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ABSTRACT: To understand how stroke risk factors mechanistically contribute to stroke, the genetic components regulating each risk factor need to be integrated and evaluated with respect to biological function and through pathway-based algorithms. This resource will provide information to researchers studying the molecular and genetic causes of stroke in terms of genomic variants, genes, and pathways.
Reported genetic variants, gene structure, phenotypes, and literature information regarding stroke were collected and extracted from publicly available databases describing variants, genome, proteome, functional annotation, and disease subtypes. Stroke related candidate pathways and etiologic genes that participate significantly in risk were analyzed in terms of canonical pathways in public biological pathway databases. These efforts resulted in a relational database of genetic signals of cerebral stroke, SigCS base, which implements an effective web retrieval system.
The current version of SigCS base documents 1943 non-redundant genes with 11472 genetic variants and 165 non-redundant pathways. The web retrieval system of SigCS base consists of two principal search flows, including: 1) a gene-based variant search using gene table browsing or a keyword search, and, 2) a pathway-based variant search using pathway table browsing. SigCS base is freely accessible at http://sysbio.kribb.re.kr/sigcs.
SigCS base is an effective tool that can assist researchers in the identification of the genetic factors associated with stroke by utilizing existing literature information, selecting candidate genes and variants for experimental studies, and examining the pathways that contribute to the pathophysiological mechanisms of stroke.
BMC Systems Biology 12/2011; 5 Suppl 2:S10. · 3.15 Impact Factor
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ABSTRACT: Stroke is the second leading cause of death and a major cause of morbidity and mortality worldwide. Evidence of variations in adiponectin (AdipoQ) genes that are associated with ischemic stroke has not been consistent, and it is unclear whether the same loci contribute to these associations in the Korean population. Using a Korean population, we tested ischemic stroke-associated AdipoQ markers.
In a preliminary genome-wide association study using 320 250 k Affymetrix NSP chips, AdipoQ was found to be associated with ischemic stroke in Koreans. To study of AdipoQ, a further 673 ischemic stroke patients and 267 unrelated individuals without a history of stroke or transient ischemic attack were examined in a case-control study.
Six polymorphisms (rs182052G > A, rs16861205G > A, rs822391T > C, rs822396A > G, rs12495941G > T and rs3774261A > G) that had a minor allele frequency of over 1% were strongly associated with stroke (p < 0.05). Two of these, rs822391T > C and rs822396A > G showed this association on both dominant and additive logistic regression analysis after adjusting for age and sex. The haplotypes ht 1 (AGGCGG and AAGTAG) were significantly associated with susceptibility to stroke.
Our findings show that polymorphisms in AdipoQ are associated with risk for ischemic stroke in the Korean population. This study lends further support to the putative role of AdipoQ in stroke.
Yonsei medical journal 01/2011; 52(1):20-5. · 0.77 Impact Factor
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ABSTRACT: Complex diseases, such as stroke and cancer, have two or more genetic influences and are affected by environmental factors, which complicates them. Due to the complex characteristics of these diseases, we must search and study comprehensive literature-based article resources. Some disease-related literature databases have been developed through specialized journal issues or major websites. Most of them, however, are scattered throughout a website, and users encounter difficulties in finding accurate and comprehensive information easily and quickly.We developed StrokeMed, an integrated literature database for stroke and the differentiation of stroke syndrome. The system allows users to explore PubMed search results, categorized by MeSH (Medical Subject Headings), and the differentiation of stroke syndrome in Oriental medicine. StrokeMed collects data from important sites, such as PubMed, Scirus, and Scopus, automatically to maintain higher-quality and updated content. Currently, the system indexes more than 20,000 PubMed abstracts that are related to stroke, stroke etiology, and Oriental medicine. The system provides valuable literature information to the scientific and medical fields in stroke.
Interdisciplinary Bio Central. 01/2010;
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ABSTRACT: Stroke, also called an attack on the brain, is a complex disease that results from the interaction of many genetic and environmental factors. StrokePortal is a comprehensive resource for information on stroke that integrates and provides essential findings regarding stroke pathology, diagnostics, and treatments, based on Oriental and Western medicine. The stroke information was collected from various sources, such as journal articles, books, websites, and news stories, and it was refined, classified, and stored into a relational database system by automatic classification and manual curation. To provide the stored information effectively to users, a specialized retrieval system, based on web interfaces, was implemented. StrokePortal provides cutting-edge information to experts; interested people, including patients and their families; and investigators to broaden their knowledge of effective treatments for patients and offer many preventive measures. It provides a specialized feature with which users can upload their information and opinions to StrokePortal, which will enrich and mature the content even further. StrokePortal is freely accessible at http://genomics.kribb.re.kr/StrokePortal/.
