2021/10/25 更新

写真a

オクダ シュウジロウ
奥田 修二郎
OKUDA Shujiro
所属
教育研究院 医歯学系 医学系列 教授
医歯学総合研究科 教授
職名
教授
外部リンク

学位

  • 博士(理学) ( 2007年5月   京都大学 )

研究キーワード

  • 環境ゲノミクス

  • バイオインフォマティクス

  • Environmental Genomics

  • Database

  • Bioinformatics

  • データベース

研究分野

  • ライフサイエンス / ゲノム生物学

  • ライフサイエンス / 生物物理学

  • ライフサイエンス / 生態学、環境学

  • ライフサイエンス / 遺伝学

  • ライフサイエンス / システムゲノム科学

経歴(researchmap)

  • 立命館大学 総合理工学院・生命科学部 生命情報学科 総合理工学院・生命科学部 生命情報学科   助教

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経歴

  • 新潟大学   医歯学総合研究科   教授

    2021年4月 - 現在

  • 新潟大学   教育研究院 医歯学系 医学系列   教授

    2021年4月 - 現在

  • 新潟大学   医歯学総合研究科 分子細胞医学専攻 新領域開拓研究センター   准教授

    2017年4月 - 2021年3月

  • 新潟大学   研究推進機構   准教授

    2016年4月 - 2017年3月

  • 新潟大学   経営戦略本部 若手研究者育成推進室   准教授

    2013年2月 - 2016年3月

学歴

  • 京都大学

    - 2006年

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  • 京都大学   理学研究科   生物科学専攻

    2001年 - 2006年

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    国名: 日本国

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  • 京都大学

    - 2003年

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  • 立命館大学   理工学部   生物工学科

    1997年 - 2001年

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    国名: 日本国

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  • 立命館大学

    - 2001年

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所属学協会

  • 日本微生物生態学会

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  • Japanese Society for Bioinformatics

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  • Molecular Biology Society of Japan

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  • The Japanese Society of Microbial Ecology

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  • 日本バイオインフォマティクス学会

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  • 日本分子生物学会

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▶ 全件表示

 

論文

  • Development of Novel PCR Assays for Improved Detection of Enterovirus D68. 国際誌

    Tatsuki Ikuse, Yuta Aizawa, Hayato Takihara, Shujiro Okuda, Kanako Watanabe, Akihiko Saitoh

    Journal of clinical microbiology   JCM0115121   2021年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Enterovirus D68 (EV-D68) causes a range of clinical manifestations, including asthma-like illness, severe respiratory disease, and acute flaccid myelitis. EV-D68 has caused worldwide outbreaks since 2014 and is now recognized as a re-emerging infection in many countries. EV-D68-specific PCR assays are widely used for the diagnosis of EV-D68 infection; however, assay sensitivity is a concern because of genetic changes in recently circulated EV-D68. To address this, we summarized EV-D68 sequences from previously reported world outbreaks from 2014 through 2020 on GenBank, and found several mutations at the primer and probe binding sites of the existing EV-D68-specific PCR assays. Subsequently, we designed two novel assays corresponding to the recently reported EV-D68 sequences: an EV-D68-specific real-time and semi-nested PCR. In an analysis of 22 EV-D68-confirmed cases during a recent EV-D68 outbreak in Japan, the new real-time PCR had higher sensitivity than the existing assay (100% vs. 45%, P < 0.01) and a lower median Ct value (27.8 vs. 32.8, P = 0.005). Sensitivity was higher for the new non-nested PCR (91%) than for the existing semi-nested PCR assay (50%, P < 0.01). The specificity of the new real-time PCR was 100% using samples from non-EV-D68-infected cases (n = 135). In conclusion, our novel assays had higher sensitivity than the existing assay and might lead to more accurate diagnosis of recently circulating EV-D68. To prepare for future EV-D68 outbreaks, EV-D68-specific assays must be continuously monitored and updated.

    DOI: 10.1128/JCM.01151-21

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  • Obesity-Related Gut Microbiota Aggravates Alveolar Bone Destruction in Experimental Periodontitis through Elevation of Uric Acid. 国際誌

    Keisuke Sato, Kyoko Yamazaki, Tamotsu Kato, Yumiko Nakanishi, Takahiro Tsuzuno, Mai Yokoji-Takeuchi, Miki Yamada-Hara, Nobuaki Miura, Shujiro Okuda, Hiroshi Ohno, Kazuhisa Yamazaki

    mBio   e0077121   2021年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Obesity is a risk factor for periodontal disease (PD). Initiation and progression of PD are modulated by complex interactions between oral dysbiosis and host responses. Although obesity is associated with increased susceptibility to bacterial infection, the detailed mechanisms that connect obesity and susceptibility to PD remain elusive. Using fecal microbiota transplantation and a ligature-induced PD model, we demonstrated that gut dysbiosis-associated metabolites from high-fat diet (HFD)-fed mice worsen alveolar bone destruction. Fecal metabolomics revealed elevated purine degradation pathway activity in HFD-fed mice, and recipient mice had elevated levels of serum uric acid upon PD induction. Furthermore, PD induction caused more severe bone destruction in hyperuricemic than normouricemic mice, and the worsened bone destruction was completely abrogated by allopurinol, a xanthine oxidase inhibitor. Thus, obesity increases the risk of PD by increasing production of uric acid mediated by gut dysbiosis. IMPORTANCE Obesity is an epidemic health issue with a rapid increase worldwide. It increases the risk of various diseases, including periodontal disease, an oral chronic infectious disease. Although obesity increases susceptibility to bacterial infection, the precise biological mechanisms that link obesity and susceptibility to periodontal disease remain elusive. Using fecal microbial transplantation, experimental periodontitis, and metabolomics, our study demonstrates uric acid as a causative substance for greater aggravation of alveolar bone destruction in obesity-related periodontal disease. Gut microbiota from obese mice upregulated the purine degradation pathway, and the resulting elevation of serum uric acid promoted alveolar bone destruction. The effect of uric acid was confirmed by administration of allopurinol, an inhibitor of xanthine oxidase. Overall, our study provides new insights into the pathogenic mechanisms of obesity-associated periodontal disease and the development of new therapeutic options for the disease.

    DOI: 10.1128/mBio.00771-21

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  • Histopathological characteristics and artificial intelligence for predicting tumor mutational burden-high colorectal cancer.

    Yoshifumi Shimada, Shujiro Okuda, Yu Watanabe, Yosuke Tajima, Masayuki Nagahashi, Hiroshi Ichikawa, Masato Nakano, Jun Sakata, Yasumasa Takii, Takashi Kawasaki, Kei-Ichi Homma, Tomohiro Kamori, Eiji Oki, Yiwei Ling, Shiho Takeuchi, Toshifumi Wakai

    Journal of gastroenterology   56 ( 6 )   547 - 559   2021年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Tumor mutational burden-high (TMB-H), which is detected with gene panel testing, is a promising biomarker for immune checkpoint inhibitors (ICIs) in colorectal cancer (CRC). However, in clinical practice, not every patient is tested for TMB-H using gene panel testing. We aimed to identify the histopathological characteristics of TMB-H CRC for efficient selection of patients who should undergo gene panel testing. Moreover, we attempted to develop a convolutional neural network (CNN)-based algorithm to predict TMB-H CRC directly from hematoxylin and eosin (H&E) slides. METHODS: We used two CRC cohorts tested for TMB-H, and whole-slide H&E digital images were obtained from the cohorts. The Japanese CRC (JP-CRC) cohort (N = 201) was evaluated to detect the histopathological characteristics of TMB-H using H&E slides. The JP-CRC cohort and The Cancer Genome Atlas (TCGA) CRC cohort (N = 77) were used to develop a CNN-based TMB-H prediction model from the H&E digital images. RESULTS: Tumor-infiltrating lymphocytes (TILs) were significantly associated with TMB-H CRC (P < 0.001). The area under the curve (AUC) for predicting TMB-H CRC was 0.910. We developed a CNN-based TMB-H prediction model. Validation tests were conducted 10 times using randomly selected slides, and the average AUC for predicting TMB-H slides was 0.934. CONCLUSIONS: TILs, a histopathological characteristic detected with H&E slides, are associated with TMB-H CRC. Our CNN-based model has the potential to predict TMB-H CRC directly from H&E slides, thereby reducing the burden on pathologists. These approaches will provide clinicians with important information about the applications of ICIs at low cost.

    DOI: 10.1007/s00535-021-01789-w

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  • Extracellular DNA of slow growers of mycobacteria and its contribution to biofilm formation and drug tolerance. 国際誌

    Aleksandr Ilinov, Akihito Nishiyama, Hiroki Namba, Yukari Fukushima, Hayato Takihara, Chie Nakajima, Anna Savitskaya, Gebremichal Gebretsadik, Mariko Hakamata, Yuriko Ozeki, Yoshitaka Tateishi, Shujiro Okuda, Yasuhiko Suzuki, Yuri S Vinnik, Sohkichi Matsumoto

    Scientific reports   11 ( 1 )   10953 - 10953   2021年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DNA is basically an intracellular molecule that stores genetic information and carries instructions for growth and reproduction in all cellular organisms. However, in some bacteria, DNA has additional roles outside the cells as extracellular DNA (eDNA), which is an essential component of biofilm formation and hence antibiotic tolerance. Mycobacteria include life-threating human pathogens, most of which are slow growers. However, little is known about the nature of pathogenic mycobacteria's eDNA. Here we found that eDNA is present in slow-growing mycobacterial pathogens, such as Mycobacterium tuberculosis, M. intracellulare, and M. avium at exponential growth phase. In contrast, eDNA is little in all tested rapid-growing mycobacteria. The physiological impact of disrupted eDNA on slow-growing mycobacteria include reduced pellicle formation, floating biofilm, and enhanced susceptibility to isoniazid and amikacin. Isolation and sequencing of eDNA revealed that it is identical to the genomic DNA in M. tuberculosis and M. intracellulare. In contrast, accumulation of phage DNA in eDNA of M. avium, suggests that the DNA released differs among mycobacterial species. Our data show important functions of eDNA necessary for biofilm formation and drug tolerance in slow-growing mycobacteria.

    DOI: 10.1038/s41598-021-90156-z

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  • Three-dimensional understanding of the morphological complexity of the human uterine endometrium. 国際誌

    Manako Yamaguchi, Kosuke Yoshihara, Kazuaki Suda, Hirofumi Nakaoka, Nozomi Yachida, Haruka Ueda, Kentaro Sugino, Yutaro Mori, Kaoru Yamawaki, Ryo Tamura, Tatsuya Ishiguro, Teiichi Motoyama, Yu Watanabe, Shujiro Okuda, Kazuki Tainaka, Takayuki Enomoto

    iScience   24 ( 4 )   102258 - 102258   2021年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The fundamental morphology of the endometrial glands is not sufficiently understood by 2D observation because these glands have complicated winding and branching patterns. To construct a large picture of the endometrial gland structure, we performed tissue-clearing-based 3D imaging of human uterine endometrial tissue. Our 3D immunohistochemistry and layer analyses revealed that the endometrial glands form a plexus network in the stratum basalis and expand horizontally along the muscular layer, similar to the rhizome of grass. We then extended our method to assess the 3D morphology of tissue affected by adenomyosis, a representative "endometrium-related disease," and observed its 3D morphological features, including the direct invasion of endometrial glands into the myometrium and an ant colony-like network of ectopic endometrial glands within the myometrium. Thus, further understanding of the morphology of the human endometrium based on 3D analysis will lead to the identification of the pathogenesis of endometrium-related diseases.

    DOI: 10.1016/j.isci.2021.102258

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  • Adipose most abundant 2 protein is a predictive marker for cisplatin sensitivity in cancers. 国際誌

    Kenya Kamimura, Takeshi Suda, Yasuo Fukuhara, Shujiro Okuda, Yu Watanabe, Takeshi Yokoo, Akihiko Osaki, Nobuo Waguri, Toru Ishikawa, Toshihiro Sato, Yutaka Aoyagi, Masaaki Takamura, Toshifumi Wakai, Shuji Terai

    Scientific reports   11 ( 1 )   6255 - 6255   2021年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Cisplatin (CDDP) is one of the chemotherapeutic drugs being used to treat various cancers. Although effective in many cases, as high doses of CDDP cause cytotoxic effects that may worsen patients' condition, therefore, a marker of sensitivity to CDDP is necessary to enhance the safety and efficiency of CDDP administration. This study focused on adipose most abundant 2 (APM2) to examine its potential as a marker of CDDP sensitivity. The relationship of APM2 expression with the mechanisms of CDDP resistance was examined in vitro and in vivo using hepatocellular carcinoma (HCC) cells, tissues and serum of HCC patients (n = 71) treated initially with intrahepatic arterial infusion of CDDP followed by surgical resection. The predictability of serum APM2 for CDDP sensitivity was assessed in additional 54 HCC patients and 14 gastric cancer (GC) patients. APM2 expression in CDDP-resistant HCC was significantly higher both in serum and the tissue. Bioinformatic analyses and histological analyses demonstrated upregulation of ERCC6L (DNA excision repair protein ERCC6-like) by APM2, which accounts for the degree of APM2 expression. The serum APM2 level and chemosensitivity for CDDP were assessed and cut-off value of serum APM2 for predicting the sensitivity to CDDP was determined to be 18.7 µg/mL. The value was assessed in HCC (n = 54) and GC (n = 14) patients for its predictability of CDDP sensitivity, resulted in predictive value of 77.3% and 100%, respectively. Our study demonstrated that APM2 expression is related to CDDP sensitivity and serum APM2 can be an effective biomarker of HCC and GC for determining the sensitivity to CDDP.Trial registration: This study was registered with the University Hospital Medical Information Network Clinical Trials Registry (UMIN000028487).

    DOI: 10.1038/s41598-021-85498-7

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  • Mutational signatures in squamous cell carcinoma of the lung. 国際誌

    Atsushi Osoegawa, Kazuki Takada, Tatsuro Okamoto, Seijiro Sato, Masayuki Nagahashi, Tetsuzo Tagawa, Masanori Tsuchida, Eiji Oki, Shujiro Okuda, Toshifumi Wakai, Masaki Mori

    Journal of thoracic disease   13 ( 2 )   1075 - 1082   2021年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Background: Tumor mutational burden (TMB) has been identified as one of the predictors for the response to anti-programmed cell death-1 (anti-PD-1) antibody therapy and reported to correlate with smoking history in lung adenocarcinoma. However, in squamous cell carcinoma of the lung, the association between TMB and clinicopathological background factors, such as smoking history, has not been reported, including in our previous study. The mutational signature is a tool to identify the mutagens that are contributing to the mutational spectrum of a tumor by investigating the pattern of DNA changes. Here, we analyzed the mutational signature in lung squamous cell carcinoma to identify mutagens affecting the TMB. Methods: Seven representative mutational signatures including signature 7 (SI7) [ultraviolet (UV)-related], SI4 (smoking), SI6/15 [mismatch repair (MMR)], SI2/13 [apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC)], and SI5 (clock-like) were analyzed in Japanese patients with lung squamous cell carcinoma (n=67) using data generated by next-generation sequencing consisting of a 415-gene panel. The relationships between signatures and clinico-pathological data including TMB and programmed death-ligand 1 (PD-L1) expression were analyzed. Results: Although the reconstructed mutational counts were small with targeted sequencing (median: 30.1, range: 13.3-98.7), the distributions of signatures were comparable among samples, with 56 cases containing more than four signatures. The smoking-related SI4 was found in 45 cases and was significantly related with pack-year index (PYI) (P=0.026). The reconstructed mutation counts were highly correlated with SI4 (r=0.51, P<0.0001), whereas the correlation was weak with SI6/15 (MMR-related) and SI2/13 (APOBEC-related). There was no mutational signature related with PD-L1 expression. Some patients exhibited unique signatures; the patient with the highest mutational counts had a MMR signature, and another patient with a prominent UV signature had occupational exposure to UV, as he was employed as a neon sign engineer. Conclusions: Mutational signatures can predict the cause of lung squamous cell carcinoma. Tobacco smoking is the mutagen most related with TMB.

    DOI: 10.21037/jtd-20-2602

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  • 【胆道癌診療の最前線】胆道癌のゲノム医療

    若井 俊文, 島田 能史, 奥田 修二郎, 栗山 洋子, 須貝 美佳, 中野 麻恵, 松本 瑛生, 廣瀬 雄己, 三浦 宏平, 滝沢 一泰, 市川 寛, 坂田 純

    消化器外科   44 ( 2 )   207 - 212   2021年2月

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    記述言語:日本語   出版者・発行元:(株)へるす出版  

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  • GlycoPOST realizes FAIR principles for glycomics mass spectrometry data. 国際誌

    Yu Watanabe, Kiyoko F Aoki-Kinoshita, Yasushi Ishihama, Shujiro Okuda

    Nucleic acids research   49 ( D1 )   D1523-D1528   2021年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    For the reproducibility and sustainability of scientific research, FAIRness (Findable, Accessible, Interoperable and Re-usable), with respect to the release of raw data obtained by researchers, is one of the most important principles underpinning the future of open science. In genomics and transcriptomics, the sharing of raw data from next-generation sequencers is made possible through public repositories. In addition, in proteomics, the deposition of raw data from mass spectrometry (MS) experiments into repositories is becoming standardized. However, a standard repository for such MS data had not yet been established in glycomics. With the increasing number of glycomics MS data, therefore, we have developed GlycoPOST (https://glycopost.glycosmos.org/), a repository for raw MS data generated from glycomics experiments. In just the first year since the release of GlycoPOST, 73 projects have already been registered by researchers around the world, and the number of registered projects is continuously growing, making a significant contribution to the future FAIRness of the glycomics field. GlycoPOST is a free resource to the community and accepts (and will continue to accept in the future) raw data regardless of vendor-specific formats.

