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1.  Huntingtin-Associated Protein 1 Interacts with Breakpoint Cluster Region Protein to Regulate Neuronal Differentiation 
PLoS ONE  2015;10(2):e0116372.
Alterations in microtubule-dependent trafficking and certain signaling pathways in neuronal cells represent critical pathogenesis in neurodegenerative diseases. Huntingtin (Htt)-associated protein-1 (Hap1) is a brain-enriched protein and plays a key role in the trafficking of neuronal surviving and differentiating cargos. Lack of Hap1 reduces signaling through tropomyosin-related kinases including extracellular signal regulated kinase (ERK), resulting in inhibition of neurite outgrowth, hypothalamic dysfunction and postnatal lethality in mice. To examine how Hap1 is involved in microtubule-dependent trafficking and neuronal differentiation, we performed a proteomic analysis using taxol-precipitated microtubules from Hap1-null and wild-type mouse brains. Breakpoint cluster region protein (Bcr), a Rho GTPase regulator, was identified as a Hap1-interacting partner. Bcr was co-immunoprecipitated with Hap1 from transfected neuro-2a cells and co-localized with Hap1A isoform more in the differentiated than in the nondifferentiated cells. The Bcr downstream effectors, namely ERK and p38, were significantly less activated in Hap1-null than in wild-type mouse hypothalamus. In conclusion, Hap1 interacts with Bcr on microtubules to regulate neuronal differentiation.
PMCID: PMC4324908  PMID: 25671650
The human genome encodes a large number of non-coding RNAs, which employ a new and crucial layer of biological regulation in addition to proteins. Technical advancement in recent years, particularly, the wide application of next generation sequencing analysis, provide an unprecedented opportunity to identify new non-coding RNAs and investigate their functions and regulatory mechanisms. The aim of this workshop is to bring together experimental and computational biologist to exchange ideas on non-coding RNA studies.
PMCID: PMC3900277  PMID: 24297566
3.  E2F4 regulatory program predicts patient survival prognosis in breast cancer 
Genetic and molecular signatures have been incorporated into cancer prognosis prediction and treatment decisions with good success over the past decade. Clinically, these signatures are usually used in early-stage cancers to evaluate whether they require adjuvant therapy following surgical resection. A molecular signature that is prognostic across more clinical contexts would be a useful addition to current signatures.
We defined a signature for the ubiquitous tissue factor, E2F4, based on its shared target genes in multiple tissues. These target genes were identified by chromatin immunoprecipitation sequencing (ChIP-seq) experiments using a probabilistic method. We then computationally calculated the regulatory activity score (RAS) of E2F4 in cancer tissues, and examined how E2F4 RAS correlates with patient survival.
Genes in our E2F4 signature were 21-fold more likely to be correlated with breast cancer patient survival time compared to randomly selected genes. Using eight independent breast cancer datasets containing over 1,900 unique samples, we stratified patients into low and high E2F4 RAS groups. E2F4 activity stratification was highly predictive of patient outcome, and our results remained robust even when controlling for many factors including patient age, tumor size, grade, estrogen receptor (ER) status, lymph node (LN) status, whether the patient received adjuvant therapy, and the patient’s other prognostic indices such as Adjuvant! and the Nottingham Prognostic Index scores. Furthermore, the fractions of samples with positive E2F4 RAS vary in different intrinsic breast cancer subtypes, consistent with the different survival profiles of these subtypes.
We defined a prognostic signature, the E2F4 regulatory activity score, and showed it to be significantly predictive of patient outcome in breast cancer regardless of treatment status and the states of many other clinicopathological variables. It can be used in conjunction with other breast cancer classification methods such as Oncotype DX to improve clinical outcome prediction.
Electronic supplementary material
The online version of this article (doi:10.1186/s13058-014-0486-7) contains supplementary material, which is available to authorized users.
PMCID: PMC4303196  PMID: 25440089
4.  Mechanotransduction in intervertebral discs 
Mechanotransduction plays a critical role in intracellular functioning—it allows cells to translate external physical forces into internal biochemical activities, thereby affecting processes ranging from proliferation and apoptosis to gene expression and protein synthesis in a complex web of interactions and reactions. Accordingly, aberrant mechanotransduction can either lead to, or be a result of, a variety of diseases or degenerative states. In this review, we provide an overview of mechanotransduction in the context of intervertebral discs, with a focus on the latest methods of investigating mechanotransduction and the most recent findings regarding the means and effects of mechanotransduction in healthy and degenerative discs. We also provide some discussion of potential directions for future research and treatments.