Interdisciplinary Bio Central. 01/2010;
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ABSTRACT: RNA interference (RNAi) with small interfering RNA (siRNA) has become a powerful tool in functional and medical genomic research through directed post-transcriptional gene silencing. In order to apply RNAi technique for eukaryotic organisms, where frequent alternative splicing results in diversification of mRNAs and finally of proteins, we need spliced mRNA isoform silencing to study the function of individual proteins. AsiDesigner is a web-based siRNA design software system, which provides siRNA design capability to account for alternative splicing for mRNA level gene silencing. It provides numerous novel functions including the designing of common siRNAs for the silencing of more than two mRNAs simultaneously, a scoring scheme to evaluate the performance of designed siRNAs by adopting currently known key design factors, a stepwise off-target searching with BLAST and FASTA algorithms and checking the folding secondary structure energy of siRNAs. To do this, we developed a novel algorithm to evaluate the common target region, where siRNAs can be designed to knockdown a specific mRNA isoform or more than two mRNA isoforms from a target gene simultaneously. The developed algorithm and the AsiDesigner were tested and validated as very effective throughout widely performed gene silencing experiments. It is expected that AsiDesigner will play an important role in functional genomics, drug discovery and other molecular biological research. AsiDesigner is freely accessible at http://sysbio.kribb.re.kr/AsiDesigner/.
Nucleic Acids Research 08/2008; 36(Web Server issue):W97-103. · 8.03 Impact Factor
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ABSTRACT: MicroRNAs (miRNAs) constitute a class of small noncoding RNAs that play important roles in a variety of biological processes including development, apoptosis, proliferation, and differentiation. Here we show that the expression of miR-199a and miR-199a* (miR-199a/a*), which are processed from the same precursor, is confined to fibroblast cells among cultured cell lines. The fibroblast-specific expression pattern correlated well with methylation patterns: gene loci on chromosome 1 and 19 were fully methylated in all examined cell lines but unmethylated in fibroblasts. Transfection of miR-199a and/or -199a* mimetics into several cancer cell lines caused prominent apoptosis with miR-199a* being more pro-apoptotic. The mechanism underlying apoptosis induced by miR-199a was caspase-dependent, whereas a caspase-independent pathway was involved in apoptosis induced by miR-199a* in A549 cells. By employing microarray and immunoblotting analyses, we identified the MET proto-oncogene as a target of miR-199a*. Studies with a luciferase reporter fused to the 3'-untranslated region of the MET gene demonstrated miR-199a*-mediated down-regulation of luciferase activity through a binding site of miR-199a*. Interestingly, extracellular signal-regulated kinase 2 (ERK2) was also down-regulated by miR-199a*. Coordinated down-regulation of both MET and its downstream effector ERK2 by miR-199a* may be effective in inhibiting not only cell proliferation but also motility and invasive capabilities of tumor cells.
Journal of Biological Chemistry 07/2008; 283(26):18158-66. · 4.77 Impact Factor
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ABSTRACT: Identifying candidate genes related to complex diseases or traits and mapping their relationships require a system-level analysis at a cellular scale. The objective of the present study is to systematically analyze the complex effects of interrelated genes and provide a framework for revealing their relationships in association with a specific disease (asthma in this case). We observed that protein-protein interaction (PPI) networks associated with asthma have a power-law connectivity distribution as many other biological networks have. The hub nodes and skeleton substructure of the result network are consistent with the prior knowledge about asthma pathways, and also suggest unknown candidate target genes associated with asthma, including GNB2L1, BRCA1, CBL, and VAV1. In particular, GNB2L1 appears to play a very important role in the asthma network through frequent interactions with key proteins in cellular signaling. This network-based approach represents an alternative method for analyzing the complex effects of candidate genes associated with complex diseases and suggesting a list of gene drug targets. The full list of genes and the analysis details are available in the following online supplementary materials: http://biosoft.kaist.ac.kr:8080/resources/asthma_ppi.
Journal of Theoretical Biology 07/2008; 252(4):722-31. · 2.21 Impact Factor
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ABSTRACT: The Korean HapMap Project has been carried out for the last 5 years since it started in June, 2003. The proj-ect generated data for a sum of 1,764,000 Korean SNPs and formally registered the data to the dbSNP of NCBI (The dbSNP website. 2008). We have developed a ser-ies of software programs for association studies as well as for the comparison and analysis of Korean HapMap data with four other populations (CEPH, Yoruba, Han Chinese, and Japanese populations). The KHapmap Browser was developed and integrated to provide hap-lotype retrieval and comparative study tools of human ethnicities for comprehensive disease association stud-ies (http://www.khapmap.org). On that basis, GBrowse was adopted in the KHapmap Browser for inherent Korean genetic data, and a provision of extended serv-ices was pledged with the distributed sequence annota-tion system (DAS). The dynamic linking service of the KHapmap Browser to other tools in our intranetwork en-vironment provides many enhanced functions over GBrowse without DAS. KHapmap Browser is expected to be an invaluable tool for the study of Korean and in-ternational Hapmap data.
Genomics & Informatics. 07/2008; 6:57-63.