    DOI: 10.1093/nar/gkaa1012

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  • Activin a Receptor Type 2A Mutation Affects the Tumor Biology of Microsatellite Instability-High Gastric Cancer. 国際誌

    Kizuki Yuza, Masayuki Nagahashi, Hiroshi Ichikawa, Takaaki Hanyu, Masato Nakajima, Yoshifumi Shimada, Takashi Ishikawa, Jun Sakata, Shiho Takeuchi, Shujiro Okuda, Yasunobu Matsuda, Manabu Abe, Kenji Sakimura, Kazuaki Takabe, Toshifumi Wakai

    Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract   2021年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Activin A receptor type 2A (ACVR2A) is one of the most frequently mutated genes in microsatellite instability-high (MSI-H) gastric cancer. However, the clinical relevance of the ACVR2A mutation in MSI-H gastric cancer patients remains unclear. The aims of this study were to explore the effect of ACVR2A mutation on the tumor behavior and to identify the clinicopathological characteristics of gastric cancer patients with ACVR2A mutations. METHODS: An in vitro study was performed to investigate the biological role of ACVR2A via CRISPR/Cas9-mediated ACVR2A knockout MKN74 human gastric cancer cells. One hundred twenty-four patients with gastric cancer were retrospectively analyzed, and relations between MSI status, ACVR2A mutations, and clinicopathological factors were evaluated. RESULTS: ACVR2A knockout cells showed less aggressive tumor biology than mock-transfected cells, displaying reduced proliferation, migration, and invasion (P < 0.05). MSI mutations were found in 10% (13/124) of gastric cancer patients, and ACVR2A mutations were found in 8.1% (10/124) of patients. All ACVR2A mutations were accompanied by MSI. The 5-year overall survival rates of ACVR2A wild-type patients and ACVR2A-mutated patients were 57% and 90%, respectively (P = 0.048). Multivariate analysis revealed that older age (P = 0.015), distant metastasis (P < 0.001), and ACVR2A wild-type status (P = 0.040) were independent prognostic factors for overall survival. CONCLUSIONS: Our study demonstrated that gastric cancer patients with ACVR2A mutation have a significantly better prognosis than those without. Dysfunction of ACVR2A in MKN74 human gastric cancer cells caused less aggressive tumor biology, indicating the importance of ACVR2A in the progression of MSI-H tumors.

    DOI: 10.1007/s11605-020-04889-9

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  • p62/SQSTM1-droplet serves as a platform for autophagosome formation and anti-oxidative stress response. 国際誌

    Shun Kageyama, Sigurdur Runar Gudmundsson, Yu-Shin Sou, Yoshinobu Ichimura, Naoki Tamura, Saiko Kazuno, Takashi Ueno, Yoshiki Miura, Daisuke Noshiro, Manabu Abe, Tsunehiro Mizushima, Nobuaki Miura, Shujiro Okuda, Hozumi Motohashi, Jin-A Lee, Kenji Sakimura, Tomoyuki Ohe, Nobuo N Noda, Satoshi Waguri, Eeva-Liisa Eskelinen, Masaaki Komatsu

    Nature communications   12 ( 1 )   16 - 16   2021年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Autophagy contributes to the selective degradation of liquid droplets, including the P-Granule, Ape1-complex and p62/SQSTM1-body, although the molecular mechanisms and physiological relevance of selective degradation remain unclear. In this report, we describe the properties of endogenous p62-bodies, the effect of autophagosome biogenesis on these bodies, and the in vivo significance of their turnover. p62-bodies are low-liquidity gels containing ubiquitin and core autophagy-related proteins. Multiple autophagosomes form on the p62-gels, and the interaction of autophagosome-localizing Atg8-proteins with p62 directs autophagosome formation toward the p62-gel. Keap1 also reversibly translocates to the p62-gels in a p62-binding dependent fashion to activate the transcription factor Nrf2. Mice deficient for Atg8-interaction-dependent selective autophagy show that impaired turnover of p62-gels leads to Nrf2 hyperactivation in vivo. These results indicate that p62-gels are not simple substrates for autophagy but serve as platforms for both autophagosome formation and anti-oxidative stress.

    DOI: 10.1038/s41467-020-20185-1

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  • The jPOST Repository as a Public Data Repository for Shotgun Proteomics. 国際誌

    Yu Watanabe, Akiyasu C Yoshizawa, Yasushi Ishihama, Shujiro Okuda

    Methods in molecular biology (Clifton, N.J.)   2259   309 - 322   2021年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    In recent years, mass spectrometry-based proteomics approach has made significant progress and the number of datasets related to various proteomics projects has increased worldwide. To promote the sharing and reuse of promising datasets, it is important to build an appropriate, high-quality public data repository. For this purpose, several repositories have already been created. The jPOST repository that we developed in 2016 has successfully implemented several unique features, such as fast file upload, flexible file management, and an easy-to-use interface. In addition, this repository is an official member of the ProteomeXchange Consortium established to facilitate standard data submission and global dissemination of mass spectrometry proteomics data. Our repository contributes to the global partnership for sharing and storing all the datasets related to various proteomics experiments.

    DOI: 10.1007/978-1-0716-1178-4_20

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  • Profiling of host genetic alterations and intra-tumor microbiomes in colorectal cancer

    Shujiro Okuda, Yoshifumi Shimada, Yosuke Tajima, Kizuki Yuza, Yuki Hirose, Hiroshi Ichikawa, Masayuki Nagahashi, Jun Sakata, Yiwei Ling, Nobuaki Miura, Mika Sugai, Yu Watanabe, Shiho Takeuchi, Toshifumi Wakai

    Computational and Structural Biotechnology Journal   19   3330 - 3338   2021年

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Elsevier BV  

    DOI: 10.1016/j.csbj.2021.05.049

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  • Gallincin ameliorates colitis-associated inflammation and barrier function in mice based on network pharmacology prediction. 国際誌

    De-Jun Cui, Xiao-Lan Yang, Shujiro Okuda, Yi-Wei Ling, Zhu-Xue Zhang, Qi Liu, Wen-Qiang Yuan, Fang Yan

    The Journal of international medical research   48 ( 12 )   300060520951023 - 300060520951023   2020年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    OBJECTIVE: To explore potential mechanisms and effects of gallincin on a mouse model of colitis induced by dextran sulfate sodium (DSS). METHODS: Network pharmacology analysis was used to predict the molecular mechanism of action of gallincin for treatment of colitis. Gallincin was administered orally to mice with DSS-induced colitis. Expression of tumor necrosis factor α (TNF-α), D-lactate, and interleukin-1β (IL-1β) and myeloperoxidase activity were assessed with real-time quantitative PCR and an enzyme-linked immunoassay, respectively. Expression of occludin, zonula occludens 1 (ZO-1), and phosphorylated extracellular signal-regulated protein kinase1/2 (p-ERK1/2) was analyzed with immunohistochemical staining and/or western blot assays. RESULTS: Using a network pharmacology approach, 12 mapping targets between gallincin and colitis were obtained, including ERK/mitogen-activated protein kinase. Further investigations in an experimental colitis mouse model showed that gallincin significantly ameliorated experimental colitis, reduced D-lactate levels, and remarkably increased occludin and ZO-1 expression, possibly in part by decreasing IL-1β, TNF-α, and p-ERK1/2 levels and inhibiting leukocyte penetration. CONCLUSIONS: Gallincin regulated colonic barrier function and reduced colitis-associated inflammation, suggesting it is a promising drug for the treatment of ulcerative colitis.

    DOI: 10.1177/0300060520951023

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  • Sphingosine Kinase 1 is Associated With Immune Cell-Related Gene Expressions in Human Breast Cancer. 国際誌

    Junko Tsuchida, Masayuki Nagahashi, Masato Nakajima, Eriko Katsuta, Omar M Rashid, Qianya Qi, Li Yan, Shujiro Okuda, Kazuaki Takabe, Toshifumi Wakai

    The Journal of surgical research   256   645 - 656   2020年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Although previous experiments have implicated sphingosine-1-phosphate (S1P) as a links between immune reactions and cancer progression, the exact mechanism of this interaction has not comprehensively studied in clinical human samples. This study sought to evaluate the S1P regulation by sphingosine kinase 1 (SPHK1), an S1P-producing enzyme, in the immunity/immuno-reactivity of clinical human breast cancer surgical specimens. METHODS: S1P levels were examined in tumor, peritumoral, and normal human breast samples using mass spectrometry. Genomics Data Commons data portal of The Cancer Genome Atlas cohort was used to assess the expression of S1P-related and immune-related genes. RESULTS: S1P levels were significantly higher in tumor samples compared to peritumoral (P < 0.05) or normal human breast samples (P < 0.001). SPHK1 gene expression was elevated in tumoral samples compared to normal breast samples (P < 0.01). Furthermore, the elevated expression of SPHK1 in breast cancer tissue was associated with an increased expression of the different kinds of immune-related genes, such as CD68, CD163, CD4, and FOXP3 (forkhead box P3), in HER2-negative breast cancer. Network analysis showed the central role of SPHK1 in the interaction of S1P signaling and expression of immune cell-related proteins. CONCLUSIONS: We demonstrated that S1P is mainly produced by tumor tissue, rather than peritumoral tissue, in breast cancer patients. Our data revealed the involvement of S1P signaling in the regulation of immune-related genes, suggesting the links between S1P and complicated immune-cancer interactions in breast cancer patients.

    DOI: 10.1016/j.jss.2020.06.057

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  • Frequent Germline and Somatic Single Nucleotide Variants in the Promoter Region of the Ribosomal RNA Gene in Japanese Lung Adenocarcinoma Patients. 国際誌

    Riuko Ohashi, Hajime Umezu, Ayako Sato, Tatsuya Abé, Shuhei Kondo, Kenji Daigo, Seijiro Sato, Norikazu Hara, Akinori Miyashita, Takeshi Ikeuchi, Teiichi Motoyama, Masashi Kishi, Tadahiro Nagaoka, Keiko Horiuchi, Atsushi Shiga, Shujiro Okuda, Tomoki Sekiya, Aya Ohtsubo, Kosuke Ichikawa, Hiroshi Kagamu, Toshiaki Kikuchi, Satoshi Watanabe, Jun-Ichi Tanuma, Peter Schraml, Takao Hamakubo, Masanori Tsuchida, Yoichi Ajioka

    Cells   9 ( 11 )   2020年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Ribosomal RNA (rRNA), the most abundant non-coding RNA species, is a major component of the ribosome. Impaired ribosome biogenesis causes the dysfunction of protein synthesis and diseases called "ribosomopathies," including genetic disorders with cancer risk. However, the potential role of rRNA gene (rDNA) alterations in cancer is unknown. We investigated germline and somatic single-nucleotide variants (SNVs) in the rDNA promoter region (positions -248 to +100, relative to the transcription start site) in 82 lung adenocarcinomas (LUAC). Twenty-nine tumors (35.4%) carried germline SNVs, and eight tumors (9.8%) harbored somatic SNVs. Interestingly, the presence of germline SNVs between positions +1 and +100 (n = 12; 14.6%) was associated with significantly shorter recurrence-free survival (RFS) and overall survival (OS) by univariate analysis (p < 0.05, respectively), and was an independent prognostic factor for RFS and OS by multivariate analysis. LUAC cell line PC9, carrying rDNA promoter SNV at position +49, showed significantly higher ribosome biogenesis than H1650 cells without SNV. Upon nucleolar stress induced by actinomycin D, PC9 retained significantly higher ribosome biogenesis than H1650. These results highlight the possible functional role of SNVs at specific sites of the rDNA promoter region in ribosome biogenesis, the progression of LUAC, and their potential prognostic value.

    DOI: 10.3390/cells9112409

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  • Verification of the Japanese staging system for rectal cancer, focusing on differences with the TNM classification.

    Michiru Arabiki, Yoshifumi Shimada, Mae Nakano, Kana Tanaka, Hidehito Oyanagi, Masato Nakano, Yiwei Ling, Shujiro Okuda, Yasumasa Takii, Toshifumi Wakai

    Surgery today   50 ( 11 )   1443 - 1451   2020年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    PURPOSE: The 9th Japanese Classification of Colorectal Cancer (9th JSCCR) has two main differences from the TNM classification (8th AJCC): first, main or lateral lymph node metastasis is classified as jN3; second, tumor nodules (ND) are treated as lymph node metastasis. In this study, we verified the 9th JSCCR for rectal cancer, focusing on the differences with the 8th AJCC. METHODS: This retrospective analysis involved 212 patients with stage I-III rectal cancer. ND was evaluated using whole-mount sections. We evaluated the relapse-free survival of each staging system, and compared the prognostic significance of the different staging systems using the Akaike information criterion (AIC) and Harrell's concordance index (c-index). RESULTS: Main or lateral lymph node metastasis was detected in nine of 212 (4%) patients. ND was detected in 79 of 212 (37%) patients. The best risk stratification power was observed in the 9th JSCCR (AIC, 759; c-index, 0.708) compared with the 7th JSCCR (AIC, 771; c-index, 0.681), 8th JSCCR (AIC, 768; c-index, 0.696), and the 8th AJCC (AIC, 766; c-index, 0.691). CONCLUSIONS: The 9th JSCCR, which includes the concepts of jN3 and ND, is useful for the risk stratification of rectal cancer, and the contributes to precise decision-making for follow-up management and adjuvant therapy.

    DOI: 10.1007/s00595-020-02024-4

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  • Higher genome mutation rates of Beijing lineage of Mycobacterium tuberculosis during human infection. 国際誌

    Mariko Hakamata, Hayato Takihara, Tomotada Iwamoto, Aki Tamaru, Atsushi Hashimoto, Takahiro Tanaka, Shaban A Kaboso, Gebremichal Gebretsadik, Aleksandr Ilinov, Akira Yokoyama, Yuriko Ozeki, Akihito Nishiyama, Yoshitaka Tateishi, Hiroshi Moro, Toshiaki Kikuchi, Shujiro Okuda, Sohkichi Matsumoto

    Scientific reports   10 ( 1 )   17997 - 17997   2020年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Mycobacterium tuberculosis (Mtb) strains of Beijing lineage have caused great concern because of their rapid emergence of drug resistance and worldwide spread. DNA mutation rates that reflect evolutional adaptation to host responses and the appearance of drug resistance have not been elucidated in human-infected Beijing strains. We tracked and obtained an original Mtb isolate of Beijing lineage from the 1999 tuberculosis outbreak in Japan, as well as five other isolates that spread in humans, and two isolates from the patient caused recurrence. Three isolates were from patients who developed TB within one year after infection (rapid-progressor, RP), and the other three isolates were from those who developed TB more than one year after infection (slow-progressor, SP). We sequenced genomes of these isolates and analyzed the propensity and rate of genomic mutations. Generation time versus mutation rate curves were significantly higher for RP. The ratio of oxidative versus non-oxidation damages induced mutations was higher in SP than RP, suggesting that persistent Mtb are exposed to oxidative stress in the latent state. Our data thus demonstrates that higher mutation rates of Mtb Beijing strains during human infection is likely to account for the higher adaptability and an emergence ratio of drug resistance.

    DOI: 10.1038/s41598-020-75028-2

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  • Innate Immune Responses in Serum and Cerebrospinal Fluid From Neonates and Infants Infected With Parechovirus-A3 or Enteroviruses. 査読 国際誌

    Rie Habuka, Yuta Aizawa, Ryohei Izumita, Hisanori Domon, Yutaka Terao, Hayato Takihara, Shujiro Okuda, Akihiko Saitoh

    The Journal of infectious diseases   222 ( 4 )   681 - 689   2020年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Parechovirus (PeV)-A3 and enteroviruses (EV) are the most common viruses causing sepsis and meningoencephalitis in neonates and young infants. Clinical manifestations of PeV-A3 infection are more severe than those of EV infection, and no pleocytosis with a positive polymerase chain reaction (PCR) result for PeV-A3 in cerebrospinal fluid (CSF) are characteristic findings. We hypothesized that innate immune responses to PeV-A3 and EV are distinct in serum and CSF. METHODS: We evaluated 22 cytokines/chemokines in serum and CSF from PeV-A3- or EV-infected patients younger than 4 months in Niigata, Japan, from 2015 through 2018. Infection was diagnosed with real-time PCR followed by sequencing. Febrile neonates and infants with sepsis-like syndrome who had negative bacterial culture and viral PCR for both PeV-A and EV were also included (non-PeV-A/EV patients). RESULTS: Among 192 febrile patients, we evaluated 16 PeV-A3-infected, 15 EV-infected, and 8 non-PeV-A/EV patients. Serum pro-/anti-inflammatory cytokine/chemokine levels were higher in PeV-A3-infected patients than in EV-infected patients (P < .02). Although most cytokine/chemokine were elevated in CSF from EV-infected patients, levels were low or undetectable in PeV-A3-infected and non-PeV-A/EV patients (P < .001). CONCLUSIONS: Distinct cytokine/chemokine patterns in serum and CSF may explain the different clinical manifestations of PeV-A3-infected and EV-infected neonates and young infants.

