Jo C.,University of Rochester |
Jo C.,Korea National Institute of Health |
Gundemir S.,University of Rochester |
Pritchard S.,University of Rochester |
And 3 more authors.
Nature Communications | Year: 2014
Nuclear factor erythroid 2-related factor 2 (Nrf2) is a pivotal transcription factor in the defence against oxidative stress. Here we provide evidence that activation of the Nrf2 pathway reduces the levels of phosphorylated tau by induction of an autophagy adaptor protein NDP52 (also known as CALCOCO2) in neurons. The expression of NDP52, which we show has three antioxidant response elements (AREs) in its promoter region, is strongly induced by Nrf2, and its overexpression facilitates clearance of phosphorylated tau in the presence of an autophagy stimulator. In Nrf2-knockout mice, phosphorylated and sarkosyl-insoluble tau accumulates in the brains concurrent with decreased levels of NDP52. Moreover, NDP52 associates with phosphorylated tau from brain cortical samples of Alzheimer disease cases, and the amount of phosphorylated tau in sarkosyl-insoluble fractions is inversely proportional to that of NDP52. These results suggest that NDP52 plays a key role in autophagy-mediated degradation of phosphorylated tau in vivo. © 2014 Macmillan Publishers Limited. All rights reserved.
Park Y.K.,Sungkyunkwan University |
Park Y.K.,Korea National Institute of Health |
Lee J.-Y.,Sungkyunkwan University |
Ko K.S.,Sungkyunkwan University
Clinical Microbiology and Infection | Year: 2015
The emergence of colistin-resistant Acinetobacter baumannii is concerning, as colistin is often regarded as the last option for treating multidrug-resistant (MDR) A. baumannii infections. Using mRNA sequencing, we compared whole transcriptomes of colistin-susceptible and colistin-resistant A. baumannii strains, with the aim of identifying genes involved in colistin resistance. A clinical colistin-susceptible strain (06AC-179) and a colistin-resistant strain (07AC-052) were analysed in this study. In addition, a colistin-resistant mutant (06AC-179-R1) derived from 06AC-179 was also included in this study. High throughput mRNA sequencing was performed with an Illumina HiSeq TM 2000. In total, six genes were identified as associated with colistin resistance in A. baumannii. These six genes encode PmrAB two-component regulatory enzymes, PmrC (a lipid A phosphoethanolamine transferase), a glycosyltransferase, a poly-β-1,6-. N-acetylglucosamine deacetylase, and a putative membrane protein. Matrix-assisted laser desorption/ionization time of flight mass spectrometry revealed that all three colistin-resistant strains used in this study had modified lipid A structure by addition of phosphoethanolamine. As genes found in our results are all associated with either lipopolysaccharide biosynthesis or electrostatic changes in the bacterial cell membrane, lipopolysaccharide modification might be one of the principal modes of acquisition of colistin resistance in some A. baumannii strains. © 2015 European Society of Clinical Microbiology and Infectious Diseases.
Kim S.-M.,Seoul National University |
Go M.J.,Korea National Institute of Health |
Sung J.-J.,Seoul National University |
Park K.S.,Seoul National University |
Lee K.-W.,Seoul National University
Archives of Neurology | Year: 2012
Objectives: To evaluate the diagnostic utility and clinical characteristics of painful tonic spasm (PTS) in neuromyelitis optica (NMO). Design : Retrospective study. Setting: Two referral hospitals. Patients: Forty patients who had NMO spectrum disorder with anti-aquaporin 4 autoantibody or met the revised diagnostic criteria for definite NMO; 35 patients with multiple sclerosis; and 41 patients with idiopathic acute transverse myelitis without anti-aquaporin 4 antibody. Main Outcome Measures: The incidence and clinical characteristics of PTS in the different groups, diagnostic value of PTS in identifying patients with NMO, and predictors of PTS in NMO. Results: The incidence of PTS was significantly higher in the patients with NMO (10 patients [25.0%]) than in those with multiple sclerosis (1 patient [2.9%]) or idiopathic acute transverse myelitis without anti-aquaporin 4 antibody (1 patient [2.4%]). Most PTS episodes (in 8 of 10 patients [80.0%]) in the NMO group occurred after a mean interval of 48.13 days from the onset of the first myelitis episode and were not accompanied by another demyelinating episode with its onset. Painful tonic spasm associated with myelitis had a specificity of 98.7% for identifying the NMO group. Myelitis at disease onset was a predictor of PTS in the NMO group (odds ratio= 6.545, presence vs absence). Conclusions: Painful tonic spasm is a common symptom in NMO. When associated with myelitis, it is relatively specific to patients with NMO and is most commonly observed during recovery from the first myelitis episode. Patients with NMO presenting with myelitis at disease onset appear to be at higher risk for developing PTS compared with other patients with NMO. ©2012 American Medical Association. All rights reserved.
