Publications by authors named "Yuko Makita"

56 Publications

Nasal-associated lymphoid tissue is the major induction site for nephritogenic IgA in murine IgA nephropathy.

Kidney Int 2021 May 5. Epub 2021 May 5.

Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan. Electronic address:

Dysregulation of mucosal immunity may play a role in the pathogenesis of IgA nephropathy (IgAN). However, it is unclear whether the nasal-associated lymphoid tissue (NALT) or gut-associated lymphatic tissue is the major induction site of nephritogenic IgA synthesis. To examine whether exogenous mucosal antigens exacerbate the pathogenesis of IgAN, we assessed the disease phenotypes of IgAN-onset ddY mice housed germ-free. These mice were transferred to a specific pathogen-free environment and divided into three groups: challenged with the Toll-like receptor 9 (TLR9) ligand CpG-oligodeoxynucleotide, fecal transplantation, and the untreated control group. The levels of aberrantly glycosylated IgA and IgG-IgA immune complexes were measured in the serum and supernatant of cultured cells purified from the NALT, mesenteric lymph nodes, and Peyer's patch. Although the germ-free IgAN-onset ddY mice did not develop IgAN, they showed aggravation of kidney injury with mesangial IgA deposition after transfer to the specific pathogen-free state. The NALT cells produced more aberrantly glycosylated IgA than those from the mesenteric lymph node and Peyer's patch, resulting in induction of IgG-IgA immune complexes formation. Additionally, TLR9 enhanced the production of nephritogenic IgA and IgG-IgA immune complexes by nasal-associated lymphoid but not gut-associated lymphatic cells. Furthermore, the germ-free IgAN-onset ddY mice nasally immunized with CpG-oligonucleotide showed aggravation of kidney injury with mesangial IgA deposition, whereas those that received fecal transplants did not develop IgAN. Thus, NALT is the major induction site of the production of aberrantly glycosylated IgA in murine IgAN.
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http://dx.doi.org/10.1016/j.kint.2021.04.026DOI Listing
May 2021

Renal pathological analysis using galactose-deficient IgA1-specific monoclonal antibody is a strong tool for differentiation of primary IgA nephropathy from secondary IgA nephropathy.

CEN Case Rep 2021 02 16;10(1):17-22. Epub 2020 Jul 16.

Department of Nephrology, Juntendo University Faculty of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.

In several cases with IgA nephropathy (IgAN), differential diagnosis is difficult due to the complication with other systemic diseases which can induce secondary IgAN. Recently, we demonstrated that immunostaining with galactose-deficient IgA1-specific monoclonal antibody (KM55 mAb) specifically showed positive in primary IgAN cases. Here, we report four cases which we could make definitive diagnosis by immunohistological analysis using KM55 mAb. The underlying systemic diseases are rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), hepatitis C (HCV) and Crohn's disease (CD). Renal pathological findings in the four cases revealed mesangial proliferative glomerulonephritis with IgA and C3 deposits. Immunostaining with KM55 mAb was positive for three cases complicated with RA, SLE and CD, respectively. Thus, these three cases were diagnosed as primary IgAN and treated with tonsillectomy and steroid pulse therapy. These three cases finally achieved clinical remission. On the other hand, the case with HCV showed negative for KM55. Finally, we diagnosed as HCV-related nephropathy and successfully treated by antiviral agents. These cases suggested KM55 mAb is a strong tool to differentiate primary IgAN from secondary IgAN.
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http://dx.doi.org/10.1007/s13730-020-00508-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7829275PMC
February 2021

Crucial Role of AIM/CD5L in the Development of Glomerular Inflammation in IgA Nephropathy.

J Am Soc Nephrol 2020 09 1;31(9):2013-2024. Epub 2020 Jul 1.

Department of Nephrology, Juntendo University, Tokyo, Japan

Background: IgA nephropathy (IgAN) begins with aberrant IgA deposition in glomeruli, progresses to IgM/IgG/complement codeposition, and results in chronic inflammation and glomerular damage. However, the mechanism that drives such phlogogenic cascade has been unclear. Recently, apoptosis inhibitor of macrophage (AIM) protein was shown to modulate macrophages' function in various pathologic conditions, thereby profoundly affecting the progression of renal disorders, including AKI. A spontaneous IgAN model, grouped ddY (gddY) mouse, revealed the requirement of AIM for the overall inflammatory glomerular injury following IgA deposition.

Methods: We established an AIM-deficient IgAN model ( gddY) using CRISPR/Cas9 and compared its phenotype with that of wild-type gddY with or without recombinant AIM administration. An IgA-deficient IgAN model ( gddY) was also generated to further determine the role of AIM.

Results: In both human and murine IgAN, AIM colocalized with IgA/IgM/IgG in glomeruli, whereas control kidneys did not exhibit AIM deposition. Although gddY showed IgA deposition at levels comparable with those of wild-type gddY, they did not exhibit glomerular accumulation of IgM/IgG complements, CD45 leukocyte infiltration, and upregulation of inflammatory/fibrogenic genes, indicating protection from glomerular lesions and proteinuria/hematuria. Recombinant AIM administration reconstituted the IgAN phenotype, resulting in IgM/IgG/complement IgA codeposition. Neither spontaneous IgM/IgG codeposition nor disease was observed in gddY mice.

Conclusions: AIM may contribute to stable immune complex formation in glomeruli, thereby facilitating IgAN progression. Therefore, AIM deposition blockage or disassociation from IgM/IgG may present a new therapeutic target on the basis of its role in IgAN inflammation initiation.
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http://dx.doi.org/10.1681/ASN.2019100987DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7461693PMC
September 2020

Regulatory Potential of bHLH-Type Transcription Factors on the Road to Rubber Biosynthesis in .

Plants (Basel) 2020 May 26;9(6). Epub 2020 May 26.

Synthetic Genomics Research Group, RIKEN Center for Sustainable Resource Science, Yokohama, Kanagawa 230-0045, Japan.