PMCID: PMC4302640  PMID: 25267492
mechanotransduction; intervertebral discs; physical forces; gene expression; biochemical activities; protein synthesis
5.  Rho-kinase inhibition is involved in the activation of PI3-kinase/Akt during ischemic-preconditioning-induced cardiomyocyte apoptosis 
We and others have reported that Rho-kinase plays an important role in the pathogenesis of heart ischemia/reperfusion (I/R) injury. Studies also have demonstrated that the activation of Rho-kinase was reversed in ischemic preconditioning (IPC). This study aimed to explain the mechanism of Rho-kinase-mediated cardiomyocyte apoptosis increased in I/R and reversed in IPC. Materials and methods: Studies were performed with female Wistar rats. The I/R rats were created by ligating the left anterior descending branch (LAD) for 30 min and releasing the ligature for 180 min. The IPC rats underwent IPC (two cycles of 5 min ligation of the LAD and 5 min reflow) before I/R. Results: Ischemia followed by reperfusion caused a significant increase in Rho-kinase and a decrease in Akt phosphorylation. Administration of fasudil, an inhibitor of Rho-kinase, decreased myocardial infarction size and cardiomyocyte apoptosis and increased Akt activation. IPC also caused the reduced Rho-kinase activity and cardiomyocyte apoptosis and a significant increase in Akt activity (P<0.05 vs I/R). Conclusion: Rho-kinase inhibition by IPC leads to reduced cardiomyocyte apoptosis may be mediated by activation of PI3-kinase/Akt.
PMCID: PMC4276178  PMID: 25550920
Rho-kinase; heart ischemia/reperfusion; ischemic preconditioning; apoptosis; PI3-kinase/Akt
6.  Peroxisome Proliferator-Activated Receptor γ Deficiency in T Cells Accelerates Chronic Rejection by Influencing the Differentiation of CD4+ T Cells and Alternatively Activated Macrophages 
PLoS ONE  2014;9(11):e112953.
In a previous study, activation of the peroxisome proliferator–activated receptor γ (PPARγ) inhibited chronic cardiac rejection. However, because of the complexity of chronic rejection and the fact that PPARγ is widely expressed in immune cells, the mechanism of the PPARγ - induced protective effect was unclear.
Materials and Methods
A chronic rejection model was established using B6.C-H-2bm12KhEg (H-2bm12) mice as donors, and MHC II-mismatched T-cell-specific PPARγ knockout mice or wild type (WT) littermates as recipients. The allograft lesion was assessed by histology and immunohistochemistry. T cells infiltrates in the allograft were isolated, and cytokines and subpopulations were detected using cytokine arrays and flow cytometry. Transcription levels in the allograft were measured by RT-PCR. In vitro, the T cell subset differentiation was investigated after culture in various polarizing conditions. PPARγ-deficient regularory T cells (Treg) were cocultured with monocytes to test their ability to induce alternatively activated macrophages (AAM).
T cell-specific PPARγ knockout recipients displayed reduced cardiac allograft survival and an increased degree of pathology compared with WT littermates. T cell-specific PPARγ knockout resulted in more CD4+ T cells infiltrating into the allograft and altered the Th1/Th2 and Th17/Treg ratios. The polarization of AAM was also reduced by PPARγ deficiency in T cells through the action of Th2 and Treg. PPARγ-deficient T cells eliminated the pioglitazone-induced polarization of AAM and reduced allograft survival.
PPARγ-deficient T cells influenced the T cell subset and AAM polarization in chronic allograft rejection. The mechanism of PPARγ activation in transplantation tolerance could yield a novel treatment without side effects.
PMCID: PMC4226585  PMID: 25383620
7.  ChIP-seq and In Vivo Transcriptome Analyses of the Aspergillus fumigatus SREBP SrbA Reveals a New Regulator of the Fungal Hypoxia Response and Virulence 
PLoS Pathogens  2014;10(11):e1004487.
The Aspergillus fumigatus sterol regulatory element binding protein (SREBP) SrbA belongs to the basic Helix-Loop-Helix (bHLH) family of transcription factors and is crucial for antifungal drug resistance and virulence. The latter phenotype is especially striking, as loss of SrbA results in complete loss of virulence in murine models of invasive pulmonary aspergillosis (IPA). How fungal SREBPs mediate fungal virulence is unknown, though it has been suggested that lack of growth in hypoxic conditions accounts for the attenuated virulence. To further understand the role of SrbA in fungal infection site pathobiology, chromatin immunoprecipitation followed by massively parallel DNA sequencing (ChIP-seq) was used to identify genes under direct SrbA transcriptional regulation in hypoxia. These results confirmed the direct regulation of ergosterol biosynthesis and iron uptake by SrbA in hypoxia and revealed new roles for SrbA in nitrate assimilation and heme biosynthesis. Moreover, functional characterization of an SrbA target gene with sequence similarity to SrbA identified a new transcriptional regulator of the fungal hypoxia response and virulence, SrbB. SrbB co-regulates genes involved in heme biosynthesis and demethylation of C4-sterols with SrbA in hypoxic conditions. However, SrbB also has regulatory functions independent of SrbA including regulation of carbohydrate metabolism. Loss of SrbB markedly attenuates A. fumigatus virulence, and loss of both SREBPs further reduces in vivo fungal growth. These data suggest that both A. fumigatus SREBPs are critical for hypoxia adaptation and virulence and reveal new insights into SREBPs' complex role in infection site adaptation and fungal virulence.