    DOI: 10.1093/infdis/jiaa131

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  • The GlyCosmos Portal: a unified and comprehensive web resource for the glycosciences. 査読 国際誌

    Issaku Yamada, Masaaki Shiota, Daisuke Shinmachi, Tamiko Ono, Shinichiro Tsuchiya, Masae Hosoda, Akihiro Fujita, Nobuyuki P Aoki, Yu Watanabe, Noriaki Fujita, Kiyohiko Angata, Hiroyuki Kaji, Hisashi Narimatsu, Shujiro Okuda, Kiyoko F Aoki-Kinoshita

    Nature methods   17 ( 7 )   649 - 650   2020年7月

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  • Phosphoproteomic and bioinformatic methods for analyzing signaling in vertebrate axon growth and regeneration. 査読 国際誌

    Michihiro Igarashi, Asami Kawasaki, Yuya Ishikawa, Atsuko Honda, Masayasu Okada, Shujiro Okuda

    Journal of neuroscience methods   339   108723 - 108723   2020年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Phosphorylation is the most important post-translational modification of proteins in many cells, including neurons. Phosphoproteomics is a relatively new technique for comprehensively identifying phosphorylation sites in the whole proteome of a given system. We applied this method to developmental neurobiology research to understand the signaling pathways that regulate the mammalian growth cone, which is formed at the tips of developing neurites to ensure accurate neuronal network formation. Using this powerful technique, we identified at least four phosphorylation sites tightly associated with axon growth. Because phosphoproteomic results include relatively large numbers of phosphopeptides, the data are typically analyzed using bioinformatics. We utilized three bioinformatics tools to identify the responsible protein kinases, the putative functions of the phosphorylated protein groups, and the evolutional aspects of the phosphorylated proteins. Collectively, these data indicate phosphoproteomics is a cutting-edge tool for neuroscience research.

    DOI: 10.1016/j.jneumeth.2020.108723

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  • RNF43 mutation is associated with aggressive tumor biology along with BRAF V600E mutation in right-sided colorectal cancer 査読 国際誌

    43 ( 6 )   1853 - 1862   2020年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.3892/or.2020.7561

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  • XCL1 expression correlates with CD8-positive T cells infiltration and PD-L1 expression in squamous cell carcinoma arising from mature cystic teratoma of the ovary. 査読 国際誌

    Ryo Tamura, Kosuke Yoshihara, Hirofumi Nakaoka, Nozomi Yachida, Manako Yamaguchi, Kazuaki Suda, Tatsuya Ishiguro, Koji Nishino, Hiroshi Ichikawa, Keiichi Homma, Akira Kikuchi, Yutaka Ueda, Yuji Takei, Hiroyuki Fujiwara, Teiichi Motoyama, Shujiro Okuda, Toshifumi Wakai, Ituro Inoue, Takayuki Enomoto

    Oncogene   39 ( 17 )   3541 - 3554   2020年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Molecular characteristics of carcinoma arising from mature cystic teratoma of the ovary (MCT) remain unclear due to its rarity. We analyzed RNA-sequencing data of 2322 pan-cancer [1378 squamous cell carcinomas (SCC), 6 adenosquamous carcinomas (ASC), and 938 adenocarcinomas (AC)] including six carcinomas arising from MCT (four SCCs, one ASC, and one AC). Hierarchical clustering and principal component analysis showed that gene expression profiles of carcinomas arising from MCT were different between each histological type and that gene expression profiles of SCCs arising MCT (MCT-SCCs) was apparently similar to those of lung SCCs. By epidermis-associated pathways activity based on gene set enrichment analysis, 1030 SCCs were divided into two groups: epidermis-signature high (head and neck, esophagus, and skin) and low (cervix, lung, and MCT). In addition to pan-SCC transcriptome analysis, cytokeratin profiling based on immunohistochemistry in the independent samples of 21 MCT-SCCs clarified that MCT-SCC dominantly expressed CK18, suggesting the origin of MCT-SCC was columnar epithelium. Subsequently, we investigated differentially expressed genes in MCT-SCCs compared with different SCCs and identified XCL1 was specifically overexpressed in MCT-SCCs. Through immunohistochemistry analysis, we identified XCL1 expression on tumor cells in 13/24 (54%) of MCT-SCCs but not in MCTs. XCL1 expression was also significantly associated with the number of tumor-infiltrating CD8-positive T cells and PD-L1 expression on tumor cells. XCL1 produced by tumor cells may induce PD1/PD-L1 interaction and dysfunction of CD8-positive T cells in tumor microenvironment. XCL1 expression may be a novel biomarker for malignant transformation of MCT into SCC and a biomarker candidate for therapeutic response to an anti-PD1/PD-L1 therapy.

    DOI: 10.1038/s41388-020-1237-0

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  • The ProteomeXchange consortium in 2020: enabling 'big data' approaches in proteomics. 査読 国際誌

    Deutsch EW, Bandeira N, Sharma V, Perez-Riverol Y, Carver JJ, Kundu DJ, García-Seisdedos D, Jarnuczak AF, Hewapathirana S, Pullman BS, Wertz J, Sun Z, Kawano S, Okuda S, Watanabe Y, Hermjakob H, MacLean B, MacCoss MJ, Zhu Y, Ishihama Y, Vizcaíno JA

    Nucleic acids research   48 ( D1 )   D1145-D1152   2020年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1093/nar/gkz984

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  • Genetic profiling for diffuse type and genomically stable subtypes in gastric cancer. 国際誌

    Yiwei Ling, Yu Watanabe, Mayuki Nagahashi, Yoshifumi Shimada, Hiroshi Ichikawa, Toshifumi Wakai, Shujiro Okuda

    Computational and structural biotechnology journal   18   3301 - 3308   2020年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Gastric cancer is one of the most common and clinically important diseases worldwide. The traditional Laeuren classification divides gastric cancer into two histopathological subtypes: diffuse and intestinal. Recent cancer genomics research has led to the development of a new classification based on molecular characteristics. The newly defined genomically stable (GS) subtype shares many cases with the histopathologically diffuse type. In this study, we performed genetic profiling of recurrently and significantly mutated genes in diffuse type and GS subtype tumors. We observed significantly different genetic characteristics, although the two subtypes overlapped in many cases. In addition, based on the profiles of the significantly mutated genes, we identified molecular functions and mutational signatures characteristic of each subtype. These results will advance the clinical application of the diffuse type and GS subtype gastric cancer in precision medicine for treating gastric cancer.

    DOI: 10.1016/j.csbj.2020.10.021

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  • BioHackathon 2015: Semantics of data for life sciences and reproducible research. 国際誌

    Rutger A Vos, Toshiaki Katayama, Hiroyuki Mishima, Shin Kawano, Shuichi Kawashima, Jin-Dong Kim, Yuki Moriya, Toshiaki Tokimatsu, Atsuko Yamaguchi, Yasunori Yamamoto, Hongyan Wu, Peter Amstutz, Erick Antezana, Nobuyuki P Aoki, Kazuharu Arakawa, Jerven T Bolleman, Evan Bolton, Raoul J P Bonnal, Hidemasa Bono, Kees Burger, Hirokazu Chiba, Kevin B Cohen, Eric W Deutsch, Jesualdo T Fernández-Breis, Gang Fu, Takatomo Fujisawa, Atsushi Fukushima, Alexander García, Naohisa Goto, Tudor Groza, Colin Hercus, Robert Hoehndorf, Kotone Itaya, Nick Juty, Takeshi Kawashima, Jee-Hyub Kim, Akira R Kinjo, Masaaki Kotera, Kouji Kozaki, Sadahiro Kumagai, Tatsuya Kushida, Thomas Lütteke, Masaaki Matsubara, Joe Miyamoto, Attayeb Mohsen, Hiroshi Mori, Yuki Naito, Takeru Nakazato, Jeremy Nguyen-Xuan, Kozo Nishida, Naoki Nishida, Hiroyo Nishide, Soichi Ogishima, Tazro Ohta, Shujiro Okuda, Benedict Paten, Jean-Luc Perret, Philip Prathipati, Pjotr Prins, Núria Queralt-Rosinach, Daisuke Shinmachi, Shinya Suzuki, Tsuyosi Tabata, Terue Takatsuki, Kieron Taylor, Mark Thompson, Ikuo Uchiyama, Bruno Vieira, Chih-Hsuan Wei, Mark Wilkinson, Issaku Yamada, Ryota Yamanaka, Kazutoshi Yoshitake, Akiyasu C Yoshizawa, Michel Dumontier, Kenjiro Kosaki, Toshihisa Takagi

    F1000Research   9   136 - 136   2020年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    We report on the activities of the 2015 edition of the BioHackathon, an annual event that brings together researchers and developers from around the world to develop tools and technologies that promote the reusability of biological data. We discuss issues surrounding the representation, publication, integration, mining and reuse of biological data and metadata across a wide range of biomedical data types of relevance for the life sciences, including chemistry, genotypes and phenotypes, orthology and phylogeny, proteomics, genomics, glycomics, and metabolomics. We describe our progress to address ongoing challenges to the reusability and reproducibility of research results, and identify outstanding issues that continue to impede the progress of bioinformatics research. We share our perspective on the state of the art, continued challenges, and goals for future research and development for the life sciences Semantic Web.

    DOI: 10.12688/f1000research.18236.1

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  • Rice Endosperm Protein Administration to Juvenile Mice Regulates Gut Microbiota and Suppresses the Development of High-Fat Diet-Induced Obesity and Related Disorders in Adulthood. 査読 国際誌

    Yuki Higuchi, Michihiro Hosojima, Hideyuki Kabasawa, Shoji Kuwahara, Sawako Goto, Koji Toba, Ryohei Kaseda, Takahiro Tanaka, Nobutaka Kitamura, Hayato Takihara, Shujiro Okuda, Masayuki Taniguchi, Hitoshi Arao, Ichiei Narita, Akihiko Saito

    Nutrients   11 ( 12 )   2019年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Obesity and related disorders, which are increasing in adults worldwide, are closely linked to childhood diet and are associated with chronic inflammation. Rice endosperm protein (REP) intake during adulthood has been reported to improve lipid metabolism and suppress the progression of diabetic kidney disease in animal models. However, the effects of REP intake during childhood on adulthood health are unclear. Therefore, we used a mouse model to experimentally investigate the preconditioning effects of REP intake during childhood on the development of obesity and related disorders in adulthood. Male C57BL/6J mice were pair-fed a normal-fat diet containing casein or REP during the juvenile period and then a high-fat diet (HFD) containing casein or REP during adulthood. Mice fed REP during the juvenile period showed better body weight, blood pressure, serum lipid profiles, lipopolysaccharide (LPS)-binding protein levels, and glucose tolerance in adulthood than those fed casein during the juvenile period. HFD-induced renal tubulo-glomerular alterations and hepatic microvesicular steatosis were less evident in REP-fed mice than in casein-fed ones. REP intake during the juvenile period improved HFD-induced dysbiosis (i.e., Escherichia genus proliferation and reduced gut microbiota diversity), thereby suppressing endotoxin-related chronic inflammation. Indeed, REP-derived peptides showed antibacterial activity against Escherichia coli, a major producer of LPS. In conclusion, REP supplementation during the juvenile period may regulate the gut microbiota and thus suppress the development of obesity and related disorders in adulthood in mice.

    DOI: 10.3390/nu11122919

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  • Open Agile Text Mining for Bioinformatics: The PubAnnotation Ecosystem. 査読 国際誌

    Kim JD, Wang Y, Fujiwara T, Okuda S, Callahan TJ, Cohen KB

    Bioinformatics (Oxford, England)   35 ( 21 )   4372 - 4380   2019年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1093/bioinformatics/btz227

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  • Precision Medicine 固形癌における包括的ゲノム解析に基づくPrecision Medicine(Precision Medicine)

    若井 俊文, 島田 能史, 永橋 昌幸, 市川 寛, 油座 築, 根本 万里子, 中野 麻恵, 廣瀬 雄己, 滝沢 一泰, 坂田 純, 亀山 仁史, 小林 隆, 棗田 学, 吉原 弘祐, 奥田 修二郎

    日本癌治療学会学術集会抄録集   57回   JSY1 - 4   2019年10月

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    記述言語:英語   出版者・発行元:(一社)日本癌治療学会  

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  • BioHackathon series in 2013 and 2014: improvements of semantic interoperability in life science data and services

    Toshiaki Katayama, Shuichi Kawashima, Gos Micklem, Shin Kawano, Jin-Dong Kim, Simon Kocbek, Shinobu Okamoto, Yue Wang, Hongyan Wu, Atsuko Yamaguchi, Yasunori Yamamoto, Erick Antezana, Kiyoko F. Aoki-Kinoshita, Kazuharu Arakawa, Masaki Banno, Joachim Baran, Jerven T. Bolleman, Raoul J.P. Bonnal, Hidemasa Bono, Jesualdo T. Fernández-Breis, Robert Buels, Matthew, P. Campbell, Hirokazu Chiba, Peter J. A. Cock, Kevin B. Cohen, Michel Dumontier, Takatomo Fujisawa, Toyofumi Fujiwara, Leyla Garcia, Pascale Gaudet, Emi Hattori, Robert Hoehndorf, Kotone Itaya, Maori Ito, Daniel Jamieson, Simon Jupp, Nick Juty, Alex Kalderimis, Fumihiro Kato, Hideya Kawaji, Takeshi Kawashima, Akira R. Kinjo, Yusuke Komiyama, Masaaki Kotera, Tatsuya Kushida, James Malone, Masaaki Matsubara, Satoshi Mizuno, Sayaka Mizutani, Hiroshi Mori, Yuki Moriya, Katsuhiko Murakami, Takeru Nakazato, Hiroyo Nishide, Yosuke Nishimura, Soichi Ogishima, Tazro Ohta, Shujiro Okuda, Hiromasa Ono, Yasset Perez-Riverol, Daisuke Shinmachi, Andrea Splendiani, Francesco Strozzi, Shinya Suzuki, Junichi Takehara, Mark Thompson, Toshiaki Tokimatsu, Ikuo Uchiyama, Karin Verspoor, Mark D. Wilkinson, Sarala Wimalaratne, Issaku Yamada, Nozomi Yamamoto, Masayuki Yarimizu, Shoko Kawamoto, Toshihisa Takagi

    F1000Research   8   1677   2019年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.12688/f1000research.18238.1

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  • 消化器外科領域に応用可能な分子レベルの技術開発 次世代シークエンサーを用いた遺伝子検査とゲノム解析データベース構築(Molecular Technology Development for Gastroenterological Diseases Next-generation sequencing-based gene test and construction of a genomic analysis database)

    永橋 昌幸, 若井 俊文, 島田 能史, 市川 寛, 羽入 隆晃, 滝沢 一泰, 石川 卓, 坂田 純, 小林 隆, 亀山 仁史, 竹内 志穂, 奥田 修二郎

    日本癌学会総会記事   78回   SST6 - 4   2019年9月

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    記述言語:英語   出版者・発行元:(一社)日本癌学会  

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  • Towards a standardized bioinformatics infrastructure for N- and O-glycomics. 査読 国際誌

    Rojas-Macias MA, Mariethoz J, Andersson P, Jin C, Venkatakrishnan V, Aoki NP, Shinmachi D, Ashwood C, Madunic K, Zhang T, Miller RL, Horlacher O, Struwe WB, Watanabe Y, Okuda S, Levander F, Kolarich D, Rudd PM, Wuhrer M, Kettner C, Packer NH, Aoki-Kinoshita KF, Lisacek F, Karlsson NG

    Nature communications   10 ( 1 )   3275 - 3275   2019年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1038/s41467-019-11131-x

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  • Evolutionary analysis of proline-directed phosphorylation sites in the mammalian growth cone identified using phosphoproteomics. 査読 国際誌

    Igarashi M, Okuda S

    Molecular brain   12 ( 1 )   53 - 53   2019年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1186/s13041-019-0476-x

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  • SMAD4 alteration associates with invasive-front pathological markers and poor prognosis in colorectal cancer. 査読 国際誌

    Oyanagi H, Shimada Y, Nagahashi M, Ichikawa H, Tajima Y, Abe K, Nakano M, Kameyama H, Takii Y, Kawasaki T, Homma KI, Ling Y, Okuda S, Takabe K, Wakai T

    Histopathology   74 ( 6 )   873 - 882   2019年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1111/his.13805

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  • Autophagy regulates lipid metabolism through selective turnover of NCoR1. 査読 国際誌

    Tetsuya Saito, Akiko Kuma, Yuki Sugiura, Yoshinobu Ichimura, Miki Obata, Hiroshi Kitamura, Shujiro Okuda, Hyeon-Cheol Lee, Kazutaka Ikeda, Yumi Kanegae, Izumu Saito, Johan Auwerx, Hozumi Motohashi, Makoto Suematsu, Tomoyoshi Soga, Takehiko Yokomizo, Satoshi Waguri, Noboru Mizushima, Masaaki Komatsu

    Nature communications   10 ( 1 )   1567 - 1567   2019年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Selective autophagy ensures the removal of specific soluble proteins, protein aggregates, damaged mitochondria, and invasive bacteria from cells. Defective autophagy has been directly linked to metabolic disorders. However how selective autophagy regulates metabolism remains largely uncharacterized. Here we show that a deficiency in selective autophagy is associated with suppression of lipid oxidation. Hepatic loss of Atg7 or Atg5 significantly impairs the production of ketone bodies upon fasting, due to decreased expression of enzymes involved in β-oxidation following suppression of transactivation by PPARα. Mechanistically, nuclear receptor co-repressor 1 (NCoR1), which interacts with PPARα to suppress its transactivation, binds to the autophagosomal GABARAP family proteins and is degraded by autophagy. Consequently, loss of autophagy causes accumulation of NCoR1, suppressing PPARα activity and resulting in impaired lipid oxidation. These results suggest that autophagy contributes to PPARα activation upon fasting by promoting degradation of NCoR1 and thus regulates β-oxidation and ketone bodies production.