Natural rubber is the main component of latex obtained from laticifer cells of . For improving rubber yield, it is essential to understand the genetic molecular mechanisms responsible for laticifer differentiation and rubber biosynthesis. Jasmonate enhances both secondary laticifer differentiation and rubber biosynthesis. Here, we carried out time-course RNA-seq analysis in suspension-cultured cells treated with methyljasmonic acid (MeJA) to characterize the gene expression profile. Gene Ontology (GO) analysis showed that the term "cell differentiation" was enriched in upregulated genes at 24 hours after treatment, but inversely, the term was enriched in downregulated genes at 5 days, indicating that MeJA could induce cell differentiation at an early stage of the response. Jasmonate signaling is activated by MYC2, a basic helix-loop-helix (bHLH)-type transcription factor (TF). The aim of this work was to find any links between transcriptomic changes after MeJA application and regulation by TFs. Using an in vitro binding assay, we traced candidate genes throughout the whole genome that were targeted by four bHLH TFs: Hb_MYC2-1, Hb_MYC2-2, Hb_bHLH1, and Hb_bHLH2. The latter two are highly expressed in laticifer cells. Their physical binding sites were found in the promoter regions of a variety of other TF genes, which are differentially expressed upon MeJA exposure, and rubber biogenesis-related genes including and . These studies suggest the possibilities that and regulate cell differentiation and that and promote rubber biosynthesis. We expect that our findings will help to increase natural rubber yield through genetic control in the future.
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http://dx.doi.org/10.3390/plants9060674DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7355734PMC
May 2020

Time-Course Transcriptome Study Reveals Mode of bZIP Transcription Factors on Light Exposure in .

Int J Mol Sci 2020 Mar 14;21(6). Epub 2020 Mar 14.

Synthetic Genomics Research Group, RIKEN Center for Sustainable Resource Science, Yokohama, Kanagawa 230-0045, Japan.

The etiolation process, which occurs after germination, is terminated once light is perceived and then de-etiolation commences. During the de-etiolation period, monochromatic lights (blue, red and far-red) induce differences in gene expression profiles and plant behavior through their respective photoreceptors. ELONGATED HYPOCOTYL 5 (HY5), a bZIP-type transcription factor (TF), regulates gene expression in the de-etiolation process, and other bZIP TFs are also involved in this regulation. However, transcriptomic changes that occur in etiolated seedlings upon monochromatic light irradiation and the relationship with the bZIP TFs still remain to be elucidated. Here, we track changes in the transcriptome after exposure to white, blue, red and far-red light following darkness and reveal both shared and non-shared trends of transcriptomic change between the four kinds of light. Interestingly, after exposure to light, expression synchronized with those of the related bZIP TF genes, and , rather than (). To speculate on the redundancy of target genes between the bZIP TFs, we inspected the genome-wide physical binding sites of homodimers of seven bZIP TFs, HY5, HYH, GBF1, GBF2, GBF3, GBF4 and EEL, using an in vitro binding assay. The results reveal large overlaps of target gene candidates, indicating a complicated regulatory literature among TFs. This work provides novel insight into understanding the regulation of gene expression of the plant response to monochromatic light irradiation.
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http://dx.doi.org/10.3390/ijms21061993DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139404PMC
March 2020

Translational Landscape of Protein-Coding and Non-Protein-Coding RNAs upon Light Exposure in Arabidopsis.

Plant Cell Physiol 2020 Mar;61(3):536-545

Synthetic Genomics Research Group, RIKEN Center for Sustainable Resource Science, Yokohama, Kanagawa, 230-0045 Japan.

Light is one of the most essential environmental clues for plant growth and morphogenesis. Exposure to blue monochromatic light from darkness is a turning point for plant biological activity, and as a result dramatic changes in gene expression occur. To understand the translational impacts of blue light, we have performed ribosome profiling analysis and called translated open reading frames (ORFs) de novo within not only mRNAs but also non-coding RNAs (ncRNAs). Translation efficiency of 3,823 protein-coding ORFs, such as nuclear chloroplast-related genes, was up-regulated by blue light exposure. Moreover, the translational activation of the microRNA biogenesis-related genes, DCL1 and HYL1, was induced by blue light. Considering the 3-nucleotide codon periodicity of ribosome footprints, a few hundred short ORFs lying on ncRNAs and upstream ORFs (uORFs) on mRNAs were found that had differential translation status between blue light and dark. uORFs are known to have a negative effect on the expression of the main ORFs (mORFs) on the same mRNAs. Our analysis suggests that the translation of uORFs is likely to be more stimulated than that of the corresponding mORFs, and uORF-mediated translational repression of the mORFs in five genes was alleviated by blue light exposure. With data-based annotation of the ORFs, our analysis provides insights into the translatome in response to environmental changes, such as those involving light.
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http://dx.doi.org/10.1093/pcp/pcz219DOI Listing
March 2020

TLR9 activation induces aberrant IgA glycosylation via APRIL- and IL-6-mediated pathways in IgA nephropathy.

Kidney Int 2020 02 5;97(2):340-349. Epub 2019 Sep 5.

Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan. Electronic address:

Galactose-deficient IgA1 (Gd-IgA1) plays a crucial role in the development of IgA nephropathy (IgAN). However, the pathogenic mechanisms driving Gd-IgA1 production have not been fully elucidated. Innate-immune activation via Toll-like receptor 9 (TLR9) is known to be involved in Gd-IgA1 production. A proliferation inducing ligand (APRIL) and IL-6 are also known to enhance Gd-IgA1 synthesis in IgAN. With this as background, we investigated how TLR9 activation in IgA secreting cells results in overproduction of nephritogenic IgA in the IgAN-prone ddY mouse and in human IgA1-secreting cells. Injection of the TLR9 ligand CpG-oligonucleotides increased production of aberrantly glycosylated IgA and IgG-IgA immune complexes in ddY mice that, in turn, exacerbated kidney injury. CpG-oligonucleotide-stimulated mice had elevated serum levels of APRIL that correlated with those of aberrantly glycosylated IgA and IgG-IgA immune complexes. In vitro, TLR9 activation enhanced production of the nephritogenic IgA as well as APRIL and IL-6 in splenocytes of ddY mice and in human IgA1-secreting cells. However, siRNA knock-down of APRIL completely suppressed overproduction of Gd-IgA1 induced by IL-6. Neutralization of IL-6 decreased CpG-oligonucleotide-induced overproduction of Gd-IgA1. Furthermore, APRIL and IL-6 pathways each independently mediated TLR9-induced overproduction of Gd-IgA1. Thus, TLR9 activation enhanced synthesis of aberrantly glycosylated IgA that, in a mouse model of IgAN, further enhanced kidney injury. Hence, APRIL and IL-6 synergistically, as well as independently, enhance synthesis of Gd-IgA1.
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http://dx.doi.org/10.1016/j.kint.2019.08.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7372907PMC
February 2020

Transcripts from downstream alternative transcription start sites evade uORF-mediated inhibition of gene expression in .

Proc Natl Acad Sci U S A 2018 07 18;115(30):7831-7836. Epub 2018 Jun 18.