Author Summary
Despite improvements in diagnostics and antifungal drug treatments, mortality rates from invasive mold infections remain high. Defining the fungal adaptation and growth mechanisms at the infection site microenvironment is one research focus that is expected to improve treatment of established invasive fungal infections. The Aspergillus fumigatus transcription factor SrbA is a major regulator of the fungal response to hypoxia found at sites of invasive fungal growth in vivo. In this study, new insights into how SrbA mediates hypoxia adaptation and virulence were revealed through identification of direct transcriptional targets of SrbA under hypoxic conditions. A major novel finding from these studies is the identification of a critical role in fungal hypoxia adaptation and virulence of an SrbA target gene, srbB, which is also in the SREBP family. SrbB plays a major role in regulation of heme biosynthesis and carbohydrate metabolism early in the response to hypoxia. The discovery of SrbA-dependent regulation of srbB gene expression, and the target genes they regulate opens new avenues to understand how SREBPs and their target genes mediate adaptation to the in vivo infection site microenvironment and responses to current antifungal therapies.
PMCID: PMC4223079  PMID: 25375670
8.  Enterovirus-71 Virus-Like Particles Induce the Activation and Maturation of Human Monocyte-Derived Dendritic Cells through TLR4 Signaling 
PLoS ONE  2014;9(10):e111496.
Enterovirus 71 (EV71) causes seasonal epidemics of hand-foot-and-mouth disease and has a high mortality rate among young children. We recently demonstrated potent induction of the humoral and cell-mediated immune response in monkeys immunized with EV71 virus-like particles (VLPs), with a morphology resembling that of infectious EV71 virions but not containing a viral genome, which could potentially be safe as a vaccine for EV71. To elucidate the mechanisms through which EV71 VLPs induce cell-mediated immunity, we studied the immunomodulatory effects of EV71 VLPs on human monocyte-derived dendritic cells (DCs), which bind to and incorporate EV71 VLPs. DC treatment with EV71 VLPs enhanced the expression of CD80, CD86, CD83, CD40, CD54, and HLA-DR on the cell surface; increased the production of interleukin (IL)-12 p40, IL-12 p70, and IL-10 by DCs; and suppressed the capacity of DCs for endocytosis. Treatment with EV71 VLPs also enhanced the ability of DCs to stimulate naïve T cells and induced secretion of interferon (IFN)-γ by T cells and Th1 cell responses. Neutralization with antibodies against Toll-like receptor (TLR) 4 suppressed the capacity of EV71 VLPs to induce the production of IL-12 p40, IL-12 p70, and IL-10 by DCs and inhibited EV71 VLPs binding to DCs. Our study findings clarified the important role for TLR4 signaling in DCs in response to EV71 VLPs and showed that EV71 VLPs induced inhibitor of kappaB alpha (IκBα) degradation and nuclear factor of kappaB (NF-κB) activation.
PMCID: PMC4216083  PMID: 25360749
9.  Correlation of Chitinase 3-Like 1 Single Nucleotide Polymorphisms and Haplotypes with Uterine Cervical Cancer in Taiwanese Women 
PLoS ONE  2014;9(9):e104038.
This study aimed to investigate the relationships of chitinase 3-like 1 (CHI3L1) single nucleotide polymorphisms (SNPs) and haplotypes with the development of uterine cervical cancer in Taiwanese women. The SNPs frequencies and haplotypes were also correlated with the clinicopathologic variables of cervical cancer, cancer recurrence, and patient survival.
