217-1221.
Novel bowl-like single-crystalline BaTiO3 nanoparticles were synthesized by a simple hydrothermal method using Ba(OH)2·8H2O and TiO2 as precursors. The as-prepared products were characterized by XRD, Raman spectroscopy, SEM and TEM. The results show that the bowl-like BaTiO3 nanoparticles are single-crystalline and have a size about 100–200 nm in diameter. Local piezoresponse force measurements indicate that the BaTiO3 nanoparticles have switchable polarization at room temperature. The local effective piezoelectric coefficient is approximately 28 pm/V.
PMCID: PMC2894195  PMID: 20596350
BaTiO3; Bowl-like; Single-crystalline; Piezoelectric properties
22.  Mobilized bone marrow progenitor cells serve as donors of cytoprotective genes for cardiac repair 
We proposed here that mobilized progenitor cells (MPCs) from the bone marrow are special cell types which carry cytoprotective proteins for cardiac repair following ischemia. Myocardial ischemia was induced by ligation of the left anterior descending coronary artery (LAD) in mice. Granulocyte colony stimulating factor (G-CSF) was used as the mobilizer of progenitor cells from the bone marrow. Progenitor cells in peripheral blood were analyzed by fluorescence-activated cell sorting (FACS). The expression of cytoprotective genes was assayed by ELISA, RT-PCR and/or real-time PCR. G-CSF was markedly up-regulated in the ischemic myocardium. A good correlation was observed between serum G-CSF and progenitor cells in circulation following LAD ligation. MPCs over-expressed cardiac transcription factor, GATA-4 and anti-apoptotic factor, Bcl-2 besides expression of the surface markers of bone marrow stem cells (BMSCs). Transplantation of cultured MPCs into the ischemic border area significantly improved cardiac function by reducing infarction size. More important, MPCs significantly protected cardiomyocytes against apoptosis when co-cultured with cardiomyocytes. The cardiac protection by MPCs was blocked by Bcl-2 neutralizing antibody and GATA-4 siRNA. In contrast, transfection of BMSCs with GATA-4 provided increased protection of myocytes against apoptosis. It is concluded that MPCs are highly cytoprotective and carry protective genes responsible for cardiac repair.
PMCID: PMC2685071  PMID: 18221754
ischemia; mobilization; progenitor cells; G-CSF; BMSCs; GATA-4; cytoprotective protein; Bcl-2
23.  HIF-1α induced-VEGF over-expression in bone marrow stem cells protects cardiomyocytes against ischemia 
Hypoxia inducible factor-1α (HIF-1α) is a proangiogenic transcription factor stabilized and activated under hypoxia. It regulates the expression of numerous target genes, including vascular endothelial growth factor (VEGF) and other cytoprotective proteins. In this study, we hypothesized that bone marrow stem cells (BMSCs) secrete growth factors which protect cardiomyocytes via HIF-1α pathway.
BMSCs were obtained from transgenic mice overexpressing green fluorescent protein (GFP). The study was carried out in vitro using co-culture of BMSCs with cardiomyocytes. LDH release, MTT uptake, DNA fragmentation and annexin-V positive cells were used as cell injury markers. The level of HIF-1α protein as well as its activated form and VEGF were measured by ELISA. The expression of HIF-1α and VEGF in BMSCs were analyzed by quantitative PCR and cellular localization was determined by immunohistochemistry.
LDH release was increased and MTT uptake was decreased after exposure of cardiomyocytes to hypoxia for 24 hours, which were prevented by co-culturing cardiomyocytes with BMSCs. Cardiomyocyte apoptosis induced by hypoxia and H2O2 was also reduced by co-culture with BMSCs. VEGF release from BMSCs was significantly increased in parallel with high level of HIF-1α in BMSCs following anoxia or hypoxia in time-dependent manner. Although no significant up-regulation could be seen in HIF-1α mRNA, HIF-1α protein and its activated form were markedly increased and translocated to the nucleus or peri-nuclear area. The increase and translocation of HIF-1α in BMSCs were completely blocked by 2-methoxyestradiol (2-ME2; 5μmol), a HIF-1α inhibitor. Moreover, the protection of cardiomyocytes by BMSC and VEGF secretion were abolished by neutralizing HIF-1α antibodies in a concentration dependent manner (200~ 3200ng/ml).