    DOI: 10.1038/s41467-019-08829-3

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  • BRAF V600E and SRC mutations as molecular markers for predicting prognosis and conversion surgery in Stage IV colorectal cancer. 査読 国際誌

    Shimada Y, Muneoka Y, Nagahashi M, Ichikawa H, Tajima Y, Hirose Y, Ando T, Nakano M, Sakata J, Kameyama H, Takii Y, Ling Y, Okuda S, Takabe K, Wakai T

    Scientific reports   9 ( 1 )   2466 - 2466   2019年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1038/s41598-019-39328-6

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  • Characterisation of N-glycans in the epithelial-like tissue of the rat cochlea. 査読 国際誌

    Yoriko Nonomura, Seishiro Sawamura, Ken Hanzawa, Takashi Nishikaze, Sadanori Sekiya, Taiga Higuchi, Fumiaki Nin, Satoru Uetsuka, Hidenori Inohara, Shujiro Okuda, Eiji Miyoshi, Arata Horii, Sugata Takahashi, Shunji Natsuka, Hiroshi Hibino

    Scientific reports   9 ( 1 )   1551 - 1551   2019年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Membrane proteins (such as ion channels, transporters, and receptors) and secreted proteins are essential for cellular activities. N-linked glycosylation is involved in stability and function of these proteins and occurs at Asn residues. In several organs, profiles of N-glycans have been determined by comprehensive analyses. Nevertheless, the cochlea of the mammalian inner ear, a tiny organ mediating hearing, has yet to be examined. Here, we focused on the stria vascularis, an epithelial-like tissue in the cochlea, and characterised N-glycans by liquid chromatography with mass spectrometry. This hypervascular tissue not only expresses several ion transporters and channels to control the electrochemical balance in the cochlea but also harbours different transporters and receptors that maintain structure and activity of the organ. Seventy-nine N-linked glycans were identified in the rat stria vascularis. Among these, in 55 glycans, the complete structures were determined; in the other 24 species, partial glycosidic linkage patterns and full profiles of the monosaccharide composition were identified. In the process of characterisation, several sialylated glycans were subjected sequentially to two different alkylamidation reactions; this derivatisation helped to distinguish α2,3-linkage and α2,6-linkage sialyl isomers with mass spectrometry. These data should accelerate elucidation of the molecular architecture of the cochlea.

    DOI: 10.1038/s41598-018-38079-0

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  • Knowledge base toward understanding actionable alterations and realizing precision oncology. 査読

    Takeuchi S, Okuda S

    International journal of clinical oncology   24 ( 2 )   123 - 130   2019年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1007/s10147-018-1378-0

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  • The jPOST environment: an integrated proteomics data repository and database. 査読 国際誌

    Yuki Moriya, Shin Kawano, Shujiro Okuda, Yu Watanabe, Masaki Matsumoto, Tomoyo Takami, Daiki Kobayashi, Yoshinori Yamanouchi, Norie Araki, Akiyasu C Yoshizawa, Tsuyoshi Tabata, Mio Iwasaki, Naoyuki Sugiyama, Satoshi Tanaka, Susumu Goto, Yasushi Ishihama

    Nucleic acids research   47 ( D1 )   D1218-D1224 - D1224   2019年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Oxford University Press (OUP)  

    Rapid progress is being made in mass spectrometry (MS)-based proteomics, yielding an increasing number of larger datasets with higher quality and higher throughput. To integrate proteomics datasets generated from various projects and institutions, we launched a project named jPOST (Japan ProteOme STandard Repository/Database, https://jpostdb.org/) in 2015. Its proteomics data repository, jPOSTrepo, began operations in 2016 and has accepted more than 10 TB of MS-based proteomics datasets in the past two years. In addition, we have developed a new proteomics database named jPOSTdb in which the published raw datasets in jPOSTrepo are reanalyzed using standardized protocol. jPOSTdb provides viewers showing the frequency of detected post-translational modifications, the co-occurrence of phosphorylation sites on a peptide and peptide sharing among proteoforms. jPOSTdb also provides basic statistical analysis tools to compare proteomics datasets.

    DOI: 10.1093/nar/gky899

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  • Identification of TRA-1-60-positive cells as a potent refractory population in follicular lymphomas. 査読 国際誌

    Katsuyoshi Takata, Ken Saito, Satoshi Maruyama, Tomoko Miyata-Takata, Hidekazu Iioka, Shujiro Okuda, Yiwei Ling, Kennosuke Karube, Yukari Miki, Yoshinobu Maeda, Tadashi Yoshino, Christian Steidl, Eisaku Kondo

    Cancer science   110 ( 1 )   443 - 457   2019年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Despite receiving rituximab-combined chemotherapy, follicular lymphoma (FL) patients often suffer tumor recurrence and understand that the cause of relapse in FL would thus significantly ameliorate the tumor therapeutics. In the present study, we show that TRA-1-60-expressing cells are a unique population in FL, converge to the conventional stem cell marker Oct3/4 and ALDH1-positive population, and resist current B-lymphoma agents. TRA-1-60 expression was observed in scattered lymphoma cells in FL tissues only as well as in resting B-lymphocytes inside germinal centers. Retrospective comparison between recurrent and cognate primary tissues showed that the number of TRA-1-60-positive cells from rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone (R-CHOP)-treated FL had increased relative to primary tissue, a finding corroborated by assays on different rituximab-treated FL cell lines, FL-18 and DOHH2, wherein TRA-positive cell numbers increased over 10-fold compared to the untreated sample. Concordantly, scanty TRA-1-60-positive FL-18 cells implanted s.c. into mice evinced potent tumor-initiating capacity in vivo, where tumors were 12-fold larger in volume (P = 0.0021 < 0.005) and 13-fold heavier in weight (P = 0.0015 < 0.005) compared to those xenografted from TRA-negative cells. To explain these results, gene expression profiling and qPCR analysis indicated that TRA-1-60-positive cells defined a distinct population from that of TRA-negative cells, with upregulation of multiple drug transporters and therapeutic resistance genes. Hence, TRA-1-60-expressing cells in FL are considered to be vigorously intractable against conventional therapeutic agents, which may explain its refractory recurrence.

    DOI: 10.1111/cas.13870

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  • Next generation sequencing-based gene panel tests for the management of solid tumors. 査読 国際誌

    Nagahashi M, Shimada Y, Ichikawa H, Kameyama H, Takabe K, Okuda S, Wakai T

    Cancer science   110 ( 1 )   6 - 15   2019年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1111/cas.13837

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  • The Human Gut Microbiome is Structured to Optimize Molecular Interaction Networks. 査読 国際誌

    Ling Y, Watanabe Y, Okuda S

    Computational and structural biotechnology journal   17   1040 - 1046   2019年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.csbj.2019.07.011

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  • The GlyCosmos Web Portal: glycan structures, glycogenes, glycoproteins, pathways, diseases and more! 査読

    Masaaki Shiota, Shinichiro Tsuchiya, Tamiko Ono, Thukaa Kuoka, Nobuaki Miura, Aiko Hiraki, Issaku Yamada, Daisuke Shinmachi, Nobuyuki P. Aoki, Jin-Dong Kim, Yu Watanabe, Shujiro Okuda, Yoshinori Suzuki, Noriaki Fujita, Kiyohiko Angata, Hisashi Narimatsu, Kiyoko F. Aoki-Kinoshita

    GLYCOBIOLOGY   28 ( 12 )   1070 - 1071   2018年12月

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    記述言語:英語   出版者・発行元:OXFORD UNIV PRESS INC  

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  • Novel gene fusions found in cervical cancer. 査読 国際誌

    Ling Y, Okuda S

    EBioMedicine   38   13 - 14   2018年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.ebiom.2018.11.013

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  • Clinical Significance of BRAF Non-V600E Mutations in Colorectal Cancer: A Retrospective Study of Two Institutions. 査読 国際誌

    Shimada Y, Tajima Y, Nagahashi M, Ichikawa H, Oyanagi H, Okuda S, Takabe K, Wakai T

    The Journal of surgical research   232   72 - 81   2018年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.jss.2018.06.020

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  • Novel MXD4-NUTM1 fusion transcript identified in primary ovarian undifferentiated small round cell sarcoma. 査読 国際誌

    Ryo Tamura, Hirofumi Nakaoka, Kosuke Yoshihara, Yutaro Mori, Nozomi Yachida, Nobumichi Nishikawa, Teiichi Motoyama, Shujiro Okuda, Ituro Inoue, Takayuki Enomoto

    Genes, chromosomes & cancer   57 ( 11 )   557 - 563   2018年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Primary ovarian sarcomas are extremely rare tumors, and their genomic and transcriptomic alterations remain to be elucidated. We performed whole exome sequencing of primary tumor and matched normal blood samples derived from one patient with ovarian undifferentiated small round cell sarcoma. We identified 8 nonsynonymous somatic mutations, and all mutations were missense or nonsense changes. Next, we performed RNA sequencing of the tumor sample and identified two in-frame fusion transcripts: MXD4-NUTM1 and ARL6-POT1. Most NUTM1 exons were retained in the MXD4-NUTM1 fusion transcript, and we confirmed an increase in NUTM1 mRNA and protein expression in tumor tissue. Further genomic and transcriptomic analyses might lead to the development of new therapeutic strategies based on the molecular characteristics of ovarian undifferentiated small round cell sarcoma.

    DOI: 10.1002/gcc.22668

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  • Common driver mutations and smoking history affect tumor mutation burden in lung adenocarcinoma. 査読 国際誌

    Nagahashi M, Sato S, Yuza K, Shimada Y, Ichikawa H, Watanabe S, Takada K, Okamoto T, Okuda S, Lyle S, Takabe K, Tsuchida M, Wakai T

    The Journal of surgical research   230   181 - 185   2018年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.jss.2018.07.007

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  • Sharing of human milk oligosaccharides degradants within bifidobacterial communities in faecal cultures supplemented with Bifidobacterium bifidum. 査読 国際誌

    Aina Gotoh, Toshihiko Katoh, Mikiyasu Sakanaka, Yiwei Ling, Chihaya Yamada, Sadaki Asakuma, Tadasu Urashima, Yusuke Tomabechi, Ayako Katayama-Ikegami, Shin Kurihara, Kenji Yamamoto, Gaku Harata, Fang He, Junko Hirose, Motomitsu Kitaoka, Shujiro Okuda, Takane Katayama

    Scientific reports   8 ( 1 )   13958 - 13958   2018年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Gut microbiota of breast-fed infants are generally rich in bifidobacteria. Recent studies show that infant gut-associated bifidobacteria can assimilate human milk oligosaccharides (HMOs) specifically among the gut microbes. Nonetheless, little is known about how bifidobacterial-rich communities are shaped in the gut. Interestingly, HMOs assimilation ability is not related to the dominance of each species. Bifidobacterium longum susbp. longum and Bifidobacterium breve are commonly found as the dominant species in infant stools; however, they show limited HMOs assimilation ability in vitro. In contrast, avid in vitro HMOs consumers, Bifidobacterium bifidum and Bifidobacterium longum subsp. infantis, are less abundant in infant stools. In this study, we observed altruistic behaviour by B. bifidum when incubated in HMOs-containing faecal cultures. Four B. bifidum strains, all of which contained complete sets of HMO-degrading genes, commonly left HMOs degradants unconsumed during in vitro growth. These strains stimulated the growth of other Bifidobacterium species when added to faecal cultures supplemented with HMOs, thereby increasing the prevalence of bifidobacteria in faecal communities. Enhanced HMOs consumption by B. bifidum-supplemented cultures was also observed. We also determined the complete genome sequences of B. bifidum strains JCM7004 and TMC3115. Our results suggest B. bifidum-mediated cross-feeding of HMOs degradants within bifidobacterial communities.

    DOI: 10.1038/s41598-018-32080-3

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  • Analysis of polyamine biosynthetic- and transport ability of human indigenous Bifidobacterium. 査読 国際誌

    Yuta Sugiyama, Misaki Nara, Mikiyasu Sakanaka, Aya Kitakata, Shujiro Okuda, Shin Kurihara

    Bioscience, biotechnology, and biochemistry   82 ( 9 )   1606 - 1614   2018年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Bifidobacteria are members of the human intestinal microbiota, being numerically dominant in the colon of infants, and also being prevalent in the large intestine of adults. In this study, we measured the concentrations of major polyamines (putrescine, spermidine, and spermine) in cells and culture supernatant of 13 species of human indigenous Bifidobacterium at growing and stationary phase. Except for Bifidobacterium bifidum and Bifidobacterium gallicum, 11 species contained spermidine and/or spermine when grown in Gifu-anaerobic medium (GAM). However, Bifidobacterium scardovii and Bifidobacterium longum subsp. infantis, which contain spermidine when grown in GAM, did not contain spermidine when grown in polyamine-free 199 medium. Of the tested 13 Bifidobacterium species, 10 species showed polyamine transport ability. Combining polyamine concentration analysis in culture supernatant and in cells, with basic local alignment search tool analysis suggested that novel polyamine transporters are present in human indigenous Bifidobacterium. ABBREVIATIONS: Put: putrescine; Spd: spermidine; Spm: spermine; GAM: Gifu anaerobic medium; BHI: brain-heart infusion.

    DOI: 10.1080/09168451.2018.1475211

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  • Publisher Correction: IMSindel: An accurate intermediate-size indel detection tool incorporating de novo assembly and gapped global-local alignment with split read analysis. 査読 国際誌

    Shigemizu D, Miya F, Akiyama S, Okuda S, Boroevich KA, Fujimoto A, Nakagawa H, Ozaki K, Niida S, Kanemura Y, Okamoto N, Saitoh S, Kato M, Yamasaki M, Matsunaga T, Mutai H, Kosaki K, Tsunoda T

    Scientific reports   8 ( 1 )   10367 - 10367   2018年7月

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  • Growth Cone Phosphoproteomics Reveals that GAP-43 Phosphorylated by JNK Is a Marker of Axon Growth and Regeneration. 査読 国際誌

    Asami Kawasaki, Masayasu Okada, Atsushi Tamada, Shujiro Okuda, Motohiro Nozumi, Yasuyuki Ito, Daiki Kobayashi, Tokiwa Yamasaki, Ryo Yokoyama, Takeshi Shibata, Hiroshi Nishina, Yutaka Yoshida, Yukihiko Fujii, Kosei Takeuchi, Michihiro Igarashi

    iScience   4   190 - 203   2018年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Neuronal growth cones are essential for nerve growth and regeneration, as well as for the formation and rearrangement of the neural network. To elucidate phosphorylation-dependent signaling pathways and establish useful molecular markers for axon growth and regeneration, we performed a phosphoproteomics study of mammalian growth cones, which identified >30,000 phosphopeptides of ∼1,200 proteins. The phosphorylation sites were highly proline directed and primarily MAPK dependent, owing to the activation of JNK, suggesting that proteins that undergo proline-directed phosphorylation mediate nerve growth in the mammalian brain. Bioinformatics analysis revealed that phosphoproteins were enriched in microtubules and the cortical cytoskeleton. The most frequently phosphorylated site was S96 of GAP-43 (growth-associated protein 43-kDa), a vertebrate-specific protein involved in axon growth. This previously uncharacterized phosphorylation site was JNK dependent. S96 phosphorylation was specifically detected in growing and regenerating axons as the most frequent target of JNK signaling; thus it represents a promising new molecular marker for mammalian axonal growth and regeneration.

    DOI: 10.1016/j.isci.2018.05.019

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  • Clinical and Genetic Implications of Mutation Burden in Squamous Cell Carcinoma of the Lung. 査読 国際誌

    Tatsuro Okamoto, Kazuki Takada, Seijiro Sato, Gouji Toyokawa, Tetsuzo Tagawa, Fumihiro Shoji, Ryota Nakanishi, Eiji Oki, Terumoto Koike, Masayuki Nagahashi, Hiroshi Ichikawa, Yoshifumi Shimada, Satoshi Watanabe, Toshiaki Kikuchi, Kouhei Akazawa, Stephen Lyle, Kazuaki Takabe, Shujiro Okuda, Kenji Sugio, Toshifumi Wakai, Masanori Tsuchida, Yoshihiko Maehara

    Annals of surgical oncology   25 ( 6 )   1564 - 1571   2018年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Springer New York LLC  

    BACKGROUND: Lung squamous cell carcinoma (LSCC) is a major histological subtype of lung cancer. In this study, we investigated genomic alterations in LSCC and evaluated the clinical implications of mutation burden (MB) in LSCC. METHODS: Genomic alterations were determined in Japanese patients with LSCC (N = 67) using next-generation sequencing of 415 known cancer genes. MB was defined as the number of non-synonymous mutations per 1 Mbp. Programmed death-ligand 1 (PD-L1) protein expression in cancer cells was evaluated by immunohistochemical analysis. RESULTS: TP53 gene mutations were the most common alteration (n = 51/67, 76.1%), followed by gene alterations in cyclin-dependent kinase inhibitor 2B (CDKN2B; 35.8%), CDKN2A (31.3%), phosphatase and tensin homolog (30.0%), and sex-determining region Y-box 2 (SOX2, 28.3%). Histological differentiation was significantly poorer in tumors with high MB (greater than or equal to the median MB) compared with that in tumors with low MB (less than the median MB; p = 0.0446). The high MB group had more tumors located in the upper or middle lobe than tumors located in the lower lobe (p = 0.0019). Moreover, cancers in the upper or middle lobes had significantly higher MB than cancers in the lower lobes (p = 0.0005), and tended to show higher PD-L1 protein expression (p = 0.0573). SOX2 and tyrosine kinase non-receptor 2 amplifications were associated with high MB (p = 0.0065 and p = 0.0010, respectively). CONCLUSIONS: The MB level differed according to the tumor location in LSCC, suggesting that the location of cancer development may influence the genomic background of the tumor.