Methodology and Principal Findings
Ninety-nine patients with invasive cancer and 61 with pre-cancerous lesions of the uterine cervix were compared to 310 healthy control subjects. Three SNPs rs6691378 (−1371, G/A), rs10399805 (−247, G/A) and rs4950928 (−131, C/G) in the promoter region, and one SNP rs880633 (+2950, T/C) in exon 5 were analyzed by real time polymerase chain reaction and genotyping. The results showed that the mutant homozygous genotype AA of CHI3L1 SNP rs6691378 and AA of rs10399805, and haplotypes AACC and AACT increased the risk of developing pre-cancerous lesions and invasive cancer. The patients with these risk haplotypes had higher than stage I tumors, larger tumors, and vaginal invasion. In logistic regression model, they also tended to have poor survival event [p = 0.078; odds ratio (OR): 2.99, 95% confidence interval (CI): 0.89–10.08] and a higher probability of recurrence event (p = 0.081; OR: 3.07, 95% CI: 0.87–10.81). There was a significant association between the CHI3L1 risk haplotypes and probability of recurrence (p = 0.002; hazard ratio: 6.21, 95% CI: 1.90–20.41), and a marginal association between the risk haplotypes and overall survival (p = 0.051; hazard ratio: 3.76, 95% CI: 0.99–14.29) in the patients with SCC, using Cox proportional hazard model.
The CHI3L1 SNPs rs6691378 and rs10399805 and CHI3L1 haplotypes all correlated with the development of cervical pre-cancerous lesions and invasive cancer. The cervical cancer patients with the CHI3L1 haplotypes AACC or AACT had poor clinicopathologic characteristics and poor recurrence and survival events. These risk haplotypes were associated with higher recurrence, especially in the patients with SCC.
PMCID: PMC4159225  PMID: 25203433
10.  Architecture of the human regulatory network derived from ENCODE data 
Nature  2012;489(7414):91-100.
Transcription factors (TFs) bind in a combinatorial fashion to specify the on-and-off states of genes; the ensemble of these binding events forms a regulatory network, constituting the wiring diagram for a cell. To examine the principles of the human transcriptional regulatory network, we determined the genomic binding information of 119 TFs in 458 ChIP-Seq experiments. We found the combinatorial, co-association of TFs to be highly context specific: distinct combinations of factors bind at specific genomic locations. In particular, there are significant differences in the binding proximal and distal to genes. We organized all the TF binding into a hierarchy and integrated it with other genomic information (e.g. miRNA regulation), forming a dense meta-network. Factors at different levels have different properties: for instance, top-level TFs more strongly influence expression and middle-level ones co-regulate targets to mitigate information-flow bottlenecks. Moreover, these co-regulations give rise to many enriched network motifs -- e.g. noise-buffering feed-forward loops. Finally, more connected network components are under stronger selection and exhibit a greater degree of allele-specific activity (i.e., differential binding to the two parental alleles). The regulatory information obtained in this study will be crucial for interpreting personal genome sequences and understanding basic principles of human biology and disease.
PMCID: PMC4154057  PMID: 22955619
11.  Ultraviolet/blue light-emitting diodes based on single horizontal ZnO microrod/GaN heterojunction 
Nanoscale Research Letters  2014;9(1):446.
We report electroluminescence (EL) from single horizontal ZnO microrod (MR) and p-GaN heterojunction light-emitting diodes under forward and reverse bias. EL spectra were composed of two blue emissions centered at 431 and 490 nm under forward biases, but were dominated by a ultraviolet (UV) emission located at 380 nm from n-ZnO MR under high reverse biases. Light-output-current characteristic of the UV emission reveals that the rate of radiative recombination is faster than that of the nonradiative recombination. Highly efficient ZnO excitonic recombination at reverse bias is caused by electrons tunneling from deep-level states near the n-ZnO/p-GaN interface to the conduction band in n-ZnO.
PMCID: PMC4154899  PMID: 25232299
ZnO; Microrod; Electroluminescence
12.  Relating gene expression evolution with CpG content changes 
BMC Genomics  2014;15(1):693.
Previous studies have shown that CpG dinucleotides are enriched in a subset of promoters and the CpG content of promoters is positively correlated with gene expression levels. But the relationship between divergence of CpG content and gene expression evolution has not been investigated. Here we calculate the normalized CpG (nCpG) content in DNA regions around transcription start site (TSS) and transcription terminal site (TTS) of genes in nine organisms, and relate them with expression levels measured by RNA-seq.
The nCpG content of TSS shows a bimodal distribution in all organisms except platypus, whereas the nCpG content of TTS only has a single peak. When the nCpG contents are compared between different organisms, we observe a different evolution pattern between TSS and TTS: compared with TTS, TSS exhibits a faster divergence rate between closely related species but are more conserved between distant species. More importantly, we demonstrate the link between gene expression evolution and nCpG content changes: up-/down- regulation of genes in an organism is accompanied by the nCpG content increase/decrease in their TSS and TTS proximal regions.
Our results suggest that gene expression changes between different organisms are correlated with the alterations in normalized CpG contents of promoters. Our analyses provide evidences for the impact of nCpG content on gene expression evolution.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2164-15-693) contains supplementary material, which is available to authorized users.