Bone marrow stem cells protect cardiomyocytes by up-regulation of VEGF via activating HIF-1α.
PMCID: PMC1995444  PMID: 17498737
bone marrow stem cells; HIF-1α; VEGF; cardiomyocytes; hypoxia; HIF-1α neutralizing antibody
24.  In vitro and in vivo effects of bone marrow stem cells on cardiac structure and function 
It is hypothesized that the protection of bone marrow stem cells (BMSCs) on ischemic myocardium might be related to the anti-apoptotic effect via paracrine mechanisms. In this study, a wide array of cytokines including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), stromal cell derived factor-1 (SDF-1) and insulin growth factor-1 (IGF-1) were detected in the BMSCs cultured medium by ELISA. Myocyte apoptosis was assayed by DNA fragmentation and annexin-V staining. Myocardial infarction model was produced by ligation of mouse left anterior descending coronary arteries (LAD). Before LAD ligation, mice were myoablated by irradiation and transplanted with bone marrow cells from transgenic green fluorescent protein (GFP) mice. After LAD ligation, animals were administered stem cell factor (SCF, 200 μg / day / kg, i.p.) or saline for 6 days. Animals were sacrificed on end of SCF treatment and four weeks later. Apoptotic cardiomyocytes were assayed after treatment finished by TUNEL. Myocardial function was analyzed by echocardiography and pressure-volume loop. Bcl-2 protein was analyzed by western blotting. Our results showed that cultured BMSCs released VEGF, bFGF, SDF-1 and IGF-1. Hypoxia induced cell apoptosis was diminished in cardiomyocytes co-cultured with BMSCs. Smaller LV dimension and increased LV ejection fraction were seen in SCF treated animals. SCF significantly reduced cardiomyocytes apoptosis within peri-infarct area and up-regulation expression of Bcl-2 in ischemic area. Moreover, conditioned medium from cultured BMSCs also induced up-regulation of Bcl-2 protein in cardiomyocytes. It is concluded that paracrine mediators secreted by BMSCs might be involved in early repair of ischemic heart by preventing cardiomyocytes apoptosis and improving cardiac function.
PMCID: PMC1899533  PMID: 17187821
Stem cells; Mobilization; Paracrine effect; Myocardial infarction; Apoptosis
25.  Seroprevalence of Antibodies against Noroviruses among Students in a Chinese Military Medical University 
Journal of Clinical Microbiology  2004;42(10):4615-4619.
Noroviruses (NVs) are important causes of nonbacterial gastroenteritis in humans, but the role of NVs as a cause of diseases in the Chinese people, particularly in Chinese military personnel, remains unclear. This study investigated antibody prevalence and factors that associate with the prevalence of antibody to NVs among students attending a military medical university. Serum specimens were tested by an enzyme-linked immunosorbent assay for immunoglobulin G antibody to recombinant capsid antigens of three NVs (rNorwalk, rMxV, and rVA387). Of 588 serum samples tested, the antibody prevalence was 88.9, 54.1, or 90.0% for the three antigens, respectively. There were significant differences in the prevalence of antibody to rMxV between blood types (P < 0.05); the prevalence for type O was the highest (62.5%), and the prevalence for type B was the lowest (49.1%). The average optical density values for antibody to rNorwalk and rMxV were lowest among students with type B. The number of students who did not have antibody to any of the three antigens was the highest for blood type B (6.9%) compared to other blood types (0.8 to 3.4% [P < 0.006]). The antibody prevalence also varied with the hometown residencies of the students before joining the military, with the highest rates for students from rural areas, lower rates for students from small towns or villages, and the lowest rates for students from large cities. The numbers of students who did not have antibody to any of the three antigens were highest for students from the large cities, lower for students from small towns or villages, and lowest for students from rural areas. The distribution of ABO blood types did not differ among the three groups. These data suggest that NVs are prevalent in China and that both genetic and environmental factors play a role in NV infection.
PMCID: PMC522286  PMID: 15472318

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