    DOI: 10.1245/s10434-018-6401-1

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  • AldB controls persister formation in Escherichia coli depending on environmental stress. 査読 国際誌

    Yuto Kawai, Shinya Matsumoto, Yiwei Ling, Shujiro Okuda, Satoshi Tsuneda

    Microbiology and immunology   62 ( 5 )   299 - 309   2018年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Blackwell Publishing Asia  

    Persisters are multidrug-tolerant cells that are present within antibiotic-sensitive populations. Persister formation is not induced by genetic mutations, but rather by changes in the degree of expression of some genes. High redundancy has been observed among the pathways that have been hypothesized to respond to specific stresses. In this study, we conducted RNA sequencing of Escherichia coli persisters under various stress conditions to identify common mechanisms. We induced stresses such as glucose or amino acid exhaustion, acid stress and anaerobic conditions, all of which are encountered during bacterial pathogenesis. We found that most genes are differentially expressed depending on the specific stress condition; however, some genes were commonly expressed in persisters in most stress conditions. Commonly expressed genes are expected to be promising therapeutic targets for combating persistent infections. We found that knockdown of aldehyde dehydrogenase (aldB), which was expressed in every condition except for acid stress, decreased persisters in the non-stressed condition. However, the same strain unexpectedly showed an increased number of persisters in the amino acid-limited condition. Because the increase in persister number is glycolytic metabolite-dependent, metabolic flow may play a crucial role in aldB-mediated persister formation. These data suggest that environmental stresses alter persister mechanisms. Identification of environmental influences on persister formation during pathogenesis is therefore necessary to enabling persister eradication.

    DOI: 10.1111/1348-0421.12587

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  • IMSindel: An accurate intermediate-size indel detection tool incorporating de novo assembly and gapped global-local alignment with split read analysis. 査読 国際誌

    Daichi Shigemizu, Fuyuki Miya, Shintaro Akiyama, Shujiro Okuda, Keith A Boroevich, Akihiro Fujimoto, Hidewaki Nakagawa, Kouichi Ozaki, Shumpei Niida, Yonehiro Kanemura, Nobuhiko Okamoto, Shinji Saitoh, Mitsuhiro Kato, Mami Yamasaki, Tatsuo Matsunaga, Hideki Mutai, Kenjiro Kosaki, Tatsuhiko Tsunoda

    Scientific reports   8 ( 1 )   5608 - 5608   2018年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Nature Publishing Group  

    Insertions and deletions (indels) have been implicated in dozens of human diseases through the radical alteration of gene function by short frameshift indels as well as long indels. However, the accurate detection of these indels from next-generation sequencing data is still challenging. This is particularly true for intermediate-size indels (≥50 bp), due to the short DNA sequencing reads. Here, we developed a new method that predicts intermediate-size indels using BWA soft-clipped fragments (unmatched fragments in partially mapped reads) and unmapped reads. We report the performance comparison of our method, GATK, PINDEL and ScanIndel, using whole exome sequencing data from the same samples. False positive and false negative counts were determined through Sanger sequencing of all predicted indels across these four methods. The harmonic mean of the recall and precision, F-measure, was used to measure the performance of each method. Our method achieved the highest F-measure of 0.84 in one sample, compared to 0.56 for GATK, 0.52 for PINDEL and 0.46 for ScanIndel. Similar results were obtained in additional samples, demonstrating that our method was superior to the other methods for detecting intermediate-size indels. We believe that this methodology will contribute to the discovery of intermediate-size indels associated with human disease.

    DOI: 10.1038/s41598-018-23978-z

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  • Novel therapeutic strategy for cervical cancer harboring FGFR3-TACC3 fusions. 査読 国際誌

    Ryo Tamura, Kosuke Yoshihara, Tetsuya Saito, Ryosuke Ishimura, Juan Emmanuel Martínez-Ledesma, Hu Xin, Tatsuya Ishiguro, Yutaro Mori, Kaoru Yamawaki, Kazuaki Suda, Seiya Sato, Hiroaki Itamochi, Teiichi Motoyama, Yoichi Aoki, Shujiro Okuda, Cristine R Casingal, Hirofumi Nakaoka, Ituro Inoue, Roel G W Verhaak, Masaaki Komatsu, Takayuki Enomoto

    Oncogenesis   7 ( 1 )   4 - 4   2018年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    We previously found that therapeutic targetable fusions are detected across various cancers. To identify therapeutic targetable fusion in uterine cervical cancer, for which no effective gene targeted therapy has yet been clinically applied, we analyzed RNA sequencing data from 306 cervical cancer samples. We detected 445 high confidence fusion transcripts and identified four samples that harbored FGFR3-TACC3 fusion as an attractive therapeutic target. The frequency of FGFR3-TACC3-fusion-positive cervical cancer is also 1.9% (2/103) in an independent cohort. Continuous expression of the FGFR3-TACC3 fusion transcript and protein induced anchorage-independent growth in the cervical epithelial cell line established from the ectocervix (Ect1/E6E7) but not in that from endocervix (End1/E6E7). Injection of FGFR3-TACC3 fusion-transfected-Ect1/E6E7 cells subcutaneously into NOG mice generated squamous cell carcinoma xenograft tumors, suggesting the association between FGFR3-TACC3 fusion and squamous cell carcinogenesis. Transfection of a FGFR3-TACC3 fusion transcript into four cervical cancer cell lines (SiHa, ME180, HeLa, and Ca Ski) induced activation of the MAPK pathway and enhancement of cell proliferation. Transcriptome analysis of the FGFR3-TACC3 fusion-transfected cell lines revealed that an IL8-triggered inflammatory response was increased, via activation of FGFR3-MAPK signaling. Continuous expression of FGFR3-TACC3 fusion led to activation of the PI3K-AKT pathway only in the two cell lines that harbored PIK3CA mutations. Sensitivity to the FGFR inhibitor, BGJ398, was found to depend on PIK3CA mutation status. Dual inhibition of both FGFR and AKT showed an obvious synergistic effect in cell lines that harbor mutant PIK3CA. Additionally, TACC3 inhibitor, KHS101, suppressed FGFR3-TACC3 fusion protein expression and showed antitumor effect against FGFR3-TACC3 fusion-transfected cell lines. FGFR3-TACC3 fusion-positive cancer has frequent genetic alterations of the PI3K/AKT pathway and selection of appropriate treatment based on PI3K/AKT pathway status should be required.

    DOI: 10.1038/s41389-017-0018-2

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  • Impact of Concurrent Genomic Alterations Detected by Comprehensive Genomic Sequencing on Clinical Outcomes in East-Asian Patients with EGFR-Mutated Lung Adenocarcinoma. 査読 国際誌

    Seijiro Sato, Masayuki Nagahashi, Terumoto Koike, Hiroshi Ichikawa, Yoshifumi Shimada, Satoshi Watanabe, Toshiaki Kikuchi, Kazuki Takada, Ryota Nakanishi, Eiji Oki, Tatsuro Okamoto, Kouhei Akazawa, Stephen Lyle, Yiwei Ling, Kazuaki Takabe, Shujiro Okuda, Toshifumi Wakai, Masanori Tsuchida

    Scientific reports   8 ( 1 )   1005 - 1005   2018年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Nature Publishing Group  

    Next-generation sequencing (NGS) has enabled comprehensive detection of genomic alterations in lung cancer. Ethnic differences may play a critical role in the efficacy of targeted therapies. The aim of this study was to identify and compare genomic alterations of lung adenocarcinoma between Japanese patients and the Cancer Genome Atlas (TCGA), which majority of patients are from the US. We also aimed to examine prognostic impact of additional genomic alterations in patients harboring EGFR mutations. Genomic alterations were determined in Japanese patients with lung adenocarcinoma (N = 100) using NGS-based sequencing of 415 known cancer genes, and correlated with clinical outcome. EGFR active mutations, i.e., those involving exon 19 deletion or an L858R point mutation, were seen in 43% of patients. Some differences in driver gene mutation prevalence were observed between the Japanese cohort described in the present study and the TCGA. Japanese cohort had significantly more genomic alterations in cell cycle pathway, i.e., CDKN2B and RB1 than TCGA. Concurrent mutations, in genes such as CDKN2B or RB1, were associated with worse clinical outcome in patients with EGFR active mutations. Our data support the utility of comprehensive sequencing to detect concurrent genomic variations that may affect clinical outcomes in this disease.

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  • Unique transcriptional profile of native persisters in Escherichia coli. 査読

    Shinya Matsumoto, Yuto Kawai, Satoshi Miyagawa, Yuka Iwamoto, Shujiro Okuda, Alicia Sánchez-Gorostiaga, Miguel Vicente, Satoshi Tsuneda

    Journal of bioscience and bioengineering   125 ( 1 )   15 - 22   2018年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Elsevier B.V.  

    Non-dividing persisters, bacteria that can survive in the presence of antibiotics by pausing their metabolic activity, are among the many causes of the refractory nature of bacterial infections. Here we constructed a recombinant Escherichia coli strain that enables to distinguish non-dividing from dividing cell based on Z-ring during cell division. Then, non-dividing cells and dividing cells were successfully separated using a fluorescence activated cell sorter. The sorted non-dividing cells showed significantly higher tolerance toward ofloxacin than dividing cells, which indicates that persisters were concentrated with the methodology. Transcriptional analysis revealed that genes involved in guanosine tetraphosphate synthesis are upregulated in persisters, which represses transcription and DNA replication and leads to ofloxacin tolerance. Lactate dehydrogenase and several ATP-binding cassette transporters were upregulated in persisters to adapt to anaerobic metabolism. In addition, nitrite and dimethyl sulfoxide (DMSO) may be used as reducible substrates for alternative energy generation pathways. Our methodology revealed a unique transcriptional profile of E. coli persisters.

    DOI: 10.1016/j.jbiosc.2017.07.015

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  • Actionable gene mutations in Asian populations with triple negative breast cancer 査読 国際誌

    Nagahashi M, Ling Y, Hayashida T, Kitagawa Y, Futamura M, Yoshida K, Kuwayama T, Nakamura S, Toshikawa C, Yamauchi H, Kaneko K, Kanbayashi C, Sato N, Miyoshi Y, Tsuchida J, Nakajima M, Shimada Y, Ichikawa H, Lyle S, Takabe K, Okuda S, Wakai T

    JCO Precision Oncoloty   2   e131111   2018年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1200/po.17.00211

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  • Pathogenic germline <i>BRCA1/2</i> mutations and familial predisposition to gastric cancer. 査読 国際誌

    Ichikawa H, Wakai T, Nagahashi M, Shimada Y, Hanyu T, Kano Y, Muneoka Y, Ishikawa T, Takizawa K, Tajima Y, Sakata J, Kobayashi T, Kemeyama H, Yabusaki H, Nakagawa S, Sato N, Kawasaki T, Homma K, Okuda S, Lyle S, Takabe K

    JCO precision oncology   2   2018年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1200/PO.18.00097

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  • 変異頻度に基づくガンゲノムデータの新規クラスタリング手法とその臨床応用 査読

    凌 一葦, 渡辺 由, 永橋 昌幸, 島田 能史, 市川 寛, 若井 俊文, 奥田 修二郎

    日本情報学   38 ( 5 )   305 - 312   2018年

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

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  • Comprehensive analysis of polyamine transport and biosynthesis in the dominant human gut bacteria: Potential presence of novel polyamine metabolism and transport genes. 査読 国際誌

    Yuta Sugiyama, Misaki Nara, Mikiyasu Sakanaka, Aina Gotoh, Aya Kitakata, Shujiro Okuda, Shin Kurihara

    The international journal of biochemistry & cell biology   93   52 - 61   2017年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Recent studies have reported that polyamines in the colonic lumen might affect animal health and these polyamines are thought to be produced by gut bacteria. In the present study, we measured the concentrations of three polyamines (putrescine, spermidine, and spermine) in cells and culture supernatants of 32 dominant human gut bacterial species in their growing and stationary phases. Combining polyamine concentration analysis in culture supernatant and cells with available genomic information showed that novel polyamine biosynthetic proteins and transporters were present in dominant human gut bacteria. Based on these findings, we suggested strategies for optimizing polyamine concentrations in the human colonic lumen via regulation of genes responsible for polyamine biosynthesis and transport in the dominant human gut bacteria.

    DOI: 10.1016/j.biocel.2017.10.015

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  • Comprehensive genomic sequencing detects important genetic differences between right-sided and left-sided colorectal cancer. 査読 国際誌

    Yoshifumi Shimada, Hitoshi Kameyama, Masayuki Nagahashi, Hiroshi Ichikawa, Yusuke Muneoka, Ryoma Yagi, Yosuke Tajima, Takuma Okamura, Masato Nakano, Jun Sakata, Takashi Kobayashi, Hitoshi Nogami, Satoshi Maruyama, Yasumasa Takii, Tetsu Hayashida, Hiromasa Takaishi, Yuko Kitagawa, Eiji Oki, Tsuyoshi Konishi, Fumio Ishida, Shin-Ei Kudo, Jennifer E Ring, Alexei Protopopov, Stephen Lyle, Yiwei Ling, Shujiro Okuda, Takashi Ishikawa, Kohei Akazawa, Kazuaki Takabe, Toshifumi Wakai

    Oncotarget   8 ( 55 )   93567 - 93579   2017年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:IMPACT JOURNALS LLC  

    Objectives: Anti-epidermal growth factor receptor (EGFR) therapy has been found to be more effective against left-sided colorectal cancer (LCRC) than right-sided colorectal cancer (RCRC). We hypothesized that RCRC is more likely to harbor genetic alterations associated with resistance to anti-EGFR therapy and tested this using comprehensive genomic sequencing. Materials and methods: A total of 201 patients with either primary RCRC or LCRC were analyzed. We investigated tumors for genetic alterations using a 415-gene panel, which included alterations associated with resistance to anti-EGFR therapy: TK receptors (ERBB2, MET, EGFR, FGFR1, and PDGFRA), RAS pathway (KRAS, NRAS, HRAS, BRAF, and MAPK2K1), and PI3K pathway (PTEN and PIK3CA). Patients whose tumors had no alterations in these 12 genes, theoretically considered to respond to anti-EGFR therapy, were defined as "all wild-type", while remaining patients were defined as "mutant-type". Results: Fifty-six patients (28%) and 145 patients (72%) had RCRC and LCRC, respectively. Regarding genetic alterations associated with anti-EGFR therapy, only 6 of 56 patients (11%) with RCRC were "all wild-type" compared with 41 of 145 patients (28%) with LCRC (P = 0.009). Among the 49 patients who received anti-EGFR therapy, RCRC showed significantly worse progression-free survival (PFS) than LCRC (P = 0.022), and "mutant-type" RCRC showed significantly worse PFS compared with "all wild-type" LCRC (P = 0.004). Conclusions: RCRC is more likely to harbor genetic alterations associated with resistance to anti-EGFR therapy compared with LCRC. Furthermore, our data shows primary tumor sidedness is a surrogate for the non-random distribution of genetic alterations in CRC.

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  • Rare PDCD11 variations are not associated with risk of schizophrenia in Japan. 査読 国際誌

    Satoshi Hoya, Yuichiro Watanabe, Akitoyo Hishimoto, Ayako Nunokawa, Naoshi Kaneko, Tatsuyuki Muratake, Naofumi Shinmyo, Ikuo Otsuka, Shujiro Okuda, Emiko Inoue, Hirofumi Igeta, Masako Shibuya, Jun Egawa, Naoki Orime, Ichiro Sora, Toshiyuki Someya

    Psychiatry and clinical neurosciences   71 ( 11 )   780 - 788   2017年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY  

    AIM: Rare gene variations are thought to confer substantial risk for schizophrenia. We performed a three-stage study to identify rare variations that have a strong impact on the risk of developing schizophrenia. METHODS: In the first stage, we prioritized rare missense variations using whole-exome sequencing (WES) data from three families, consisting of a proband, an affected sibling, and parents. In the second stage, we performed targeted resequencing of the PDCD11 coding region in 96 patients. In the third stage, we conducted an association study of rare PDCD11 variations with schizophrenia in a total of 1357 patients and 1394 controls. RESULTS: Via WES, we identified two rare missense PDCD11 variations, p.(Asp961Asn) and p.(Val1240Leu), shared by two affected siblings within families. Targeted resequencing of the PDCD11 coding region identified three rare non-synonymous variations: p.(Asp961Asn), p.(Phe1835del), and p.(Arg1837His). The case-control study demonstrated no significant associations between schizophrenia and four rare PDCD11 variations: p.(Asp961Asn), p.(Val1240Leu), p.(Phe1835del), and p.(Arg1837His). CONCLUSION: Our data do not support the role of rare PDCD11 variations in conferring substantial risk for schizophrenia in the Japanese population.