PMCID: PMC4148958  PMID: 25142157
13.  The Histone Methyltransferase Activity of MLL1 Is Dispensable for Hematopoiesis and Leukemogenesis 
Cell reports  2014;7(4):1239-1247.
Despite correlations between histone methyltransferase (HMT) activity and gene regulation, direct evidence that HMT activity is responsible for gene activation is sparse. We address the role of the HMT activity for MLL1, a histone H3 lysine 4 (H3K4) methyltransferase critical for maintaining hematopoietic stem cells (HSCs). Here, we show that the SET domain, and thus HMT activity of MLL1, is dispensable for maintaining HSCs and supporting leukemogenesis driven by the MLL-AF9 fusion oncoprotein. Upon Mll1 deletion, histone H4 lysine 16 (H4K16) acetylation is selectively depleted at MLL1 target genes in conjunction with reduced transcription. Surprisingly, inhibition of SIRT1 is sufficient to prevent the loss of H4K16 acetylation and the reduction in MLL1 target gene expression. Thus, recruited MOF activity, and not the intrinsic HMT activity of MLL1, is central for the maintenance of HSC target genes. In addition, this work reveals a role for SIRT1 in opposing MLL1 function.
PMCID: PMC4120120  PMID: 24813891
14.  Overexpression of membrane-type 2 matrix metalloproteinase induced by hypoxia-inducible factor-1α in pancreatic cancer: Implications for tumor progression and prognosis 
Molecular and Clinical Oncology  2014;2(6):973-981.
Membrane-type 2 matrix metalloproteinase (MT2-MMP) has been identified as a powerful modulator of the pericellular environment that promotes tumor invasion and metastasis. In this study, we investigated the association of MT2-MMP and hypoxia-inducible factor-1α (HIF-1α) expression in pancreatic cancer with regard to their clinical prognostic significance. Of the tissue specimens obtained from the 78 patients included in this study, 46 (59%) were found to be positive for MT2-MMP immunostaining and MT2-MMP expression was colocalized with HIF-1α in pancreatic cancer. Using the Spearman’s rank analysis, the protein and mRNA expression level of MT2-MMP was found to be significantly correlated with HIF-1α and CD34-microvascular density in pancreatic cancer. Furthermore, the expression of MT2-MMP in response to hypoxia was increased in a time-dependent manner and the promoter luciferase reporter revealed upregulation of MT2-MMP expression induced by HIF-1α in pancreatic cancer cells. Moreover, the Cox regression model indicated that MT2-MMP was an independent prognostic factor in patients with pancreatic cancer. Our results demonstrated that the overexpression of MT2-MMP was induced by HIF-1α in response to hypoxia and was an independent prognostic factor for pancreatic cancer progression.
PMCID: PMC4179790  PMID: 25279184
membrane-type 2 matrix metalloproteinase; pancreatic cancer; hypoxia-inducible factor-1α; tumor progression; prognosis
15.  The tumor suppressive role of NUMB isoform 1 in esophageal squamous cell carcinoma 
Oncotarget  2014;5(14):5602-5614.
Esophageal quamous cell carcinoma (ESCC) is the predominant histological type of esophageal carcinoma in Asian populations. To date, few biomarkers have been identified for ESCC. In present study, we found a tumor suppressor, NUMB isoform 1 (NUMB-1), as a promising prognostic biomarker for patients with ESCC. NUMB-1 mRNA was downregulated in 66.7% of primary ESCC tissues when compared with matched adjacent non-tumor tissues. The low expression of NUMB-1 was significantly associated with high tumor recurrence (p=0.029) and poor post-operative overall survival (p=0.016). To further explore the underlying mechanisms by which NUMB-1 regulates ESCC, we demonstrated that ectopic expression of NUMB-1 inhibited cell proliferation through inducing G2/M phase arrest, which was accompanied by an increase in p21 and cyclin B1-cdc2 levels. However, it had no impact on apoptosis of ESCC cells. In addition, overexpression of NUMB-1 prevented epithelial-mesenchymal transition, inhibited invasion of ESCC cells and NOTCH pathway, suppressed Aurora-A activity by preventing phosphorylation of Aurora-A at T288 which resulted in cell cycle arrest. Taken together, our findings suggested NUMB-1 functions as a tumor-suppressor and serves as a prognositc biomarker for ESCC patients; thus, NUMB-1 may be a potential novel therapeutic target for treatment of ESCC.