So A.-Y.,Seoul National University |
Jung J.-W.,Korea National Institute of Health |
Lee S.,Seoul National University |
Kim H.-S.,Seoul National University |
Kang K.-S.,Seoul National University
PLoS ONE | Year: 2011
Epigenetic regulation of gene expression is well known mechanism that regulates cellular senescence of cancer cells. Here we show that inhibition of DNA methyltransferases (DNMTs) with 5-azacytidine (5-AzaC) or with specific small interfering RNA (siRNA) against DNMT1 and 3b induced the cellular senescence of human umbilical cord blood-derived multipotent stem cells (hUCB-MSCs) and increased p16INK4A and p21CIP1/WAF1 expression. DNMT inhibition changed histone marks into the active forms and decreased the methylation of CpG islands in the p16INK4A and p21CIP1/WAF1 promoter regions. Enrichment of EZH2, the key factor that methylates histone H3 lysine 9 and 27 residues, was decreased on the p16INK4A and p21CIP1/WAF1 promoter regions. We found that DNMT inhibition decreased expression levels of Polycomb-group (PcG) proteins and increased expression of microRNAs (miRNAs), which target PcG proteins. Decreased CpG island methylation and increased levels of active histone marks at genomic regions encoding miRNAs were observed after 5-AzaC treatment. Taken together, DNMTs have a critical role in regulating the cellular senescence of hUCB-MSCs through controlling not only the DNA methylation status but also active/inactive histone marks at genomic regions of PcG-targeting miRNAs and p16INK4A and p21CIP1/WAF1 promoter regions. © 2011 So et al.
Yanagihara R.,University of Hawaii at Manoa |
Gu S.H.,University of Hawaii at Manoa |
Arai S.,Japan National Institute of Infectious Diseases |
Kang H.J.,Korea National Institute of Health |
Song J.-W.,Korea University
Virus Research | Year: 2014
Virus and host gene phylogenies, indicating that antigenically distinct hantaviruses (family Bunyaviridae, genus Hantavirus) segregate into clades, which parallel the molecular evolution of rodents belonging to the Murinae, Arvicolinae, Neotominae and Sigmodontinae subfamilies, suggested co-divergence of hantaviruses and their rodent reservoirs. Lately, this concept has been vigorously contested in favor of preferential host switching and local host-specific adaptation. To gain insights into the host range, spatial and temporal distribution, genetic diversity and evolutionary origins of hantaviruses, we employed reverse transcription-polymerase chain reaction to analyze frozen, RNAlater®-preserved and ethanol-fixed tissues from 1546 shrews (9 genera and 47 species), 281 moles (8 genera and 10 species) and 520 bats (26 genera and 53 species), collected in Europe, Asia, Africa and North America during 1980-2012. Thus far, we have identified 24 novel hantaviruses in shrews, moles and bats. That these newfound hantaviruses are geographically widespread and genetically more diverse than those harbored by rodents suggests that the evolutionary history of hantaviruses is far more complex than previously conjectured. Phylogenetic analyses indicate four distinct clades, with the most divergent comprising hantaviruses harbored by the European mole and insectivorous bats, with evidence for both co-divergence and host switching. Future studies will provide new knowledge about the transmission dynamics and pathogenic potential of these newly discovered, still-orphan, non-rodent-borne hantaviruses. © 2014 The Authors.
Bennett S.N.,University of Hawaii at Manoa |
Bennett S.N.,California Academy of Sciences |
Gu S.H.,University of Hawaii at Manoa |
Kang H.J.,Korea National Institute of Health |
And 2 more authors.
Trends in Microbiology | Year: 2014
Rodents have long been recognized as the principal reservoirs of hantaviruses. However, with the discovery of genetically distinct and phylogenetically divergent lineages of hantaviruses in multiple species of shrews, moles, and insectivorous bats from widely separated geographic regions, a far more complex landscape of hantavirus host distribution, evolution, and phylogeography is emerging. Detailed phylogenetic analyses, based on partial and full-length genomes of previously described rodent-borne hantaviruses and newly detected non-rodent-borne hantaviruses, indicate an Asian origin and support the emerging concept that ancestral non-rodent mammals may have served as the hosts of primordial hantaviruses. © 2014.
Piao Y.,Chungbuk National University |
Piao M.,Chungbuk National University |
Park K.,Korea National Institute of Health |
Ryu K.H.,Chungbuk National University
Bioinformatics | Year: 2012
Motivation: Gene selection for cancer classification is one of the most important topics in the biomedical field. However, microarray data pose a severe challenge for computational techniques. We need dimension reduction techniques that identify a small set of genes to achieve better learning performance. From the perspective of machine learning, the selection of genes can be considered to be a feature selection problem that aims to find a small subset of features that has the most discriminative information for the target.Results: In this article, we proposed an Ensemble Correlation-Based Gene Selection algorithm based on symmetrical uncertainty and Support Vector Machine. In our method, symmetrical uncertainty was used to analyze the relevance of the genes, the different starting points of the relevant subset were used to generate the gene subsets and the Support Vector Machine was used as an evaluation criterion of the wrapper. The efficiency and effectiveness of our method were demonstrated through comparisons with other feature selection techniques, and the results show that our method outperformed other methods published in the literature.Availability: By request from the author. © 2012 The Author.