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  • Actionable gene-based classification toward precision medicine in gastric cancer. 査読 国際誌

    Hiroshi Ichikawa, Masayuki Nagahashi, Yoshifumi Shimada, Takaaki Hanyu, Takashi Ishikawa, Hitoshi Kameyama, Takashi Kobayashi, Jun Sakata, Hiroshi Yabusaki, Satoru Nakagawa, Nobuaki Sato, Yuki Hirata, Yuko Kitagawa, Toshiyuki Tanahashi, Kazuhiro Yoshida, Ryota Nakanishi, Eiji Oki, Dana Vuzman, Stephen Lyle, Kazuaki Takabe, Yiwei Ling, Shujiro Okuda, Kohei Akazawa, Toshifumi Wakai

    Genome medicine   9 ( 1 )   93 - 93   2017年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:BIOMED CENTRAL LTD  

    BACKGROUND: Intertumoral heterogeneity represents a significant hurdle to identifying optimized targeted therapies in gastric cancer (GC). To realize precision medicine for GC patients, an actionable gene alteration-based molecular classification that directly associates GCs with targeted therapies is needed. METHODS: A total of 207 Japanese patients with GC were included in this study. Formalin-fixed, paraffin-embedded (FFPE) tumor tissues were obtained from surgical or biopsy specimens and were subjected to DNA extraction. We generated comprehensive genomic profiling data using a 435-gene panel including 69 actionable genes paired with US Food and Drug Administration-approved targeted therapies, and the evaluation of Epstein-Barr virus (EBV) infection and microsatellite instability (MSI) status. RESULTS: Comprehensive genomic sequencing detected at least one alteration of 435 cancer-related genes in 194 GCs (93.7%) and of 69 actionable genes in 141 GCs (68.1%). We classified the 207 GCs into four The Cancer Genome Atlas (TCGA) subtypes using the genomic profiling data; EBV (N = 9), MSI (N = 17), chromosomal instability (N = 119), and genomically stable subtype (N = 62). Actionable gene alterations were not specific and were widely observed throughout all TCGA subtypes. To discover a novel classification which more precisely selects candidates for targeted therapies, 207 GCs were classified using hypermutated phenotype and the mutation profile of 69 actionable genes. We identified a hypermutated group (N = 32), while the others (N = 175) were sub-divided into six clusters including five with actionable gene alterations: ERBB2 (N = 25), CDKN2A, and CDKN2B (N = 10), KRAS (N = 10), BRCA2 (N = 9), and ATM cluster (N = 12). The clinical utility of this classification was demonstrated by a case of unresectable GC with a remarkable response to anti-HER2 therapy in the ERBB2 cluster. CONCLUSIONS: This actionable gene-based classification creates a framework for further studies for realizing precision medicine in GC.

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  • Use of Gifu Anaerobic Medium for culturing 32 dominant species of human gut microbes and its evaluation based on short-chain fatty acids fermentation profiles. 査読 国際誌

    Aina Gotoh, Misaki Nara, Yuta Sugiyama, Mikiyasu Sakanaka, Hiroyuki Yachi, Aya Kitakata, Akira Nakagawa, Hiromichi Minami, Shujiro Okuda, Toshihiko Katoh, Takane Katayama, Shin Kurihara

    Bioscience, biotechnology, and biochemistry   81 ( 10 )   2009 - 2017   2017年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:TAYLOR & FRANCIS LTD  

    Recently, a "human gut microbial gene catalogue," which ranks the dominance of microbe genus/species in human fecal samples, was published. Most of the bacteria ranked in the catalog are currently publicly available; however, the growth media recommended by the distributors vary among species, hampering physiological comparisons among the bacteria. To address this problem, we evaluated Gifu anaerobic medium (GAM) as a standard medium. Forty-four publicly available species of the top 56 species listed in the "human gut microbial gene catalogue" were cultured in GAM, and out of these, 32 (72%) were successfully cultured. Short-chain fatty acids from the bacterial culture supernatants were then quantified, and bacterial metabolic pathways were predicted based on in silico genomic sequence analysis. Our system provides a useful platform for assessing growth properties and analyzing metabolites of dominant human gut bacteria grown in GAM and supplemented with compounds of interest.

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  • Utility of comprehensive genomic sequencing for detecting HER2-positive colorectal cancer. 査読 国際誌

    Yoshifumi Shimada, Ryoma Yagi, Hitoshi Kameyama, Masayuki Nagahashi, Hiroshi Ichikawa, Yosuke Tajima, Takuma Okamura, Mae Nakano, Masato Nakano, Yo Sato, Takeaki Matsuzawa, Jun Sakata, Takashi Kobayashi, Hitoshi Nogami, Satoshi Maruyama, Yasumasa Takii, Takashi Kawasaki, Kei-Ichi Homma, Hiroshi Izutsu, Keisuke Kodama, Jennifer E Ring, Alexei Protopopov, Stephen Lyle, Shujiro Okuda, Kohei Akazawa, Toshifumi Wakai

    Human pathology   66   1 - 9   2017年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:W B SAUNDERS CO-ELSEVIER INC  

    HER2-targeted therapy is considered effective for KRAS codon 12/13 wild-type, HER2-positive metastatic colorectal cancer (CRC). In general, HER2 status is determined by the use of immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). Comprehensive genomic sequencing (CGS) enables the detection of gene mutations and copy number alterations including KRAS mutation and HER2 amplification; however, little is known about the utility of CGS for detecting HER2-positive CRC. To assess its utility, we retrospectively investigated 201 patients with stage I-IV CRC. The HER2 status of the primary site was assessed using IHC and FISH, and HER2 amplification of the primary site was also assessed using CGS, and the findings of these approaches were compared in each patient. CGS successfully detected alterations in 415 genes including KRAS codon 12/13 mutation and HER2 amplification. Fifty-nine (29%) patients had a KRAS codon 12/13 mutation. Ten (5%) patients were diagnosed as HER2 positive because of HER2 IHC 3+, and the same 10 (5%) patients had HER2 amplification evaluated using CGS. The results of HER2 status and HER2 amplification were completely identical in all 201 patients (P < .001). Nine of the 10 HER2-positive patients were KRAS 12/13 wild-type and were considered possible candidates for HER2-targeted therapy. CGS has the same utility as IHC and FISH for detecting HER2-positive patients who are candidates for HER2-targeted therapy, and facilitates precision medicine and tailor-made treatment.

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  • Cost-effectiveness analysis of the use of comprehensive molecular profiling before initiating monoclonal antibody therapy against metastatic colorectal cancer in Japan 査読

    Shota Saito, Hitoshi Kameyama, Yusuke Muneoka, Shujiro Okuda, Toshifumi Wakai, Kouhei Akazawa

    Journal of Cancer Policy   12   61 - 66   2017年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Elsevier Ltd  

    Introduction Comprehensive molecular profiling has become a pivotal component of precision medicine involving anti-epidermal growth factor receptor (EGFR) monoclonal antibody therapy for metastatic colorectal cancer. The objective of this study was to determine the cost-effectiveness of comprehensive molecular profiling before initiating anti-EGFR therapies for metastatic colorectal cancer. Methods A Markov model simulating the health outcomes and total costs was developed to estimate the life years and quality-adjusted life years (QALYs) gained by metastatic colorectal cancer patients treated with anti-EGFR drug. The cost-effectiveness of comprehensive screening versus RAS mutation screening was evaluated over a 5-year period using the incremental cost-effectiveness ratio (ICER). The ICER per additional QALY gained was calculated, and sensitivity analyses were performed to evaluate the robustness of the assumptions across a range of values. Analyses were made from the perspective of the Japanese healthcare payer. Results Comprehensive screening before monoclonal antibody therapy provided 0.063 additional QALYs (0.075 life years) at the cost of 268,274 Japanese Yen (JPY). The ICER was 4,260,187 JPY/QALY compared to RAS screening. The median progression-free survival obtained by sensitivity analyses for the subgroup not responding to anti-EGFR therapy showed that comprehensive screening and panitumumab prices had the strongest influence on cost-effectiveness. Conclusion The incremental cost per QALY gained indicated that comprehensive screening was more cost-effective compared to RAS screening. With a willingness-to-pay value of 6 million JPY/QALY, comprehensive screening can be considered for the genetic testing of patients before providing monoclonal antibody therapy.

    DOI: 10.1016/j.jcpo.2017.03.008

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  • Genome-Wide Target Analyses of Otx2 Homeoprotein in Postnatal Cortex 査読

    Akiko Sakai, Ryuichiro Nakato, Yiwei Ling, Xubin Hou, Norikazu Hara, Tomoya Iijima, Yuchio Yanagawa, Ryozo Kuwano, Shujiro Okuda, Katsuhiko Shirahige, Sayaka Sugiyama

    FRONTIERS IN NEUROSCIENCE   11   2017年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:FRONTIERS MEDIA SA  

    Juvenile brain has a unique time window, or critical period, in which neuronal circuits are remodeled by experience. Mounting evidence indicates the importance of neuronal circuit rewiring in various neurodevelopmental disorders of human cognition. We previously showed that Otx2 homeoprotein, essential for brain formation, is recaptured during postnatal maturation of parvalbumin positive interneurons (PV cells) to activate the critical period in mouse visual cortex. Cortical Otx2 is the only interneuron-enriched transcription factor known to regulate the critical period, but its downstream targets remain unknown. Here, we used ChIP-seq (chromatin immunoprecipitation sequencing) to identify genome-wide binding sites of Otx2 in juvenile mouse cortex, and interneuron-specific RNA-seq to explore the Otx2-dependent transcriptome. Otx2-bound genes were associated with human diseases such as schizophrenia as well as critical periods. Of these genes, expression of neuronal factors involved in transcription, signal transduction and mitochondria' function was moderately and broadly affected in Otx2-deficient interneurons. In contrast to reported binding sites in the embryo, genes encoding potassium ion transporters such as K(v)3.1 had juvenile cortex-specific binding sites, suggesting that Otx2 is involved in regulating fast-spiking properties during PV cell maturation. Moreover, transcripts of oxidative resistance-1 (Oxr1), whose promoter has Otx2 binding sites, were markedly downregulated in Otx2 deficient interneurons. Therefore, an important role of Otx2 may be to protect the cells from the increased oxidative stress in fast-spiking PV cells. Our results suggest that coordinated expression of Otx2 targets promotes PV cell maturation and maintains its function in neuronal plasticity and disease.

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  • Molecular Insight into Evolution of Symbiosis between Breast-Fed Infants and a Member of the Human Gut Microbiome Bifidobacterium longum. 査読 国際誌

    Chihaya Yamada, Aina Gotoh, Mikiyasu Sakanaka, Mitchell Hattie, Keith A Stubbs, Ayako Katayama-Ikegami, Junko Hirose, Shin Kurihara, Takatoshi Arakawa, Motomitsu Kitaoka, Shujiro Okuda, Takane Katayama, Shinya Fushinobu

    Cell chemical biology   24 ( 4 )   515 - 524   2017年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:CELL PRESS  

    Breast-fed infants generally have a bifidobacteria-rich microbiota with recent studies indicating that human milk oligosaccharides (HMOs) selectively promote bifidobacterial growth. Bifidobacterium bifidum possesses a glycoside hydrolase family 20 lacto-N-biosidase for liberating lacto-N-biose I from lacto-N-tetraose, an abundant HMO unique to human milk, while Bifidobacterium longum subsp. longum has a non-classified enzyme (LnbX). Here, we determined the crystal structure of the catalytic domain of LnbX and provide evidence for creation of a novel glycoside hydrolase family, GH136. The structure, in combination with inhibition and mutation studies, provides insight into the molecular mechanism and broader substrate specificity of this enzyme. Moreover, through genetic studies, we show that lnbX is indispensable for B. longum growth on lacto-N-tetraose and is a key genetic factor for persistence in the gut of breast-fed infants. Overall, this study reveals possible evolutionary routes for the emergence of symbiosis between humans and bifidobacterial species in the infant gut.

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  • Molecular Insight into Evolution of Symbiosis between Breast-Fed Infants and a Member of the Human Gut Microbiome Bifidobacterium longum. 査読 国際誌

    Chihaya Yamada, Aina Gotoh, Mikiyasu Sakanaka, Mitchell Hattie, Keith A Stubbs, Ayako Katayama-Ikegami, Junko Hirose, Shin Kurihara, Takatoshi Arakawa, Motomitsu Kitaoka, Shujiro Okuda, Takane Katayama, Shinya Fushinobu

    Cell chemical biology   24 ( 4 )   515 - 524   2017年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Breast-fed infants generally have a bifidobacteria-rich microbiota with recent studies indicating that human milk oligosaccharides (HMOs) selectively promote bifidobacterial growth. Bifidobacterium bifidum possesses a glycoside hydrolase family 20 lacto-N-biosidase for liberating lacto-N-biose I from lacto-N-tetraose, an abundant HMO unique to human milk, while Bifidobacterium longum subsp. longum has a non-classified enzyme (LnbX). Here, we determined the crystal structure of the catalytic domain of LnbX and provide evidence for creation of a novel glycoside hydrolase family, GH136. The structure, in combination with inhibition and mutation studies, provides insight into the molecular mechanism and broader substrate specificity of this enzyme. Moreover, through genetic studies, we show that lnbX is indispensable for B. longum growth on lacto-N-tetraose and is a key genetic factor for persistence in the gut of breast-fed infants. Overall, this study reveals possible evolutionary routes for the emergence of symbiosis between humans and bifidobacterial species in the infant gut.

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  • Poly(ADP-ribose) polymerase inhibitors activate the p53 signaling pathway in neural stem/progenitor cells. 査読 国際誌

    Akiko Okuda, Suguru Kurokawa, Masanori Takehashi, Aika Maeda, Katsuya Fukuda, Yukari Kubo, Hyuma Nogusa, Tomoka Takatani-Nakase, Shujiro Okuda, Kunihiro Ueda, Seigo Tanaka

    BMC neuroscience   18 ( 1 )   14 - 14   2017年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:BIOMED CENTRAL LTD  

    BACKGROUND: Poly(ADP-ribose) polymerase 1 (PARP-1), which catalyzes poly(ADP-ribosyl)ation of proteins by using NAD+ as a substrate, plays a key role in several nuclear events, including DNA repair, replication, and transcription. Recently, PARP-1 was reported to participate in the somatic cell reprogramming process. Previously, we revealed a role for PARP-1 in the induction of neural apoptosis in a cellular model of cerebral ischemia and suggested the possible use of PARP inhibitors as a new therapeutic intervention. In the present study, we examined the effects of PARP inhibitors on neural stem/progenitor cells (NSPCs) of the mouse brain. RESULTS: PARP-1 was more abundant and demonstrated higher activity in NSPCs than in mouse embryonic fibroblasts. Treatment with PARP inhibitors suppressed the formation of neurospheres by NSPCs through the suppression of cell cycle progression and the induction of apoptosis. In order to identify the genes responsible for these effects, we investigated gene expression profiles by microarray analyses and found that several genes in the p53 signaling pathway were upregulated, including Cdkn1a, which is critical for cell cycle control, and Fas, Pidd, Pmaip1, and Bbc3, which are principal factors in the apoptosis pathway. Inhibition of poly(ADP-ribosyl)ation increased the levels of p53 protein, but not p53 mRNA, and enhanced the phosphorylation of p53 at Ser18. Experiments with specific inhibitors and also shRNA demonstrated that PARP-1, but not PARP-2, has a role in the regulation of p53. The effects of PARP inhibitors on NSPCs were not observed in Trp53 -/- NSPCs, suggesting a key role for p53 in these events. CONCLUSIONS: On the basis of the finding that PARP inhibitors facilitated the p53 signaling pathway, we propose that poly(ADP-ribosyl)ation contributes to the proliferation and self-renewal of NSPCs through the suppression of p53 activation.

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  • jPOSTrepo: an international standard data repository for proteomes. 査読 国際誌

    Shujiro Okuda, Yu Watanabe, Yuki Moriya, Shin Kawano, Tadashi Yamamoto, Masaki Matsumoto, Tomoyo Takami, Daiki Kobayashi, Norie Araki, Akiyasu C Yoshizawa, Tsuyoshi Tabata, Naoyuki Sugiyama, Susumu Goto, Yasushi Ishihama

    Nucleic acids research   45 ( D1 )   D1107-D1111 - D1111   2017年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:OXFORD UNIV PRESS  

    Major advancements have recently been made in mass spectrometry-based proteomics, yielding an increasing number of datasets from various proteomics projects worldwide. In order to facilitate the sharing and reuse of promising datasets, it is important to construct appropriate, high-quality public data repositories. jPOSTrepo (https://repository.jpostdb.org/) has successfully implemented several unique features, including high-speed file uploading, flexible file management and easy-to-use interfaces. This repository has been launched as a public repository containing various proteomic datasets and is available for researchers worldwide. In addition, our repository has joined the ProteomeXchange consortium, which includes the most popular public repositories such as PRIDE in Europe for MS/MS datasets and PASSEL for SRM datasets in the USA. Later MassIVE was introduced in the USA and accepted into the ProteomeXchange, as was our repository in July 2016, providing important datasets from Asia/Oceania. Accordingly, this repository thus contributes to a global alliance to share and store all datasets from a wide variety of proteomics experiments. Thus, the repository is expected to become a major repository, particularly for data collected in the Asia/Oceania region.