PMCID: PMC4170621  PMID: 24980814
esophageal squamous cell carcinoma; ESCC; NUMB isoform 1; Aurora-A; G2/M arrest
16.  Quantitative assessment of iron in heart and liver phantoms using dual-energy computed tomography 
The aim of the present study was to determine the correlation between dual-energy computed tomography (DECT) Hounsfield units (HU) and iron concentration, as well as the correlation between HU and magnetic resonance imaging (MRI)-derived R2* values, in phantoms of the heart and liver tissue. Phantoms were constructed containing pig heart or liver tissue and varying concentrations of iron (0.1, 5, 10, 15, 20 and 25 mg/ml). The phantoms were then examined by DECT and MRI. Linear regression analysis was used to determine the correlations between HU and iron concentration and HU and R2* values. The HU value of DECT increased with increasing iron concentrations in the liver and heart phantoms in a linear manner. The slope of the HU value change against iron concentration revealed that ΔH80–140 provided a better discernment of iron concentration as compared with ΔH100–140. The derived R2 values were all >0.9 for the associations of DECT and MRI measurements with iron concentrations. Therefore, DECT may be used for the determination of iron concentration in the liver and heart tissue, with the results correlating with those obtained with MRI.
PMCID: PMC4113552  PMID: 25120622
thalassemia; iron; dual-energy computed tomography; magnetic resonance imaging; Hounsfield units
17.  The Laparoscopic Nissen Fundoplication Eliminates Obstructive Sleep Apnea Syndrome Due to Gastroesophageal Reflux Disease 
The Indian Journal of Surgery  2012;75(Suppl 1):326-328.
Gastroesophageal reflux disease may produce esophageal syndromes, such as heartburn and regurgitation. It is a common clinical presentation with extraesophageal manifestations, such as asthma, arrhythmia, snoring, and sleep disturbance, which could make identifying it more difficult than the usual esophageal symptoms. The aim of this study is to characterize the extraesophageal manifestations in patients with gastroesophageal reflux disease and investigate the effect of laparoscopic Nissen fundoplication. We describe the case of a 38-year-old male patient with a history of sleep disturbance attributable to gastroesophageal reflux disease, which resolved on successful laparoscopic Nissen fundoplication treatment. The long-standing sleep apnea obviously improved after laparoscopic Nissen fundoplication treatment. To our knowledge, this is a rare case of successful laparoscopic Nissen fundoplication treatment of a patient with extraesophageal manifestations induced by gastroesophageal reflux disease. The results indicate an underlying mechanism for extraesophageal manifestations and the success of laparoscopic Nissen fundoplication treatment.
PMCID: PMC3693228  PMID: 24426606
Laparoscopic Nissen fundoplication; Obstructive sleep apnea syndrome; Gastroesophageal reflux disease
18.  Machine learning and genome annotation: a match meant to be? 
Genome Biology  2013;14(5):205.
By its very nature, genomics produces large, high-dimensional datasets that are well suited to analysis by machine learning approaches. Here, we explain some key aspects of machine learning that make it useful for genome annotation, with illustrative examples from ENCODE.
PMCID: PMC4053789  PMID: 23731483
19.  Overexpression of SATB1 Is Associated with Biologic Behavior in Human Renal Cell Carcinoma 
PLoS ONE  2014;9(5):e97406.
Special AT-rich sequence-binding protein-1 (SATB1) has been reported to be aberrantly expressed in various cancers and correlated with the malignant behavior of cancer cells. However, the function of SATB1 in RCC remains unclear. With the combination of immunohistochemistry, western blotting, immunofluorescence, qRT-PCR, and cell proliferation, migration and invasion assays, we found that levels of SATB1 mRNA and protein were dramatically increased in human ccRCC tissues (P<0.001 for both), and upregulation of SATB1 was significantly associated with depth of invasion (P<0.001), lymph node status (P = 0.001) and TNM stage (P = 0.009). SATB1 knockdown inhibited the proliferation, migration and invasion of 786-O cells, whereas SATB1 overexpression promoted the growth and aggressive phenotype of ACHN cells in vitro. Furthermore, SATB1 expression was positively correlated with ZEB2 expression (P = 0.013), and inversely linked to levels of SATB2 and E-cadherin (P = 0.005 and P<0.001, respectively) in ccRCC tissues. Our data provide a basis for the concept that overexpression of SATB1 may play a critical role in the acquisition of an aggressive phenotype for RCC cells through EMT, providing new insights into the significance of SATB1 in invasion and metastasis of ccRCC, which may contribute to fully elucidating the exact mechanism of development and progression of RCC.
PMCID: PMC4023980  PMID: 24835085
20.  Phosphotriesterase-related protein sensed albuminuria and conferred renal tubular cell activation in membranous nephropathy 
Membranous nephropathy (MN) is a common cause of nephrotic syndrome that may progress to end-stage renal disease (ESRD). The formation of MN involves the in situ formation of subepithelial immune deposits and leads to albuminuria; however, the underlying mechanism of how MN leads to ESRD remains unclear. The aim of this study was to investigate the expression and biological functions of phosphotriesterase-related protein (PTER) in MN.