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ABSTRACT: Improvement in the pharmacokinetic properties of short interfering RNAs (siRNAs) is a prerequisite for the therapeutic application of RNA interference technology. When injected into mice as unmodified siRNAs complexed to DOTAP/Chol-based cationic liposomes, all 12 tested siRNA duplexes caused a strong induction of cytokines including interferon alpha, indicating that the immune activation by siRNA duplexes is independent of sequence context. When modified by various combinations of 2'-OMe, 2'-F, and phosphorothioate substitutions, introduction of as little as three 2'-OMe substitutions into the sense strand was sufficient to suppress immune activation by siRNA duplexes, whereas the same modifications were much less efficient at inhibiting the immune response of single stranded siRNAs. It is unlikely that Toll-like receptor 3 (TLR3) signaling is involved in immune stimulation by siRNA/liposome complexes since potent immune activation by ds siRNAs was induced in TLR3 knockout mice. Together, our results indicate that chemical modification of siRNA provides an effective means to avoid unwanted immune activation by therapeutic siRNAs. This improvement in the in vivo properties of siRNAs should greatly facilitate successful development of siRNA therapeutics.
Molecules and Cells 11/2007; 24(2):247-54. · 2.18 Impact Factor
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ABSTRACT: The single nucleotide polymorphisms (SNPs) in conserved protein regions have been thought to be strong candidates that alter protein functions. Thus, we have developed SNP@Domain, a web resource, to identify SNPs within human protein domains. We annotated SNPs from dbSNP with protein structure-based as well as sequence-based domains: (i) structure-based using SCOP and (ii) sequence-based using Pfam to avoid conflicts from two domain assignment methodologies. Users can investigate SNPs within protein domains with 2D and 3D maps. We expect this visual annotation of SNPs within protein domains will help scientists select and interpret SNPs associated with diseases. A web interface for the SNP@Domain is freely available at http://snpnavigator.net/ and from http://bioportal.net/.
Nucleic Acids Research 08/2006; 34(Web Server issue):W642-4. · 8.03 Impact Factor
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ABSTRACT: Development of RNA interference as a novel class of therapeutics requires improved pharmacokinetic properties of short interfering RNA (siRNA). To confer enhanced serum stability to Sur10058, a hyperfunctional siRNA which targets survivin mRNA, a systematic modification at the 2'-sugar position and phosphodiester linkage was introduced into Sur10058. End modification of three terminal nucleotides by 2'-OMe and phosphorothioate substitutions resulted in a modest increase in serum stability, with 3' end modification being more effective. Alternating modification by 2'-OMe substitution significantly stabilized Sur10058, whereas phosphorothioate modification was only marginally effective. Through various combinations of 2'-OMe, 2'-F and phosphorothioate modifications that were directed mainly at pyrimidine nucleotides, we have identified several remarkably stable as well as efficient forms of Sur10058. Thus, our results provide an effective means to stabilize siRNA in human serum without compromising the knockdown efficiency. This advancement will prove useful for augmenting the in vivo potency of RNA interference.
Biochemical and Biophysical Research Communications 05/2006; 342(3):919-27. · 2.48 Impact Factor
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ABSTRACT: Utilizing starch-containing alginate beads, a novel drug delivery system (DDS) was developed. With the starch inside, the composite bead could be dried in its original bead shape and handled in the dried state. By employing alginate multi-coating strategy on the starch-alginate beads, detained or controlled release was efficiently achieved and successfully demonstrated for a model peptide drug, L-phenylalanine. The initial latent time and release rate of the drug inside the beads were able to be controlled simply by varying the number of multi-coatings. While the latent time for the initial release was negligible for non-coated starch-alginate beads, the latent times of beads coated one, two, and four times increased to 15, 30, and 70 min, respectively. Furthermore, the alginate component of the composite beads could adsorb and remove heavy metals such as lead from the body. These multifunctional beads combined with the novel coating process will greatly benefit alginate gel-based DDS.
Biological & Pharmaceutical Bulletin 03/2005; 28(2):394-7. · 1.66 Impact Factor
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ABSTRACT: We have created the Functional Element SNPs Database (FESD) that categorizes functional elements in human genic regions and provides a set of single nucleotide polymorphisms (SNPs) located within each area. In the FESD, the human genic regions were divided into 10 different functional elements, such as promoter regions, CpG islands, 5'-untranslated regions (5'-UTRs), translation start sites, splice sites, coding exons, introns, translation stop sites, polyadenylation signals and 3'-UTRs, and subsequently, all the known SNPs were assigned to each functional element at their respective position. With the FESD web interface, users can select a set of SNPs in the specific functional elements and get their flanking sequences for genotyping experiments, which will help in finding mutations that contribute to the common and polygenic diseases. A web interface for the FESD is freely available at http://combio.kribb.re.kr/ksnp/resd/.
Nucleic Acids Research 02/2005; 33(Database issue):D518-22. · 8.03 Impact Factor
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ABSTRACT: Recent years saw a dramatic increase in genomic and proteomic data in public archives. Now with the complete genome sequences of human and other species in hand, detailed analyses of the genome sequences will undoubtedly improve our understanding of biological systems and at the same time require sophisticated bioinformatic tools. Here we review what computational challenges are ahead and what are the new exciting developments in this exciting field.
Journal of biochemistry and molecular biology 02/2004; 37(1):75-82. · 2.02 Impact Factor