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  • The ProteomeXchange consortium in 2017: supporting the cultural change in proteomics public data deposition. 査読 国際誌

    Eric W Deutsch, Attila Csordas, Zhi Sun, Andrew Jarnuczak, Yasset Perez-Riverol, Tobias Ternent, David S Campbell, Manuel Bernal-Llinares, Shujiro Okuda, Shin Kawano, Robert L Moritz, Jeremy J Carver, Mingxun Wang, Yasushi Ishihama, Nuno Bandeira, Henning Hermjakob, Juan Antonio Vizcaíno

    Nucleic acids research   45 ( D1 )   D1100-D1106 - D1106   2017年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:OXFORD UNIV PRESS  

    The ProteomeXchange (PX) Consortium of proteomics resources (http://www.proteomexchange.org) was formally started in 2011 to standardize data submission and dissemination of mass spectrometry proteomics data worldwide. We give an overview of the current consortium activities and describe the advances of the past few years. Augmenting the PX founding members (PRIDE and PeptideAtlas, including the PASSEL resource), two new members have joined the consortium: MassIVE and jPOST. ProteomeCentral remains as the common data access portal, providing the ability to search for data sets in all participating PX resources, now with enhanced data visualization components.We describe the updated submission guidelines, now expanded to include four members instead of two. As demonstrated by data submission statistics, PX is supporting a change in culture of the proteomics field: public data sharing is now an accepted standard, supported by requirements for journal submissions resulting in public data release becoming the norm. More than 4500 data sets have been submitted to the various PX resources since 2012. Human is the most represented species with approximately half of the data sets, followed by some of the main model organisms and a growing list of more than 900 diverse species. Data reprocessing activities are becoming more prominent, with both MassIVE and PeptideAtlas releasing the results of reprocessed data sets. Finally, we outline the upcoming advances for ProteomeXchange.

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  • Genome-Wide Target Analyses of Otx2 Homeoprotein in Postnatal Cortex. 査読 国際誌

    Akiko Sakai, Ryuichiro Nakato, Yiwei Ling, Xubin Hou, Norikazu Hara, Tomoya Iijima, Yuchio Yanagawa, Ryozo Kuwano, Shujiro Okuda, Katsuhiko Shirahige, Sayaka Sugiyama

    Frontiers in neuroscience   11   307 - 307   2017年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Juvenile brain has a unique time window, or critical period, in which neuronal circuits are remodeled by experience. Mounting evidence indicates the importance of neuronal circuit rewiring in various neurodevelopmental disorders of human cognition. We previously showed that Otx2 homeoprotein, essential for brain formation, is recaptured during postnatal maturation of parvalbumin-positive interneurons (PV cells) to activate the critical period in mouse visual cortex. Cortical Otx2 is the only interneuron-enriched transcription factor known to regulate the critical period, but its downstream targets remain unknown. Here, we used ChIP-seq (chromatin immunoprecipitation sequencing) to identify genome-wide binding sites of Otx2 in juvenile mouse cortex, and interneuron-specific RNA-seq to explore the Otx2-dependent transcriptome. Otx2-bound genes were associated with human diseases such as schizophrenia as well as critical periods. Of these genes, expression of neuronal factors involved in transcription, signal transduction and mitochondrial function was moderately and broadly affected in Otx2-deficient interneurons. In contrast to reported binding sites in the embryo, genes encoding potassium ion transporters such as KV3.1 had juvenile cortex-specific binding sites, suggesting that Otx2 is involved in regulating fast-spiking properties during PV cell maturation. Moreover, transcripts of oxidative resistance-1 (Oxr1), whose promoter has Otx2 binding sites, were markedly downregulated in Otx2-deficient interneurons. Therefore, an important role of Otx2 may be to protect the cells from the increased oxidative stress in fast-spiking PV cells. Our results suggest that coordinated expression of Otx2 targets promotes PV cell maturation and maintains its function in neuronal plasticity and disease.

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  • Inhibition of dipeptidyl peptidase-4 ameliorates cardiac ischemia and systolic dysfunction by up-regulating the FGF-2/EGR-1 pathway. 査読 国際誌

    Masayoshi Suda, Ippei Shimizu, Yohko Yoshida, Yuka Hayashi, Ryutaro Ikegami, Goro Katsuumi, Takayuki Wakasugi, Yutaka Yoshida, Shujiro Okuda, Tomoyoshi Soga, Tohru Minamino

    PloS one   12 ( 8 )   e0182422   2017年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PUBLIC LIBRARY SCIENCE  

    Dipeptidyl peptidase 4 inhibitors are used worldwide in the management of diabetes, but their role in the prevention or treatment of cardiovascular disorders has yet to be defined. We found that linagliptin, a DPP-4 inhibitor, suppressed capillary rarefaction in the hearts of mice with dietary obesity. Metabolomic analysis performed with capillary electrophoresis/mass spectrometry (LC-MS/MS) showed that linagliptin promoted favorable metabolic remodeling in cardiac tissue, which was characterized by high levels of citrulline and creatine. DNA microarray analysis revealed that the cardiac tissue level of early growth response protein 1 (EGR-1), which activates angiogenesis, was significantly reduced in untreated mice with dietary obesity, while this decrease was inhibited by administration of linagliptin. Mature fibroblast growth factor 2 (FGF-2) has a putative truncation site for DPP-4 at the NH2-terminal, and LC-MS/MS showed that recombinant DPP-4 protein cleaved the NH2-terminal dipeptides of mature FGF-2. Incubation of cultured neonatal rat cardiomyocytes with FGF-2 increased Egr1 expression, while it was suppressed by recombinant DPP-4 protein. Furthermore, vascular endothelial growth factor-A had a critical role in mediating FGF-2/EGR-1 signaling. In conclusion, pharmacological inhibition of DPP-4 suppressed capillary rarefaction and contributed to favorable remodeling of cardiac metabolism in mice with dietary obesity.

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  • Genomic landscape of colorectal cancer in Japan: clinical implications of comprehensive genomic sequencing for precision medicine. 査読 国際誌

    Masayuki Nagahashi, Toshifumi Wakai, Yoshifumi Shimada, Hiroshi Ichikawa, Hitoshi Kameyama, Takashi Kobayashi, Jun Sakata, Ryoma Yagi, Nobuaki Sato, Yuko Kitagawa, Hiroyuki Uetake, Kazuhiro Yoshida, Eiji Oki, Shin-Ei Kudo, Hiroshi Izutsu, Keisuke Kodama, Mitsutaka Nakada, Julie Tse, Meaghan Russell, Joerg Heyer, Winslow Powers, Ruobai Sun, Jennifer E Ring, Kazuaki Takabe, Alexei Protopopov, Yiwei Ling, Shujiro Okuda, Stephen Lyle

    Genome medicine   8 ( 1 )   136 - 136   2016年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:BIOMED CENTRAL LTD  

    BACKGROUND: Comprehensive genomic sequencing (CGS) has the potential to revolutionize precision medicine for cancer patients across the globe. However, to date large-scale genomic sequencing of cancer patients has been limited to Western populations. In order to understand possible ethnic and geographic differences and to explore the broader application of CGS to other populations, we sequenced a panel of 415 important cancer genes to characterize clinically actionable genomic driver events in 201 Japanese patients with colorectal cancer (CRC). METHODS: Using next-generation sequencing methods, we examined all exons of 415 known cancer genes in Japanese CRC patients (n = 201) and evaluated for concordance among independent data obtained from US patients with CRC (n = 108) and from The Cancer Genome Atlas-CRC whole exome sequencing (WES) database (n = 224). Mutation data from non-hypermutated Japanese CRC patients were extracted and clustered by gene mutation patterns. Two different sets of genes from the 415-gene panel were used for clustering: 61 genes with frequent alteration in CRC and 26 genes that are clinically actionable in CRC. RESULTS: The 415-gene panel is able to identify all of the critical mutations in tumor samples as well as WES, including identifying hypermutated tumors. Although the overall mutation spectrum of the Japanese patients is similar to that of the Western population, we found significant differences in the frequencies of mutations in ERBB2 and BRAF. We show that the 415-gene panel identifies a number of clinically actionable mutations in KRAS, NRAS, and BRAF that are not detected by hot-spot testing. We also discovered that 26% of cases have mutations in genes involved in DNA double-strand break repair pathway. Unsupervised clustering revealed that a panel of 26 genes can be used to classify the patients into eight different categories, each of which can optimally be treated with a particular combination therapy. CONCLUSIONS: Use of a panel of 415 genes can reliably identify all of the critical mutations in CRC patients and this information of CGS can be used to determine the most optimal treatment for patients of all ethnicities.

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  • An adenylyl cyclase with a phosphodiesterase domain in basal plants with a motile sperm system. 査読 国際誌

    Masahiro Kasahara, Noriyuki Suetsugu, Yuki Urano, Chiaki Yamamoto, Mikiya Ohmori, Yuki Takada, Shujiro Okuda, Tomoaki Nishiyama, Hidetoshi Sakayama, Takayuki Kohchi, Fumio Takahashi

    Scientific reports   6   39232 - 39232   2016年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATURE PUBLISHING GROUP  

    Adenylyl cyclase (AC), which produces the signalling molecule cAMP, has numerous important cellular functions in diverse organisms from prokaryotes to eukaryotes. Here we report the identification and characterization of an AC gene from the liverwort Marchantia polymorpha. The encoded protein has both a C-terminal AC catalytic domain similar to those of class III ACs and an N-terminal cyclic nucleotide phosphodiesterase (PDE) domain that degrades cyclic nucleotides, thus we designated the gene MpCAPE (COMBINED AC with PDE). Biochemical analyses of recombinant proteins showed that MpCAPE has both AC and PDE activities. In MpCAPE-promoter-GUS lines, GUS activity was specifically detected in the male sexual organ, the antheridium, suggesting MpCAPE and thus cAMP signalling may be involved in the male reproductive process. CAPE orthologues are distributed only in basal land plants and charophytes that use motile sperm as the male gamete. CAPE is a subclass of class III AC and may be important in male organ and cell development in basal plants.

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  • Semantic Web Technologies for Integrating Glycan-related Databases in GlyTouCan 査読

    Aoki-Kinoshita Kiyoko F, Aoki Nobuyuki P, Fujita Akihiro, Fujita Noriaki, Matsubara Masaaki, Okuda Shujiro, Shikanai Toshihide, Shinmachi Daisuke, Solovieva Elena, Suzuki Yoshinori, Tsuchiya Shinichiro, Yamada Issaku, Narimatsu Hisashi

    GLYCOBIOLOGY   26 ( 12 )   1454 - 1455   2016年12月

  • [New Classification for Advanced Colorectal Cancer Using CancerPlex®Genomic Tests]. 査読

    Kameyama H, Shimada Y, Ichikawa H, Nagahashi M, Sakata J, Kobayashi T, Nogami H, Maruyama S, Takii Y, Okuda S, Ling Y, Izutsu H, Kodama K, Nakada M, Wakai T

    Gan to kagaku ryoho. Cancer & chemotherapy   43 ( 11 )   1361 - 1365   2016年11月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

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  • Mutations in SDR9C7 gene encoding an enzyme for vitamin A metabolism underlie autosomal recessive congenital ichthyosis. 査読 国際誌

    Yohya Shigehara, Shujiro Okuda, Georges Nemer, Adele Chedraoui, Ryota Hayashi, Fadi Bitar, Hiroyuki Nakai, Ossama Abbas, Laetitia Daou, Riichiro Abe, Maria Bou Sleiman, Abdul Ghani Kibbi, Mazen Kurban, Yutaka Shimomura

    Human molecular genetics   25 ( 20 )   4484 - 4493   2016年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:OXFORD UNIV PRESS  

    Autosomal recessive congenital ichthyosis (ARCI) is a heterogeneous group of hereditary skin disorder characterized by an aberrant cornification of the epidermis. ARCI is classified into a total of 11 subtypes (ARCI1-ARCI11) based on their causative genes or loci. Of these, the causative gene for only ARCI7 has not been identified, while it was previously mapped on chromosome 12p11.2-q13.1. In this study, we performed genetic analyses for three Lebanese families with ARCI, and successfully determined the linkage interval to 9.47 Mb region on chromosome 12q13.13-q14.1, which was unexpectedly outside of the ARCI7 locus. Whole-exome sequencing and the subsequent Sanger sequencing led to the identification of missense mutations in short chain dehydrogenase/reductase family 9C, member 7 (SDR9C7) gene on chromosome 12q13.3, i.e. two families shared an identical homozygous mutation c.599T > C (p.Ile200Thr) and one family had another homozygous mutation c.214C > T (p.Arg72Trp). In cultured cells, expression of both the mutant SDR9C7 proteins was markedly reduced as compared to wild-type protein, suggesting that the mutations severely affected a stability of the protein. In normal human skin, the SDR9C7 was abundantly expressed in granular and cornified layers of the epidermis. By contrast, in a patient’s skin, its expression in the cornified layer was significantly decreased. It has previously been reported that SDR9C7 is an enzyme to convert retinal into retinol. Therefore, our study not only adds a new gene responsible for ARCI, but also further suggests a potential role of vitamin A metabolism in terminal differentiation of the epidermis in humans.

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  • Rare UNC13B variations and risk of schizophrenia: Whole-exome sequencing in a multiplex family and follow-up resequencing and a case-control study. 査読 国際誌

    Jun Egawa, Satoshi Hoya, Yuichiro Watanabe, Ayako Nunokawa, Masako Shibuya, Masashi Ikeda, Emiko Inoue, Shujiro Okuda, Kenji Kondo, Takeo Saito, Naoshi Kaneko, Tatsuyuki Muratake, Hirofumi Igeta, Nakao Iwata, Toshiyuki Someya

    American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics   171 ( 6 )   797 - 805   2016年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY  

    Rare genomic variations inherited in multiplex schizophrenia families are suggested to play a role in the genetic etiology of the disease. To identify rare variations with large effects on the risk of developing schizophrenia, we performed whole-exome sequencing (WES) in two affected and one unaffected individual of a multiplex family with 10 affected individuals. We also performed follow-up resequencing of the unc-13 homolog B (Caenorhabditis elegans) (UNC13B) gene, a potential risk gene identified by WES, in the multiplex family and undertook a case-control study to investigate association between UNC13B and schizophrenia. UNC13B coding regions (39 exons) from 15 individuals of the multiplex family and 111 affected offspring for whom parental DNA samples were available were resequenced. Rare missense UNC13B variations identified by resequencing were further tested for association with schizophrenia in two independent case-control populations comprising a total of 1,753 patients and 1,602 controls. A rare missense variation (V1525M) in UNC13B was identified by WES in the multiplex family; this variation was present in five of six affected individuals, but not in eight unaffected individuals or one individual of unknown disease status. Resequencing UNC13B coding regions identified five rare missense variations (T103M, M813T, P1349T, I1362T, and V1525M). In the case-control study, there was no significant association between rare missense UNC13B variations and schizophrenia, although single-variant meta-analysis indicated that M813T was nominally associated with schizophrenia. These results do not support a contribution of rare missense UNC13B variations to the genetic etiology of schizophrenia in the Japanese population. © 2016 Wiley Periodicals, Inc.

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  • p62/Sqstm1 promotes malignancy of HCV-positive hepatocellular carcinoma through Nrf2-dependent metabolic reprogramming. 査読 国際誌

    Tetsuya Saito, Yoshinobu Ichimura, Keiko Taguchi, Takafumi Suzuki, Tsunehiro Mizushima, Kenji Takagi, Yuki Hirose, Masayuki Nagahashi, Tetsuro Iso, Toshiaki Fukutomi, Maki Ohishi, Keiko Endo, Takefumi Uemura, Yasumasa Nishito, Shujiro Okuda, Miki Obata, Tsuguka Kouno, Riyo Imamura, Yukio Tada, Rika Obata, Daisuke Yasuda, Kyoko Takahashi, Tsutomu Fujimura, Jingbo Pi, Myung-Shik Lee, Takashi Ueno, Tomoyuki Ohe, Tadahiko Mashino, Toshifumi Wakai, Hirotatsu Kojima, Takayoshi Okabe, Tetsuo Nagano, Hozumi Motohashi, Satoshi Waguri, Tomoyoshi Soga, Masayuki Yamamoto, Keiji Tanaka, Masaaki Komatsu

    Nature communications   7   12030 - 12030   2016年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATURE PUBLISHING GROUP  

    p62/Sqstm1 is a multifunctional protein involved in cell survival, growth and death, that is degraded by autophagy. Amplification of the p62/Sqstm1 gene, and aberrant accumulation and phosphorylation of p62/Sqstm1, have been implicated in tumour development. Herein, we reveal the molecular mechanism of p62/Sqstm1-dependent malignant progression, and suggest that molecular targeting of p62/Sqstm1 represents a potential chemotherapeutic approach against hepatocellular carcinoma (HCC). Phosphorylation of p62/Sqstm1 at Ser349 directs glucose to the glucuronate pathway, and glutamine towards glutathione synthesis through activation of the transcription factor Nrf2. These changes provide HCC cells with tolerance to anti-cancer drugs and proliferation potency. Phosphorylated p62/Sqstm1 accumulates in tumour regions positive for hepatitis C virus (HCV). An inhibitor of phosphorylated p62-dependent Nrf2 activation suppresses the proliferation and anticancer agent tolerance of HCC. Our data indicate that this Nrf2 inhibitor could be used to make cancer cells less resistant to anticancer drugs, especially in HCV-positive HCC patients.