In the progression of MN, the expression of PTER increased significantly and was mainly expressed in the renal tubular cells. Both mRNA and protein expression levels of PTER were increased in a concentration- and time-dependent manner in the in vitro albuminuria tubular cell model. Silencing the expression of PTER by RNA interference diminished albuminuria-induced inflammatory and pro-fibrotic cytokines production.
Our findings reveal that PTER may sense albuminuria in the progression of MN, induce tubular cell activation and lead to ESRD.
PMCID: PMC4012828  PMID: 24750591
Albuminuria; Nephrotic syndrome; Phosphotriesterase-related protein (PTER)
21.  MicroRNA-224 Suppresses Colorectal Cancer Cell Migration by Targeting Cdc42 
Disease Markers  2014;2014:617150.
The metastatic spread of tumor cells is the major risk factor affecting the clinical prognosis of colorectal cancer (CRC) patients. The metastatic phenotype can be modulated by dysregulating the synthesis of different structural and functional proteins of tumor cells. Micro(mi)RNAs are noncoding RNAs that recognize their cognate messenger (m)RNA targets by sequence-specific interactions with the 3′ untranslated region and are involved in the multistep process of CRC development. The objective of this study was to investigate the expression and biological roles of miR-224 in CRC. The miR-224 expression level was assessed by a quantitative real-time PCR in 79 CRC and 18 nontumor tissues. Expression levels of miR-224 in CRC tissues were significantly lower than those in nontumor tissues. Its expression level was associated with the mutation status of the APC gene. Ectopic expression of miR-224 suppressed the migratory ability of CRC cell line, but cell proliferation was less affected. Increased miR-224 diminished Cdc42 and SMAD4 expressions at both the protein and mRNA levels and inhibited the formation of actin filaments. Overall, this study indicated a role of miR-224 in negatively regulating CRC cell migration. The expression level of miR-224 may be a useful predictive biomarker for CRC progression.
PMCID: PMC4004168  PMID: 24817781
22.  Targeting Spleen Tyrosine Kinase-Bruton's Tyrosine Kinase Axis for Immunologically Mediated Glomerulonephritis 
BioMed Research International  2014;2014:814869.
The importance of B-cell activation and immune complex-mediated Fc-receptor activation in the pathogenesis of immunologically mediated glomerulonephritis has long been recognized. The two nonreceptor tyrosine kinases, spleen tyrosine kinase (Syk) and Bruton's tyrosine kinase (Btk), are primarily expressed by hematopoietic cells, and participate in B-cell-receptor- and Fc-receptor-mediated activation. Pharmacological inhibitors of Syk or Btk are undergoing preclinical development and clinical trials for several immune diseases; and Syk inhibitors have been shown to reduce disease activity in rheumatoid arthritis patients. However, the clinical therapeutic efficacies of these inhibitors in glomerulonephritis have not been evaluated. Herein, we review recent studies of Syk and Btk inhibitors in several experimental primary and secondary glomerulonephritis models. These inhibitors suppressed development of glomerular injury, and also ameliorated established kidney disease. Thus, targeting Syk and Btk signaling pathways is a potential therapeutic strategy for glomerulonephritis, and further evaluation is recommended.
PMCID: PMC3985139  PMID: 24795896
23.  Proteomics Analysis of the DF-1 Chicken Fibroblasts Infected with Avian Reovirus Strain S1133 
PLoS ONE  2014;9(3):e92154.
Avian reovirus (ARV) is a member of the Orthoreovirus genus in the Reoviridae family. It is the etiological agent of several diseases, among which viral arthritis and malabsorption syndrome are the most commercially important, causing considerable economic losses in the poultry industry. Although a small but increasing number of reports have characterized some aspects of ARV infection, global changes in protein expression in ARV-infected host cells have not been examined. The current study used a proteomics approach to obtain a comprehensive view of changes in protein levels in host cells upon infection by ARV.
Methodology and Principal Findings
The proteomics profiles of DF-1 chicken fibroblast cells infected with ARV strain S1133 were analyzed by two-dimensional differential-image gel electrophoresis. The majority of protein expression changes (≥1.5 fold, p<0.05) occurred at 72 h post-infection. Matrix-assisted laser desorption ionization time-of-flight mass spectrometry identified 51 proteins with differential expression levels, including 25 that were upregulated during ARV infection and 26 that were downregulated. These proteins were divided into eight groups according to biological function: signal transduction, stress response, RNA processing, the ubiquitin-proteasome pathway, lipid metabolism, carbohydrate metabolism, energy metabolism, and cytoskeleton organization. They were further examined by immunoblotting to validate the observed alterations in protein expression.