Synthetic Genomics Research Group, RIKEN Center for Sustainable Resource Science, 230-0045 Yokohama, Japan;

Plants adapt to alterations in light conditions by controlling their gene expression profiles. Expression of light-inducible genes is transcriptionally induced by transcription factors such as HY5. However, few detailed analyses have been carried out on the control of transcription start sites (TSSs). Of the various wavelengths of light, it is blue light (BL) that regulates physiological responses such as hypocotyl elongation and flowering time. To understand how gene expression is controlled not only by transcript abundance but also by TSS selection, we examined genome-wide TSS profiles in seedlings after exposure to BL irradiation following initial growth in the dark. Thousands of genes use multiple TSSs, and some transcripts have upstream ORFs (uORFs) that take precedence over the main ORF (mORF) encoding proteins. The uORFs often function as translation inhibitors of the mORF or as triggers of nonsense-mediated mRNA decay (NMD). Transcription from TSSs located downstream of the uORFs in 220 genes is enhanced by BL exposure. This type of regulation is found in and , major regulators of light-dependent gene expression. Translation efficiencies of the genes showing enhanced usage of these TSSs increased upon BL exposure. We also show that transcripts from TSSs upstream of uORFs in 45 of the 220 genes, including , accumulated in a mutant of NMD. These results suggest that BL controls gene expression not only by enhancing transcriptions but also by choosing the TSS, and transcripts from downstream TSSs evade uORF-mediated inhibition to ensure high expression of light-regulated genes.
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http://dx.doi.org/10.1073/pnas.1804971115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6064979PMC
July 2018

Screening of fungi for decomposition of lignin-derived products from Japanese cedar.

J Biosci Bioeng 2018 Nov 28;126(5):573-579. Epub 2018 May 28.

RIKEN Center for Sustainable Resource Science, Yokohama, Kanagawa 230-0045, Japan. Electronic address:

Lignin is an aromatic polymer that makes a network by intertwining between cellulose fibers in plant. As the lignin network retards access to carbohydrates, it is regarded as a nuisance during biomass processing. When wood is processed into paper pulp or bioethanol, lignin is produced as a by-product and utilized as fuel or a soil amendment. Recently, there has been much interest in the aromatic structure of lignin in relation to the utilization of lignocellulose and the search for petroleum substitutes. Sulfur-free pulping methods, such as soda-anthraquinone cooking, provide more opportunity for using lignin than the alternative kraft process. Our aim was to expand the availability of soda lignin from Japanese cedar, the most planted tree in Japan, by fungal degradation. We performed degradation assays to identify suitable fungi for the efficient breakdown of soda lignin from cedar. Fourteen fungi from both white-rot and leaf-litter fungi were identified using the RBBR and Sundman and Näse assays. By nuclear magnetic resonance analysis we obtained water- and/or methanol-soluble degradation products from four fungi, and the patterns indicate specific degradation mechanisms for each fungi. These results suggest that the screened fungi have more than one mechanism for degrading soda lignin from Japanese cedar.
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http://dx.doi.org/10.1016/j.jbiosc.2018.05.001DOI Listing
November 2018

Identifying the target genes of SUPPRESSOR OF GAMMA RESPONSE 1, a master transcription factor controlling DNA damage response in Arabidopsis.

Plant J 2018 05 24;94(3):439-453. Epub 2018 Mar 24.

Graduate School of Biological Sciences, Nara Institute of Science and Technology, Ikoma, Nara, 630-0192, Japan.

In mammalian cells, the transcription factor p53 plays a crucial role in transmitting DNA damage signals to maintain genome integrity. However, in plants, orthologous genes for p53 and checkpoint proteins are absent. Instead, the plant-specific transcription factor SUPPRESSOR OF GAMMA RESPONSE 1 (SOG1) controls most of the genes induced by gamma irradiation and promotes DNA repair, cell cycle arrest, and stem cell death. To date, the genes directly controlled by SOG1 remain largely unknown, limiting the understanding of DNA damage signaling in plants. Here, we conducted a microarray analysis and chromatin immunoprecipitation (ChIP)-sequencing, and identified 146 Arabidopsis genes as direct targets of SOG1. By using ChIP-sequencing data, we extracted the palindromic motif [CTT(N) AAG] as a consensus SOG1-binding sequence, which mediates target gene induction in response to DNA damage. Furthermore, DNA damage-triggered phosphorylation of SOG1 is required for efficient binding to the SOG1-binding sequence. Comparison between SOG1 and p53 target genes showed that both transcription factors control genes responsible for cell cycle regulation, such as CDK inhibitors, and DNA repair, whereas SOG1 preferentially targets genes involved in homologous recombination. We also found that defense-related genes were enriched in the SOG1 target genes. Consistent with this finding, SOG1 is required for resistance against the hemi-biotrophic fungus Colletotrichum higginsianum, suggesting that SOG1 has a unique function in controlling the immune response.
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http://dx.doi.org/10.1111/tpj.13866DOI Listing
May 2018

Construction of Pará rubber tree genome and multi-transcriptome database accelerates rubber researches.

BMC Genomics 2018 01 19;19(Suppl 1):922. Epub 2018 Jan 19.

Synthetic Genomics Research Group, Biomass Engineering Research Division, RIKEN Center for Sustainable Resource Science (CSRS), 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa, 230-0045, Japan.

Background: Natural rubber is an economically important material. Currently the Pará rubber tree, Hevea brasiliensis is the main commercial source. Little is known about rubber biosynthesis at the molecular level. Next-generation sequencing (NGS) technologies brought draft genomes of three rubber cultivars and a variety of RNA sequencing (RNA-seq) data. However, no current genome or transcriptome databases (DB) are organized by gene.

Results: A gene-oriented database is a valuable support for rubber research. Based on our original draft genome sequence of H. brasiliensis RRIM600, we constructed a rubber tree genome and transcriptome DB. Our DB provides genome information including gene functional annotations and multi-transcriptome data of RNA-seq, full-length cDNAs including PacBio Isoform sequencing (Iso-Seq), ESTs and genome wide transcription start sites (TSSs) derived from CAGE technology. Using our original and publically available RNA-seq data, we calculated co-expressed genes for identifying functionally related gene sets and/or genes regulated by the same transcription factor (TF). Users can access multi-transcriptome data through both a gene-oriented web page and a genome browser. For the gene searching system, we provide keyword search, sequence homology search and gene expression search; users can also select their expression threshold easily.