Yun M.R.,Korea National Institute of Health |
Yun M.R.,Yonsei University |
Seo J.M.,Korea National Institute of Health |
Park H.Y.,Korea National Institute of Health
Cellular Signalling | Year: 2014
Visfatin is a novel multifunctional adipocytokine with inflammatory properties. Although a link between visfatin and atherosclerosis has recently been suggested, its actions in the development of atherosclerosis remain unknown. Therefore, we investigated a potential role and underlying mechanism(s) of visfatin in monocytes/macrophages differentiation, a critical early step in atherogenesis, using phorbol-12-myristate-13-acetate (PMA)-stimulated THP-1 cell models. The co-incubation of PMA with visfatin-induced CD36 expression with a concomitant increase in the phagocytosis of latex beads compared with PMA alone treatment. Moreover, visfatin markedly increased interleukin (IL)-1β secretion by enhancing IL-1β mRNA stability in a short-term incubation. Visfatin also significantly elevated the secretion of IL-6 as well as IL-1β in a longer incubation period, which was partially suppressed by nuclear factor-κB (NF-κB) inhibitor, BAY11-7082, and c-Jun-N-terminal kinase (JNK) inhibitor, SP600125. Furthermore, silencing IL-1β successfully blocked IL-6 secretion, CD36 expression, and NF-κB activation in response to visfatin. Collectively, these results suggest that visfatin enhances the IL-1β-dependent induction of IL-6 and CD36 via distinct signaling pathways mediated by JNK and NF-κB, respectively, and consequently, leading to the acceleration of monocytes/macrophages differentiation. © 2014 Elsevier Inc.
Park K.,Sangmyung University |
Kim K.-B.,Korea National Institute of Health
Molecules and Cells | Year: 2013
MicroRNAs (miRNAs) are important regulators of gene expression and play crucial roles in many biological processes including apoptosis, differentiation, development, and tumorigenesis. Recent estimates suggest that more than 50% of human protein coding genes may be regulated by miRNAs and that each miRNA may bind to 300-400 target genes. Approximately 1,000 human miRNAs have been identified so far with each having up to hundreds of unique target mRNAs. However, the targets for a majority of these miRNAs have not been identified due to the lack of large-scale experimental detection techniques. Experimental detection of miRNA target sites is a costly and time-consuming process, even though identification of miRNA targets is critical to unraveling their functions in various biological processes. To identify miRNA targets, we developed miRTar Hunter, a novel computational approach for predicting target sites regardless of the presence or absence of a seed match or evolutionary sequence conservation. Our approach is based on a dynamic programming algorithm that incorporates more sequence-specific features and reflects the properties of various types of target sites that determine diverse aspects of complementarities between miRNAs and their targets. We evaluated the performance of our algorithm on 532 known human miRNA:target pairs and 59 experimentally-verified negative miRNA:target pairs, and also compared our method with three popular programs for 481 miRNA:target pairs. miRTar Hunter outperformed three popular existing algorithms in terms of recall and precision, indicating that our unique scheme to quantify the determinants of complementary sites is effective at detecting miRNA targets. miRTar Hunter is now available at http://18.104.22.168/~kbkim. © 2013 The Korean Society for Molecular and Cellular Biology and Springer Netherlands.
Jeong Y.-I.,Korea National Institute of Health |
Hong S.-H.,Korea National Institute of Health |
Cho S.-H.,Korea National Institute of Health |
Lee W.-J.,Korea National Institute of Health |
Lee S.-E.,Korea National Institute of Health
PLoS ONE | Year: 2012
Background: Understanding the induction of immune regulatory cells upon helminth infection is important for understanding the control of autoimmunity and allergic inflammation in helminth infection. Babesia microti, an intraerythrocytic protozoan of the genus Babesia, is a major cause of the emerging human disease babesiosis, an asymptomatic malaria-like disease. We examined the influence of acute B. microti infection on the development of regulatory B cells together with regulatory T cells. Principal Findings: Our data demonstrate that B cells stimulated in vitro with B. microti produce interleukin (IL)-10. This cytokine is also secreted by B cells isolated from B. microti-infected mice in response to lipopolysaccharide stimulation. In addition, high levels of IL-10 were detected in the serum of mice after infection with B. microti. The frequency of IL-10-producing CD1dhighCD5+ regulatory B cells (Bregs) and CD4+CD25+FoxP3+ T cells increased during the course of B. microti infection. Furthermore, adoptive transfer of IL-10-producing B cells induced by B. microti infection led to increased susceptibility of recipient mice to infection with B. microti. In contrast, experiments with B cell-deficient (μMT) mice demonstrated that lack of B cells enhances susceptibility to B. microti infection. Conclusions: This study is the first demonstration of the expansion of Bregs following infection by an intraerythrocytic protozoan parasite. These data suggest that B. microti infection in mice provides an excellent model for studying Breg-mediated immune responses and begins to elucidate the mechanism by which helminth infection regulates autoimmunity and allergic inflammation. © 2012 Jeong et al.