This is the first report of a time-course proteomic analysis of ARV-infected host cells. Notably, all identified proteins involved in signal transduction, RNA processing, and the ubiquitin-proteasome pathway were downregulated in infected cells, whereas proteins involved in DNA synthesis, apoptosis, and energy production pathways were upregulated. In addition, other differentially expressed proteins were linked with the cytoskeleton, metabolism, redox regulation, and stress response. These proteomics data provide valuable information about host cell responses to ARV infection and will facilitate further studies of the molecular mechanisms underlying ARV pathogenesis.
PMCID: PMC3965424  PMID: 24667214
24.  Identification of cell cycle–regulated genes periodically expressed in U2OS cells and their regulation by FOXM1 and E2F transcription factors 
Molecular Biology of the Cell  2013;24(23):3634-3650.
Characterization of the cell cycle–regulated transcripts in U2OS cells yielded 1871 unique genes. FOXM1 targets were identified via ChIP-seq, and novel targets in G2/M and S phases were verified using a real-time luciferase assay. ChIP-seq data were used to map cell cycle transcriptional regulators of cell cycle–regulated gene expression in U2OS cells.
We identify the cell cycle–regulated mRNA transcripts genome-wide in the osteosarcoma-derived U2OS cell line. This results in 2140 transcripts mapping to 1871 unique cell cycle–regulated genes that show periodic oscillations across multiple synchronous cell cycles. We identify genomic loci bound by the G2/M transcription factor FOXM1 by chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq) and associate these with cell cycle–regulated genes. FOXM1 is bound to cell cycle–regulated genes with peak expression in both S phase and G2/M phases. We show that ChIP-seq genomic loci are responsive to FOXM1 using a real-time luciferase assay in live cells, showing that FOXM1 strongly activates promoters of G2/M phase genes and weakly activates those induced in S phase. Analysis of ChIP-seq data from a panel of cell cycle transcription factors (E2F1, E2F4, E2F6, and GABPA) from the Encyclopedia of DNA Elements and ChIP-seq data for the DREAM complex finds that a set of core cell cycle genes regulated in both U2OS and HeLa cells are bound by multiple cell cycle transcription factors. These data identify the cell cycle–regulated genes in a second cancer-derived cell line and provide a comprehensive picture of the transcriptional regulatory systems controlling periodic gene expression in the human cell division cycle.
PMCID: PMC3842991  PMID: 24109597
25.  MiRNAs as Biomarkers of Myocardial Infarction: A Meta-Analysis 
PLoS ONE  2014;9(2):e88566.
Recent studies have demonstrated that acute myocardial infarction induces a distinctive miRNA signature, suggesting that miRNAs may serve as diagnostic markers. Although many studies have investigated the use of miRNAs in the detection of cardiac injury, some had small sample sizes (<100 patients) or reported different results for the same miRNA. Here, the role of circulating miRNAs for use as biomarkers of myocardial infarction is summarized and analyzed.
Methods and Results
Medline, SCI, Embase, and Cochrane databases were searched up to January 2013 for studies that evaluated associations between miRNAs and myocardial infarction. Relevant publications were identified by searching for combinations of “myocardial infarction,” “miRNAs,” and their synonyms. Methodological quality was scored using a standardized list of criteria, and diagnostic performance was assessed using estimates of test sensitivity and specificity. These values were summarized using summary receiver-operating characteristic curves. Nineteen studies met the inclusion criteria: 15 studies reported sensitivity, specificity, and AUC, but 4 studies did not. Total miRNAs: sensitivity: 0.78 (95%CI: 0.77–0.80; P = 0.0000); specificity: 0.82 (95%CI: 0.80–0.83; P = 0.0000). miR-499: sensitivity: 0.88 (95%CI:0.86–0.90; P = 0.0000); specificity: 0.87 (95%CI:0.84–0.90; P = 0.0000). miR-1: sensitivity: 0.63 (95%CI:0.59–0.66; P = 0.0000); specificity: 0.76 (95%CI:0.71–0.80; P = 0.0000). miR-133a: sensitivity: 0.89 (95%CI:0.83–0.94; P = 0.0047); specificity: 0.87 (95%CI:0.79–0.92; P = 0.0262). miR-208b: sensitivity: 0.78 (95%CI:0.76–0.81; P = 0.0581); specificity: 0.88 (95%CI:0.84–0.91; P = 0.0000). The correlation between miRNAs and other diagnostic biomarkers of myocardial infarction was obvious.
MiRNAs, especially miR-499 and miR-133a, may be suitable for use as diagnostic biomarkers of myocardial infarction.
PMCID: PMC3922900  PMID: 24533109

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