Conclusion: The rubber genome and transcriptome DB provides rubber tree genome sequence and multi-transcriptomics data. This DB is useful for comprehensive understanding of the rubber transcriptome. This will assist both industrial and academic researchers for rubber and economically important close relatives such as R. communis, M. esculenta and J. curcas. The Rubber Transcriptome DB release 2017.03 is accessible at http://matsui-lab.riken.jp/rubber/ .
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http://dx.doi.org/10.1186/s12864-017-4333-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5780850PMC
January 2018

IgA nephropathy and IgA vasculitis with nephritis have a shared feature involving galactose-deficient IgA1-oriented pathogenesis.

Kidney Int 2018 03 10;93(3):700-705. Epub 2018 Jan 10.

Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan. Electronic address:

Galactose-deficient IgA1 has been proposed as an important effector molecule in IgA nephropathy (IgAN). We previously showed that the galactose-deficient IgA1-specific monoclonal antibody KM55 can detect circulating galactose-deficient IgA1 in patients with IgAN, enabling us to study the molecular roles of galactose-deficient IgA1. Herein, we further examined the pathophysiological significance of galactose-deficient IgA1 in glomerular deposits of patients with IgAN by immunohistochemistry using KM55. Immunostaining of galactose-deficient IgA1 with KM55 was performed in paraffin-embedded sections of renal biopsy specimens from 48 patients with IgAN and 49 patients with other renal diseases such as lupus nephritis, HCV-related nephropathy, IgA vasculitis with nephritis (IgA-VN), and membranous nephropathy. Glomerular galactose-deficient IgA1 was specifically detected in IgAN and IgA-VN but not in the other renal diseases. Galactose-deficient IgA1 was localized predominantly in the mesangial region as IgA deposition. However, galactose-deficient IgA1 was not detected in patients with lupus nephritis accompanied by glomerular IgA deposition. Thus, our study strongly suggests that IgAN and IgA-VN have a shared feature regarding galactose-deficient IgA1-oriented pathogenesis.
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http://dx.doi.org/10.1016/j.kint.2017.10.019DOI Listing
March 2018

Serum galactose-deficient-IgA1 and IgG autoantibodies correlate in patients with IgA nephropathy.

PLoS One 2018 11;13(1):e0190967. Epub 2018 Jan 11.

Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan.

IgA nephropathy is an autoimmune disease characterized by IgA1-containing glomerular immune deposits. We previously proposed a multi-hit pathogenesis model in which patients with IgA nephropathy have elevated levels of circulatory IgA1 with some O-glycans deficient in galactose (Gd-IgA1, autoantigen). Gd-IgA1 is recognized by anti-glycan IgG and/or IgA autoantibodies, resulting in formation of pathogenic immune complexes. Some of these immune complexes deposit in the kidney, activate mesangial cells, and incite glomerular injury leading to clinical presentation of IgA nephropathy. Several studies have demonstrated that elevated circulatory levels of either Gd-IgA1 or the corresponding autoantibodies predict progressive loss of renal clearance function. In this study we assessed a possible association between serum levels of Gd-IgA1 and IgG or IgA autoantibodies specific for Gd-IgA1 in serum samples from 135 patients with biopsy-proven IgA nephropathy, 76 patients with other renal diseases, and 106 healthy controls. Our analyses revealed a correlation between the concentrations of the autoantigen and the corresponding IgG autoantibodies in sera of patients with IgA nephropathy, but not of disease or healthy controls. Moreover, our data suggest that IgG is the predominant isotype of Gd-IgA1-specific autoantibodies in IgA nephropathy. This work highlights the importance of both initial hits in the pathogenesis of IgA nephropathy.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0190967PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5764330PMC
February 2018

On-treatment decrease of NKG2D correlates to early emergence of clinically evident hepatocellular carcinoma after interferon-free therapy for chronic hepatitis C.

PLoS One 2017 15;12(6):e0179096. Epub 2017 Jun 15.

Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, Japan.

Background And Aims: Interferon (IFN)- free direct antiviral agents (DAAs) with rapid HCV eradication might evoke immunological reconstitutions, and some early recurrences of HCC after IFN-free DAAs have been reported. This study aimed to investigate whether natural killer group 2, member D (NKG2D) predicts early emergence of HCC after IFN-free DAAs.

Methods: We conducted a clinical practice-based observational study of 101 patients infected with genotype 1 HCV who received IFN-free (DAAs), and stratified them into those who did or did not develop early (i.e., during the 6-month surveillance period following treatment.) recurrence or occurrence of clinically evident HCC. We also analyzed the peripheral blood mononuclear cells, both before treatment and at end of treatment (EOT), of 24 of the patients who received IFN-free DAAs, and 16 who received IFN-combined protease inhibitor.

Results: We found early emergence of clinically evident HCC after IFN-free DAAs in 12 (12%) patients. Higher pre-treatment NKG2D expression, higher FIB-4 score, previous HCC history and failure to achieve sustained viral response were significant factors correlating to early HCC emergence. After IFN-free DAAs, a rapid decrease of NKG2D at EOT correlated with early HCC emergence in the IFN-free DAA-treated patients, but not in patients treated with the IFN-combined regimen. The decrease of NKG2D until EOT was predictive of early HCC emergence at a cut-off of -52% (AUC = 0.92).

Conclusions: On-treatment decrease of NKG2D may be a useful predictor of early emerging HCC in patients treated with IFN-free DAAs.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0179096PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5472371PMC
September 2017

Large-scale collection of full-length cDNA and transcriptome analysis in Hevea brasiliensis.

DNA Res 2017 Apr;24(2):159-167

Synthetic Genomics Research Group, Biomass Engineering Research Division, RIKEN Center for Sustainable Resource Science (CSRS), Yokohama, Kanagawa 230-0045, Japan.

Natural rubber has unique physical properties that cannot be replaced by products from other latex-producing plants or petrochemically produced synthetic rubbers. Rubber from Hevea brasiliensis is the main commercial source for this natural rubber that has a cis-polyisoprene configuration. For sustainable production of enough rubber to meet demand elucidation of the molecular mechanisms involved in the production of latex is vital. To this end, we firstly constructed rubber full-length cDNA libraries of RRIM 600 cultivar and sequenced around 20,000 clones by the Sanger method and over 15,000 contigs by Illumina sequencer. With these data, we updated around 5,500 gene structures and newly annotated around 9,500 transcription start sites. Second, to elucidate the rubber biosynthetic pathways and their transcriptional regulation, we carried out tissue- and cultivar-specific RNA-Seq analysis. By using our recently published genome sequence, we confirmed the expression patterns of the rubber biosynthetic genes. Our data suggest that the cytoplasmic mevalonate (MVA) pathway is the main route for isoprenoid biosynthesis in latex production. In addition to the well-studied polymerization factors, we suggest that rubber elongation factor 8 (REF8) is a candidate factor in cis-polyisoprene biosynthesis. We have also identified 39 transcription factors that may be key regulators in latex production. Expression profile analysis using two additional cultivars, RRIM 901 and PB 350, via an RNA-Seq approach revealed possible expression differences between a high latex-yielding cultivar and a disease-resistant cultivar.
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http://dx.doi.org/10.1093/dnares/dsw056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5397604PMC
April 2017

Evaluation of Long-Term Combination Therapy With Peritoneal Dialysis and Hemodialysis.

Ther Apher Dial 2017 Apr 10;21(2):180-184. Epub 2017 Feb 10.

Division of Nephrology, Department of Internal Medicine, Juntendo, University Faculty of Medicine, Tokyo, Japan.

It is well known that a combination therapy with peritoneal dialysis (PD) and hemodialysis (HD) is feasible and may improve clinical status in patients for whom adequate solute and fluid removal is difficult to achieve with PD alone. The objective of the present study was to evaluate whether the therapy is useful in the likelihood of long-term peritoneal membrane and cardiac function. The therapy was 6 days of PD and one session of HD per week. Physical, biochemical, dialysate-to-plasma ratio of creatinine (D/P Cr), arteriovenous fistula (AVF) blood flow, and left ventricular mass index (LVMI) data were prospectively analyzed in 30 patients with measurements performed at 0 and 6 months, and for 21 patients, 12 or 18 months after initiation of the therapy. The levels of hemoglobin (Hb) after therapy were significantly higher than those at the initiation of therapy. The levels of LVMI and human atrial natriuretic peptide (hANP) after therapy were significantly lower than those at the initiation of therapy, whereas AVF blood flow did not change significantly. D/P Cr levels at 6 months after the therapy were significantly lower than those at the initiation of therapy. D/P Cr levels at 12 or 18 months after the therapy were not aggravated. It appears that the therapy improves Hb levels and cardiac function because of adjusting body fluid status. It was indicated that peritoneal function after therapy may be improved. Therefore, combination therapy is useful from the lifestyle viewpoint of patients in the transition period of PD to HD with end-stage kidney disease.
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http://dx.doi.org/10.1111/1744-9987.12517DOI Listing
April 2017

Chemical-Induced Inhibition of Blue Light-Mediated Seedling Development Caused by Disruption of Upstream Signal Transduction Involving Cryptochromes in Arabidopsis thaliana.

Plant Cell Physiol 2017 01;58(1):95-105

Synthetic Genomics Research Group, Biomass Engineering Research Division, RIKEN Center for Sustainable Resource Science, Yokohama, Kanagawa, Japan.

Plants have a remarkable ability to perceive and respond to various wavelengths of light and initiate regulation of different cascades of light signaling and molecular components. While the perception of red light and the mechanisms of its signaling involving phytochromes are largely known, knowledge of the mechanisms of blue light signaling is still limited. Chemical genetics involves the use of diverse small active or synthetic molecules to evaluate biological processes. By combining chemicals and analyzing the effects they have on plant morphology, we identified a chemical, 3-bromo-7-nitroindazole (3B7N), that promotes hypocotyl elongation of wild-type Arabidopsis only under continuous blue light. Further evaluation with loss-of-function mutants confirmed that 3B7N inhibits photomorphogenesis through cryptochrome-mediated light signaling. Microarray analysis demonstrated that the effect of 3B7N treatment on gene expression in cry1cry2 is considerably smaller than that in the wild type, indicating that 3B7N specifically interrupts cryptochrome function in the control of seedling development in a light-dependent manner. We demonstrated that 3B7N directly binds to CRY1 protein using an in vitro binding assay. These results suggest that 3B7N is a novel chemical that directly inhibits plant cryptochrome function by physical binding. The application of 3B7N can be used on other plants to study further the blue light mechanism and the genetic control of cryptochromes in the growth and development of plant species.
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http://dx.doi.org/10.1093/pcp/pcw181DOI Listing
January 2017

The rubber tree genome shows expansion of gene family associated with rubber biosynthesis.

Sci Rep 2016 06 24;6:28594. Epub 2016 Jun 24.

Synthetic Genomics Research Group, RIKEN Center for Sustainable Resource Science, Biomass Engineering Research Division, Tsurumi, Yokohama, Kanagawa 230-0045, Japan.

Hevea brasiliensis Muell. Arg, a member of the family Euphorbiaceae, is the sole natural resource exploited for commercial production of high-quality natural rubber. The properties of natural rubber latex are almost irreplaceable by synthetic counterparts for many industrial applications. A paucity of knowledge on the molecular mechanisms of rubber biosynthesis in high yield traits still persists. Here we report the comprehensive genome-wide analysis of the widely planted H. brasiliensis clone, RRIM 600. The genome was assembled based on ~155-fold combined coverage with Illumina and PacBio sequence data and has a total length of 1.55 Gb with 72.5% comprising repetitive DNA sequences. A total of 84,440 high-confidence protein-coding genes were predicted. Comparative genomic analysis revealed strong synteny between H. brasiliensis and other Euphorbiaceae genomes. Our data suggest that H. brasiliensis's capacity to produce high levels of latex can be attributed to the expansion of rubber biosynthesis-related genes in its genome and the high expression of these genes in latex. Using cap analysis gene expression data, we illustrate the tissue-specific transcription profiles of rubber biosynthesis-related genes, revealing alternative means of transcriptional regulation. Our study adds to the understanding of H. brasiliensis biology and provides valuable genomic resources for future agronomic-related improvement of the rubber tree.
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http://dx.doi.org/10.1038/srep28594DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5008842PMC
June 2016

Impact of preoperative ultrasonography findings on the patency rate of vascular access in Japanese hemodialysis patients.

Springerplus 2016 14;5:462. Epub 2016 Apr 14.

Division of Nephrology, Department of Internal Medicine, Juntendo University Faculty of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421 Japan ; Medical Corporation SHOWAKAI, Tokyo, Japan.

Background: Although ultrasonography before a vascular access (VA) operation has become popular in recent years, benchmarks for the diameter or blood flow of arteries or veins are not defined in Japan. The objective of the present study is to analyze the relationship between preoperative US findings and the patency rate of VA in Japanese hemodialysis patients.

Methods: 139 patients with end stage kidney disease were enrolled in this study. They had been given primary radiocephalic arteriovenous fistula (AVF) from February 2009 to December 2010 at the Juntendo University Hospital and were followed up over 2 years. We defined the interval from the time of AVF creation until first access thrombosis or any intervention to maintain or restore blood flow as patency time (primary patency). We examined the correlation between the 2-year primary patency rate of VA and the diameter of the radial artery (RA), brachial artery (BA), or cephalic vein at an anastomosis presumptive region by US, the blood flow of RA or BA, as measured by US, age, gender, and primary kidney diseases.

Results: The average patency term was 448.6 ± 271.3 days, with the 1-year and 2-year patency rate as 64.0 and 51.2 %, respectively. The patency rate was significantly lower in elderly patients over the age of 75 and in patients with diabetes mellitus. US findings of 2.0 mm or less in the RA diameter also resulted in a noticeably low patency rate. A multivariate analysis indicated that those factors were risk factors for early VA failure.

Conclusions: Preoperative US findings of the diameter of RA may involve the patency rate of VA, making it appears that an RA of 2.0 mm or more in diameter at an anastomosis region may be more effective for the improvement in the patency rate of VA.
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http://dx.doi.org/10.1186/s40064-016-2082-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4831953PMC
April 2016

Functional and expression analyses of transcripts based on full-length cDNAs of Sorghum bicolor.

DNA Res 2015 Dec 5;22(6):485-93. Epub 2015 Nov 5.

Synthetic Genomics Research Group, Biomass Engineering Research Division, RIKEN Center for Sustainable Resource Science, Yokohama, Kanagawa 230-0045, Japan

Sorghum bicolor is one of the most important crops for food and bioethanol production. Its small diploid genome and resistance to environmental stress make sorghum an attractive model for studying the functional genomics of the Saccharinae and other C4 grasses. We analyzed the domain-based functional annotation of the cDNAs using the gene ontology (GO) categories for molecular function to characterize all the genes cloned in the full-length cDNA library of sorghum. The sorghum cDNA library successfully captured a wide range of cDNA-encoded proteins with various functions. To characterize the protein function of newly identified cDNAs, a search of their deduced domains and comparative analyses in the Oryza sativa and Zea mays genomes were carried out. Furthermore, genes on the sense strand corresponding to antisense transcripts were classified based on the GO of molecular function. To add more information about these genes, we have analyzed the expression profiles using RNA-Seq of three tissues (spikelet, seed and stem) during the starch-filling phase. We performed functional analysis of tissue-specific genes and expression analysis of genes of starch biosynthesis enzymes. This functional analysis of sorghum full-length cDNAs and the transcriptome information will facilitate further analysis of the Saccharinae and grass families.
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http://dx.doi.org/10.1093/dnares/dsv030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4675717PMC
December 2015

Novel lectin-independent approach to detect galactose-deficient IgA1 in IgA nephropathy.

Nephrol Dial Transplant 2015 Aug 23;30(8):1315-21. Epub 2015 Jun 23.

Division of Nephrology, Department of Internal Medicine, Juntendo University Faculty of Medicine, Tokyo, Japan.

Background: Galactose-deficient IgA1 (Gd-IgA1) is a critical effector molecule in the pathogenesis of IgA nephropathy (IgAN). Although many researchers have measured serum levels of Gd-IgA1 using snail helix aspersa agglutinin (HAA) lectin-based assay, the lectin-dependent assay has some serious problems in robustness. In this study, we aimed to establish a more robust and stable enzyme-linked immunosorbent assay (ELISA) method that uses a specific monoclonal antibody to recognize a hinge region in human Gd-IgA1 (Gd-IgA1 ELISA).

Methods: Rats were immunized with human Gd-IgA1 hinge region peptide to obtain Gd-IgA1-specific monoclonal antibody KM55. Gd-IgA1 ELISA for specifically detecting serum Gd-IgA1 was consequently constructed. Serum Gd-IgA1 concentrations in human subjects were measured using KM55 ELISA assay. To further confirm specificity of the Gd-IgA1-specific antibody, KM55 was also applied for immunofluorescence staining of glomerular Gd-IgA1 in paraffin-embedded sections of renal biopsy specimens.

Results: Measurement of serum levels of Gd-IgA1 in human subjects by Gd-IgA1 ELISA revealed increased serum Gd-IgA1 level in patients with IgAN compared with patients with other renal diseases or non-renal diseases. Importantly, the results obtained from Gd-IgA1 ELISA positively correlated with those from the HAA lectin-based assay (R = 0.75). Immunofluorescence staining of renal biopsy specimens with KM55 detected glomerular co-localization of Gd-IgA1 and IgA.

Conclusion: This novel lectin-independent method with KM55 for measuring serum levels of Gd-IgA1 can pave the way for more convincing diagnosis and activity assessment of IgAN, and can expedite clinical research to better understand this difficult disease.
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http://dx.doi.org/10.1093/ndt/gfv221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4513896PMC
August 2015

Next-generation sequencing of genomic DNA fragments bound to a transcription factor in vitro reveals its regulatory potential.

Genes (Basel) 2014 Dec 19;5(4):1115-31. Epub 2014 Dec 19.

Synthetic Genomics Research Team, Biomass Engineering Program Cooperation Division, RIKEN Center for Sustainable Resource Science, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa, 230-0045, Japan.

Several transcription factors (TFs) coordinate to regulate expression of specific genes at the transcriptional level. In Arabidopsis thaliana it is estimated that approximately 10% of all genes encode TFs or TF-like proteins. It is important to identify target genes that are directly regulated by TFs in order to understand the complete picture of a plant's transcriptome profile. Here, we investigate the role of the LONG HYPOCOTYL5 (HY5) transcription factor that acts as a regulator of photomorphogenesis. We used an in vitro genomic DNA binding assay coupled with immunoprecipitation and next-generation sequencing (gDB-seq) instead of the in vivo chromatin immunoprecipitation (ChIP)-based methods. The results demonstrate that the HY5-binding motif predicted here was similar to the motif reported previously and that in vitro HY5-binding loci largely overlapped with the HY5-targeted candidate genes identified in previous ChIP-chip analysis. By combining these results with microarray analysis, we identified hundreds of HY5-binding genes that were differentially expressed in hy5. We also observed delayed induction of some transcripts of HY5-binding genes in hy5 mutants in response to blue-light exposure after dark treatment. Thus, an in vitro gDNA-binding assay coupled with sequencing is a convenient and powerful method to bridge the gap between identifying TF binding potential and establishing function.
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http://dx.doi.org/10.3390/genes5041115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4276929PMC
December 2014

MOROKOSHI: transcriptome database in Sorghum bicolor.

Plant Cell Physiol 2015 Jan 9;56(1):e6. Epub 2014 Dec 9.

Synthetic Genomics Research Team, Biomass Research Cooperation Division (BMEP), RIKEN Center for Sustainable Resource Science (CSRS), 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa, 230-0045 Japan

In transcriptome analysis, accurate annotation of each transcriptional unit and its expression profile is essential. A full-length cDNA (FL-cDNA) collection facilitates the refinement of transcriptional annotation, and accurate transcription start sites help to unravel transcriptional regulation. We constructed a normalized FL-cDNA library from eight growth stages of aerial tissues in Sorghum bicolor and isolated 37,607 clones. These clones were Sanger sequenced from the 5' and/or 3' ends and in total 38,981 high-quality expressed sequence tags (ESTs) were obtained. About one-third of the transcripts of known genes were captured as FL-cDNA clone resources. In addition to these, we also annotated 272 novel genes, 323 antisense transcripts and 1,672 candidate isoforms. These clones are available from the RIKEN Bioresource Center. After obtaining accurate annotation of transcriptional units, we performed expression profile analysis. We carried out spikelet-, seed- and stem-specific RNA sequencing (RNA-Seq) analysis and confirmed the expression of 70.6% of the newly identified genes. We also downloaded 23 sorghum RNA-Seq samples that are publicly available and these are shown on a genome browser together with our original FL-cDNA and RNA-Seq data. Using our original and publicly available data, we made an expression profile of each gene and identified the top 20 genes with the most similar expression. In addition, we visualized their relationships in gene co-expression networks. Users can access and compare various transcriptome data from S, bicolor at http://sorghum.riken.jp.
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http://dx.doi.org/10.1093/pcp/pcu187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4301747PMC
January 2015

Diagnosis and activity assessment of immunoglobulin A nephropathy: current perspectives on noninvasive testing with aberrantly glycosylated immunoglobulin A-related biomarkers.

Int J Nephrol Renovasc Dis 2014 30;7:409-14. Epub 2014 Oct 30.

Division of Nephrology, Department of Internal Medicine, Juntendo University Faculty of Medicine, Tokyo.

Immunoglobulin (Ig) A nephropathy (IgAN) is the most common form of glomerular disease worldwide and is associated with a poor prognosis. Thus, development of a curative treatment and strategies for early diagnosis and treatment are urgently needed. Pathological analysis of renal biopsy is the gold standard for the diagnosis and assessment of disease activity; however, immediate and frequent assessment based on biopsy specimens is difficult. Therefore, a simple and safe alternative is desirable. On the other hand, it is now widely accepted that multi-hit steps, including production of aberrantly glycosylated serum IgA1 (first hit), and IgG or IgA autoantibodies that recognize glycan containing epitopes on glycosylated serum IgA1 (second hit) and their subsequent immune complex formation (third hit) and glomerular deposition (fourth hit), are required for continued progression of IgAN. Although the prognostic and predictive values of several markers have been discussed elsewhere, we recently developed a highly sensitive and specific diagnostic method by measuring serum levels of glycosylated serum IgA1 and related IgA immune complex. In addition, we confirmed a significant correlation between serum levels of these essential effector molecules and disease activity after treatment, suggesting that each can be considered as a practical surrogate marker of therapeutic effects in this slowly progressive disease. Such a noninvasive diagnostic and activity assessment method using these disease-oriented specific biomarkers may be useful in the early diagnosis of and intervention in IgAN, with appropriate indication for treatment, and thus aid in the future development and dissemination of specific and curative treatments.
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http://dx.doi.org/10.2147/IJNRD.S50513DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4219541PMC
November 2014

A panel of serum biomarkers differentiates IgA nephropathy from other renal diseases.

PLoS One 2014 23;9(5):e98081. Epub 2014 May 23.

Division of Nephrology, Department of Internal Medicine, Juntendo University Faculty of Medicine, Tokyo, Japan.

Background And Objectives: There is increasing evidence that galactose-deficient IgA1 (Gd-IgA1) and Gd-IgA1-containing immune complexes are important for the pathogenesis of IgA nephropathy (IgAN). In the present study, we assessed a novel noninvasive multi-biomarker approach in the diagnostic test for IgAN.

Materials And Methods: We compared serum levels of IgA, IgG, Gd-IgA1, Gd-IgA1-specific IgG and Gd-IgA1-specific IgA in 135 IgAN patients, 79 patients with non-IgAN chronic kidney disease (CKD) controls and 106 healthy controls. Serum was collected at the time of kidney biopsy from all IgAN and CKD patients.

Results: Each serum marker was significantly elevated in IgAN patients compared to CKD (P<0.001) and healthy controls (P<0.001). While 41% of IgAN patients had elevated serum Gd-IgA1 levels, 91% of these patients exhibited Gd-IgA1-specific IgG levels above the 90th percentile for healthy controls (sensitivity 89%, specificity 92%). Although up to 25% of CKD controls, particularly those with immune-mediated glomerular diseases including lupus nephritis, also had elevated serum levels of Gd-IgA1-specific IgG, most IgAN patients had elevated levels of Gd-IgA1-specific antibody of both isotypes. Serum levels of Gd-IgA1-specific IgG were associated with renal histological grading. Furthermore, there was a trend toward higher serum levels of Gd-IgA1-specific IgG in IgAN patients with at least moderate proteinuria (≥1.0 g/g), compared to patients with less proteinuria.

Conclusions: Serum levels of Gd-IgA1-specific antibodies are elevated in most IgAN patients, and their assessment, together with serum levels of Gd-IgA1, improves the specificity of the assays. Our observations suggest that a panel of serum biomarkers may be helpful in differentiating IgAN from other glomerular diseases.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0098081PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4032235PMC
February 2015

Database construction for PromoterCAD: synthetic promoter design for mammals and plants.

ACS Synth Biol 2014 Mar 6;3(3):192-6. Epub 2014 Jan 6.

Integrated Database Unit, Advanced Center for Computing and Communication (ACCC), RIKEN , 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.

Synthetic promoters can control a gene's timing, location, and expression level. The PromoterCAD web server ( http://promotercad.org ) allows the design of synthetic promoters to control plant gene expression, by novel arrangement of cis-regulatory elements. Recently, we have expanded PromoterCAD's scope with additional plant and animal data: (1) PLACE (Plant Cis-acting Regulatory DNA Elements), including various sized sequence motifs; (2) PEDB (Mammalian Promoter/Enhancer Database), including gene expression data for mammalian tissues. The plant PromoterCAD data now contains 22 000 Arabidopsis thaliana genes, 2 200 000 microarray measurements in 20 growth conditions and 79 tissue organs and developmental stages, while the new mammalian PromoterCAD data contains 679 Mus musculus genes and 65 000 microarray measurements in 96 tissue organs and cell types ( http://promotercad.org/mammal/ ). This work presents step-by-step instructions for adding both regulatory motif and gene expression data to PromoterCAD, to illustrate how users can expand PromoterCAD functionality for their own applications and organisms.
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http://dx.doi.org/10.1021/sb400178cDOI Listing
March 2014

Variable procedural strategies adapted to anatomical characteristics in catheter ablation of the cavotricuspid isthmus using a preoperative multidetector computed tomography analysis.

J Cardiovasc Electrophysiol 2013 Dec;24(12):1344-51

Objectives: This study aimed to investigate the anatomical characteristics complicating cavotricuspid isthmus (CTI) ablation and the effectiveness of various procedural strategies.

Methods And Results: This study included 446 consecutive patients (362 males; mean age 60.5 ± 10.4 years) in whom CTI ablation was performed. A total of 80 consecutive patients were evaluated in a preliminary study. The anatomy of the CTI was evaluated by multidetector row-computed tomography (MDCT) prior to the procedure. A multivariate logistic regression analysis revealed that the angle and mean wall thickness of the CTI, a concave CTI morphology, and a prominent Eustachian ridge, were associated with a difficult CTI ablation (P < 0.01). In the main study, 366 consecutive patients were divided into 2 groups: a modulation group (catheter inversion technique for a concave aspect, prominent Eustachian ridge, and steep angle of the CTI or increased output for a thicker CTI) and nonmodulation group (conventional strategy). The duration and total amount of radiofrequency energy delivered were significantly shorter and smaller in the modulation group than those in the nonmodulation group (162.2 ± 153.5 vs 222.7 ± 191.9 seconds, P < 0.01, and 16,962.4 ± 11,545.6 vs 24,908.5 ± 22,804.2 J, P < 0.01, respectively). The recurrence rate of type 1 atrial flutter after the CTI ablation in the nonmodulation group was significantly higher than that in the modulation group (6.3 vs 1.7%, P = 0.02).

Conclusion: Changing the procedural strategies by adaptating them to the anatomical characteristics improved the outcomes of the CTI ablation.
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http://dx.doi.org/10.1111/jce.12231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4229059PMC
December 2013

PromoterCAD: Data-driven design of plant regulatory DNA.

Nucleic Acids Res 2013 Jul 12;41(Web Server issue):W569-74. Epub 2013 Jun 12.

Bioinformatics and Systems Engineering Division, RIKEN, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.

Synthetic promoters can control the timing, location and amount of gene expression for any organism. PromoterCAD is a web application for designing synthetic promoters with altered transcriptional regulation. We use a data-first approach, using published high-throughput expression and motif data from for Arabidopsis thaliana to guide DNA design. We demonstrate data mining tools for finding motifs related to circadian oscillations and tissue-specific expression patterns. PromoterCAD is built on the LinkData open platform for data publication and rapid web application development, allowing new data to be easily added, and the source code modified to add new functionality. PromoterCAD URL: http://promotercad.org. LinkData URL: http://linkdata.org.
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http://dx.doi.org/10.1093/nar/gkt518DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3692106PMC
July 2013

PosMed: Ranking genes and bioresources based on Semantic Web Association Study.

Nucleic Acids Res 2013 Jul 12;41(Web Server issue):W109-14. Epub 2013 Jun 12.

Bioinformatics and Systems Engineering Division, RIKEN, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.

Positional MEDLINE (PosMed; http://biolod.org/PosMed) is a powerful Semantic Web Association Study engine that ranks biomedical resources such as genes, metabolites, diseases and drugs, based on the statistical significance of associations between user-specified phenotypic keywords and resources connected directly or inferentially through a Semantic Web of biological databases such as MEDLINE, OMIM, pathways, co-expressions, molecular interactions and ontology terms. Since 2005, PosMed has long been used for in silico positional cloning studies to infer candidate disease-responsible genes existing within chromosomal intervals. PosMed is redesigned as a workbench to discover possible functional interpretations for numerous genetic variants found from exome sequencing of human disease samples. We also show that the association search engine enhances the value of mouse bioresources because most knockout mouse resources have no phenotypic annotation, but can be associated inferentially to phenotypes via genes and biomedical documents. For this purpose, we established text-mining rules to the biomedical documents by careful human curation work, and created a huge amount of correct linking between genes and documents. PosMed associates any phenotypic keyword to mouse resources with 20 public databases and four original data sets as of May 2013.
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http://dx.doi.org/10.1093/nar/gkt474DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3692089PMC
July 2013

Pulmonary artery mapping for differential diagnosis of left-sided atrial tachycardia.

Circ J 2013 26;77(2):345-51. Epub 2012 Oct 26.

Department of Cardiovascular Medicine, Hiroshima University Graduate School of Biomedical Science, Hiroshima 734-8551, Japan.

Background: Distinguishing left-and right-sided atrial tachycardia (AT) is often challenging. The coronary sinus (CS) provides information only concerning the anterior left atrium (LA). Potentials recorded in the pulmonary artery (PA) have been substituted for those of the upper posterior LA because of their anatomical relationship.

Methods And Results: Three patterns were designed, using potentials in the PA, right atrium (RA) and CS, to predict the side of AT. Two patterns were for left-sided AT and 1 pattern was for right-sided AT. Ten left-sided and 11 right-sided ATs were investigated regardless of mechanism. Electrode catheters were inserted in the RA, His bundle region, and CS, and an ablation catheter was inserted into the left and/or right PA. The sequences from these catheters were analyzed before detailed electroanatomical mapping. Patterns were obtained for 20 of 21 ATs. The mechanism was focal in 16 ATs and macroreentry in 5. The method predicted left-sided AT with a sensitivity of 78%, a specificity of 100%, a positive predictive value of 100%, a negative predictive value of 84%, and an accuracy of 90%.

Conclusions: The use of potentials in PA combined with conventional RA and CS electrograms is useful for distinguishing left-sided AT from right-sided AT, regardless of mechanism.
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http://dx.doi.org/10.1253/circj.cj-12-0698DOI Listing
August 2013