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  • Species-function relationships shape ecological properties of the human gut microbiome. 査読 国際誌

    Sara Vieira-Silva, Gwen Falony, Youssef Darzi, Gipsi Lima-Mendez, Roberto Garcia Yunta, Shujiro Okuda, Doris Vandeputte, Mireia Valles-Colomer, Falk Hildebrand, Samuel Chaffron, Jeroen Raes

    Nature microbiology   1 ( 8 )   16088 - 16088   2016年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATURE PUBLISHING GROUP  

    Despite recent progress, the organization and ecological properties of the intestinal microbial ecosystem remain under-investigated. Here, using a manually curated metabolic module framework for (meta-)genomic data analysis, we studied species-function relationships in gut microbial genomes and microbiomes. Half of gut-associated species were found to be generalists regarding overall substrate preference, but we observed significant genus-level metabolic diversification linked to bacterial life strategies. Within each genus, metabolic consistency varied significantly, being low in Firmicutes genera and higher in Bacteroides. Differentiation of fermentable substrate degradation potential contributed to metagenomic functional repertoire variation between individuals, with different enterotypes showing distinct saccharolytic/proteolytic/lipolytic profiles. Finally, we found that module-derived functional redundancy was reduced in the low-richness Bacteroides enterotype, potentially indicating a decreased resilience to perturbation, in line with its frequent association to dysbiosis. These results provide insights into the complex structure of gut microbiome-encoded metabolic properties and emphasize the importance of functional and ecological assessment of gut microbiome variation in clinical studies.

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  • Mutation burden and microsatellite instability in colorectal cancer in Japan and US 査読

    Nagahashi Masayuki, Wakai Toshifumi, Shimada Yoshifumi, Ichikawa Hiroshi, Kameyama Hitoshi, Kobayashi Takashi, Nakajima Masato, Muneoka Yusuke, Akazawa Kohei, Moro Kazuki, Tsuchida Junko, Soma Daiki, Yuza Kizuki, Ando Takuya, Izutsu Hiroshi, Tse Julie, Okuda Shujiro, Takabe Kazuaki, Protopopov Alexei, Lyle Stephen

    JOURNAL OF CLINICAL ONCOLOGY   34 ( 15 )   2016年5月

  • Identification of Enzyme Genes Using Chemical Structure Alignments of Substrate-Product Pairs. 査読 国際誌

    Yuki Moriya, Takuji Yamada, Shujiro Okuda, Zenichi Nakagawa, Masaaki Kotera, Toshiaki Tokimatsu, Minoru Kanehisa, Susumu Goto

    Journal of chemical information and modeling   56 ( 3 )   510 - 6   2016年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER CHEMICAL SOC  

    Although there are several databases that contain data on many metabolites and reactions in biochemical pathways, there is still a big gap in the numbers between experimentally identified enzymes and metabolites. It is supposed that many catalytic enzyme genes are still unknown. Although there are previous studies that estimate the number of candidate enzyme genes, these studies required some additional information aside from the structures of metabolites such as gene expression and order in the genome. In this study, we developed a novel method to identify a candidate enzyme gene of a reaction using the chemical structures of the substrate-product pair (reactant pair). The proposed method is based on a search for similar reactant pairs in a reference database and offers ortholog groups that possibly mediate the given reaction. We applied the proposed method to two experimentally validated reactions. As a result, we confirmed that the histidine transaminase was correctly identified. Although our method could not directly identify the asparagine oxo-acid transaminase, we successfully found the paralog gene most similar to the correct enzyme gene. We also applied our method to infer candidate enzyme genes in the mesaconate pathway. The advantage of our method lies in the prediction of possible genes for orphan enzyme reactions where any associated gene sequences are not determined yet. We believe that this approach will facilitate experimental identification of genes for orphan enzymes.

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  • GlyTouCan international glycan structure repository using semantic web technologies 査読

    Issaku Yamada, Kiyoko Aoki-Kinoshita, Nobuyuki Aoki, Daisuke Shinmachi, Masaaki Matsubara, Akihiro Fujita, Shinichiro Tsuchiya, Shujiro Okuda, Noriaki Fujita, Hisashi Narimatsu

    ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY   251   2016年3月

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    記述言語:英語   出版者・発行元:AMER CHEMICAL SOC  

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  • GlyTouCan 1.0--The international glycan structure repository. 査読 国際誌

    Kiyoko Aoki-Kinoshita, Sanjay Agravat, Nobuyuki P Aoki, Sena Arpinar, Richard D Cummings, Akihiro Fujita, Noriaki Fujita, Gerald M Hart, Stuart M Haslam, Toshisuke Kawasaki, Masaaki Matsubara, Kelley W Moreman, Shujiro Okuda, Michael Pierce, René Ranzinger, Toshihide Shikanai, Daisuke Shinmachi, Elena Solovieva, Yoshinori Suzuki, Shinichiro Tsuchiya, Issaku Yamada, William S York, Joseph Zaia, Hisashi Narimatsu

    Nucleic acids research   44 ( D1 )   D1237-42 - D1242   2016年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:OXFORD UNIV PRESS  

    Glycans are known as the third major class of biopolymers, next to DNA and proteins. They cover the surfaces of many cells, serving as the 'face' of cells, whereby other biomolecules and viruses interact. The structure of glycans, however, differs greatly from DNA and proteins in that they are branched, as opposed to linear sequences of amino acids or nucleotides. Therefore, the storage of glycan information in databases, let alone their curation, has been a difficult problem. This has caused many duplicated efforts when integration is attempted between different databases, making an international repository for glycan structures, where unique accession numbers are assigned to every identified glycan structure, necessary. As such, an international team of developers and glycobiologists have collaborated to develop this repository, called GlyTouCan and is available at http://glytoucan.org/, to provide a centralized resource for depositing glycan structures, compositions and topologies, and to retrieve accession numbers for each of these registered entries. This will thus enable researchers to reference glycan structures simply by accession number, as opposed to by chemical structure, which has been a burden to integrate glycomics databases in the past.

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  • Novel kinase fusion transcripts found in endometrial cancer. 査読 国際誌

    Ryo Tamura, Kosuke Yoshihara, Kaoru Yamawaki, Kazuaki Suda, Tatsuya Ishiguro, Sosuke Adachi, Shujiro Okuda, Ituro Inoue, Roel G W Verhaak, Takayuki Enomoto

    Scientific reports   5   18657 - 18657   2015年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATURE PUBLISHING GROUP  

    Recent advances in RNA-sequencing technology have enabled the discovery of gene fusion transcripts in the transcriptome of cancer cells. However, it remains difficult to differentiate the therapeutically targetable fusions from passenger events. We have analyzed RNA-sequencing data and DNA copy number data from 25 endometrial cancer cell lines to identify potential therapeutically targetable fusion transcripts, and have identified 124 high-confidence fusion transcripts, of which 69% are associated with gene amplifications. As targetable fusion candidates, we focused on three in-frame kinase fusion transcripts that retain a kinase domain (CPQ-PRKDC, CAPZA2-MET, and VGLL4-PRKG1). We detected only CPQ-PRKDC fusion transcript in three of 122 primary endometrial cancer tissues. Cell proliferation of the fusion-positive cell line was inhibited by knocking down the expression of wild-type PRKDC but not by blocking the CPQ-PRKDC fusion transcript expression. Quantitative real-time RT-PCR demonstrated that the expression of the CPQ-PRKDC fusion transcript was significantly lower than that of wild-type PRKDC, corresponding to a low transcript allele fraction of this fusion, based on RNA-sequencing read counts. In endometrial cancers, the CPQ-PRKDC fusion transcript may be a passenger aberration related to gene amplification. Our findings suggest that transcript allele fraction is a useful predictor to find bona-fide therapeutic-targetable fusion transcripts.

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  • Cytotoxic Glycosylated Fatty Acid Amides from a Stelletta sp. Marine Sponge. 査読 国際誌

    Victoria Peddie, Kentaro Takada, Shujiro Okuda, Yuji Ise, Yasuhiro Morii, Nobuhiro Yamawaki, Tomohiro Takatani, Osamu Arakawa, Shigeru Okada, Shigeki Matsunaga

    Journal of natural products   78 ( 11 )   2808 - 13   2015年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER CHEMICAL SOC  

    We have discovered new glycosylated fatty acid amides, stellettosides, from a Stelletta sp. marine sponge. They were detected through LC-MS analysis of the extract combined with the cytotoxicity assay of the prefractionated sample. Their planar structures were determined by analyses of the NMR and tandem FABMS data. Stellettosides A1 and A2 (1 and 2) as well as stellettosides B1-B4 (3-6) were obtained as inseparable mixtures. Careful analysis of the NMR and tandem FABMS data of each mixture, along with comparison of the tandem FABMS data with that of a synthetic model compound, permitted us to assign the structure of the constituents in the mixture. The absolute configuration of the monosaccharide unit was determined by LC-MS after chiral derivatization. The relative configurations of the vicinal oxygenated methines in the fatty acid chains were assigned by the (1)H NMR data of the isopropylidene derivative. The mixture of stellettosides B1-B4 (3-6) exhibit moderate cytotoxic activity against HeLa cells with an IC50 value of 9 μM, whereas the mixture of stellettosides A1 and A2 (1 and 2) was not active at a concentration of 10 μM.

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  • The Official Release of the International Glycan Structure Repository 査読

    Nobuyuki P. Aoki, Kiyoko Aoki-Kinoshita, Sanjay Agravat, Sena Arpinar, Richard D. Cummings, Akihiro Fujita, Noriaki Fujita, Gerald M. Hart, Stuart Haslam, Toshisuke Kawasaki, Masaaki Matsubara, Kelley W. Moreman, Hisashi Narimatsu, Shujiro Okuda, J. Michael Pierce, Rene Ranzinger, Toshihide Shikanai, Daisuke Shinmachi, Elena Solovieva, Yoshinori Suzuki, Shinichiro Tsuchiya, Issaku Yamada, William S. York, Joseph Zaia

    GLYCOBIOLOGY   25 ( 11 )   1279 - 1280   2015年11月

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    記述言語:英語   出版者・発行元:OXFORD UNIV PRESS INC  

    DOI: 10.1093/nar/gkv1041

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  • Human T-cell leukemia virus type 1 Tax oncoprotein represses the expression of the BCL11B tumor suppressor in T-cells. 査読 国際誌

    Takayuki Takachi, Masahiko Takahashi, Manami Takahashi-Yoshita, Masaya Higuchi, Miki Obata, Yukio Mishima, Shujiro Okuda, Yuetsu Tanaka, Masao Matsuoka, Akihiko Saitoh, Patrick L Green, Masahiro Fujii

    Cancer science   106 ( 4 )   461 - 5   2015年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    Human T-cell leukemia virus type 1 (HTLV-1) is the etiological agent of adult T cell leukemia (ATL), which is an aggressive form of T-cell malignancy. HTLV-1 oncoproteins, Tax and HBZ, play crucial roles in the immortalization of T-cells and/or leukemogenesis by dysregulating the cellular functions in the host. Recent studies show that HTLV-1-infected T-cells have reduced expression of the BCL11B tumor suppressor protein. In the present study, we explored whether Tax and/or HBZ play a role in downregulating BCL11B in HTLV-1-infected T-cells. Lentiviral transduction of Tax in a human T-cell line repressed the expression of BCL11B at both the protein and mRNA levels, whereas the transduction of HBZ had little effect on the expression. Tax mutants with a decreased activity for the NF-κB, CREB or PDZ protein pathways still showed a reduced expression of the BCL11B protein, thereby implicating a different function of Tax in BCL11B downregulation. In addition, the HTLV-2 Tax2 protein reduced the BCL11B protein expression in T-cells. Seven HTLV-1-infected T-cell lines, including three ATL-derived cell lines, showed reduced BCL11B mRNA and protein expression relative to an uninfected T-cell line, and the greatest reductions were in the cells expressing Tax. Collectively, these results indicate that Tax is responsible for suppressing BCL11B protein expression in HTLV-1-infected T-cells; Tax-mediated repression of BCL11B is another mechanism that Tax uses to promote oncogenesis of HTLV-1-infected T-cells.

    DOI: 10.1111/cas.12618

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  • GlycoRDF: an ontology to standardize glycomics data in RDF. 査読 国際誌

    Rene Ranzinger, Kiyoko F Aoki-Kinoshita, Matthew P Campbell, Shin Kawano, Thomas Lütteke, Shujiro Okuda, Daisuke Shinmachi, Toshihide Shikanai, Hiromichi Sawaki, Philip Toukach, Masaaki Matsubara, Issaku Yamada, Hisashi Narimatsu

    Bioinformatics (Oxford, England)   31 ( 6 )   919 - 25   2015年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:OXFORD UNIV PRESS  

    MOTIVATION: Over the last decades several glycomics-based bioinformatics resources and databases have been created and released to the public. Unfortunately, there is no common standard in the representation of the stored information or a common machine-readable interface allowing bioinformatics groups to easily extract and cross-reference the stored information. RESULTS: An international group of bioinformatics experts in the field of glycomics have worked together to create a standard Resource Description Framework (RDF) representation for glycomics data, focused on glycan sequences and related biological source, publications and experimental data. This RDF standard is defined by the GlycoRDF ontology and will be used by database providers to generate common machine-readable exports of the data stored in their databases. AVAILABILITY AND IMPLEMENTATION: The ontology, supporting documentation and source code used by database providers to generate standardized RDF are available online (http://www.glycoinfo.org/GlycoRDF/).

    DOI: 10.1093/bioinformatics/btu732

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  • Glycoepitope: Database for carbohydrate antigen and antibody 査読

    Shujiro Okuda, Hiromi Nakao, Toshisuke Kawasaki

    Glycoscience: Biology and Medicine   267 - 273   2015年1月

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    記述言語:英語   掲載種別:論文集(書籍)内論文   出版者・発行元:Springer Japan  

    Glycan research has increasingly spread tomany fields in the life sciences. Glycans are carbohydrate sugar chains, which are found in a wide variety of cell types and are recognized by various proteins, viruses, bacteria, and antibodies. Antibodies in particular that detect carbohydrates have been widely used for analyzing glycan functions. GlycoEpitope has been developed as a database to integrate carbohydrate antigens and their recognizing antibodies. The current version of GlycoEpitope was constructed by integrating a new database engine, and several search tools have been implemented. Semantic web data have also been generated based on this data. This database is useful for not only glycobiologists but also a wide range of life science researchers in that it provides an important link between glycans and other biomolecules, including proteins and lipids.

    DOI: 10.1007/978-4-431-54841-6_27

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  • Resequencing and Association Analysis of CLN8 with Autism Spectrum Disorder in a Japanese Population. 査読 国際誌

    Emiko Inoue, Yuichiro Watanabe, Jingrui Xing, Itaru Kushima, Jun Egawa, Shujiro Okuda, Satoshi Hoya, Takashi Okada, Yota Uno, Kanako Ishizuka, Atsunori Sugimoto, Hirofumi Igeta, Ayako Nunokawa, Toshiro Sugiyama, Norio Ozaki, Toshiyuki Someya

    PloS one   10 ( 12 )   e0144624   2015年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PUBLIC LIBRARY SCIENCE  

    Rare variations contribute substantially to autism spectrum disorder (ASD) liability. We recently performed whole-exome sequencing in two families with affected siblings and then carried out a follow-up study and identified ceroid-lipofuscinosis neuronal 8 (epilepsy, progressive with mental retardation) (CLN8) as a potential genetic risk factor for ASD. To further investigate the role of CLN8 in the genetic etiology of ASD, we performed resequencing and association analysis of CLN8 with ASD in a Japanese population. Resequencing the CLN8 coding region in 256 ASD patients identified five rare missense variations: g.1719291G>A (R24H), rs201670636 (F39L), rs116605307 (R97H), rs143701028 (T108M) and rs138581191 (N152S). These variations were genotyped in 568 patients (including the resequenced 256 patients) and 1017 controls. However, no significant association between these variations and ASD was identified. This study does not support a contribution of rare missense CLN8 variations to ASD susceptibility in the Japanese population.

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  • Large-scale analysis of the evolutionary histories of phosphorylation motifs in the human genome. 査読 国際誌

    Hisayoshi Yoshizaki, Shujiro Okuda

    GigaScience   4   21 - 21   2015年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:BIOMED CENTRAL LTD  

    BACKGROUND: Protein phosphorylation is a post-translational modification that is essential for a wide range of eukaryotic physiological processes, such as transcription, cytoskeletal regulation, cell metabolism, and signal transduction. Although more than 200,000 phosphorylation sites have been reported in the human genome, the physiological roles of most remain unknown. In this study, we provide some useful datasets for the assessment of functional phosphorylation signaling using a comparative genome analysis of phosphorylation motifs. FINDINGS: We described the evolutionary patterns of conservation of these and comparative genomic data for 93,101 phosphosites and 1,003,756 potential phosphosites in human phosphomotifs, using 178 phosphomotifs identified in a previous study that occupied 69% of known phosphosites in public databases. Comparative genomic analyses were performed using genomes from nine species from yeast to humans. Here we provide an overview of the evolutionary patterns of phosphomotif acquisition and indicate the dependence on motif structures. Using the data from our previous study, we describe the interaction networks of phosphoproteins, identify the kinase substrates associated with phosphoproteins, and perform gene ontology enrichment analyses. In addition, we show how this dataset can help to elucidate the function of phosphomotifs. CONCLUSIONS: Our characterizations of motif structures and assessments of evolutionary conservation of phosphosites reveal physiological roles of unreported phosphosites. Thus, interactions between protein groups that share motifs are likely to be helpful for inferring kinase-substrate interaction networks. Our computational methods can be used to elucidate the relationships between phosphorylation signaling and cellular functions.

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  • RNA Sequencing Revealed Numerous Polyketide Synthase Genes in the Harmful Dinoflagellate Karenia mikimotoi. 査読 国際誌

    Kei Kimura, Shujiro Okuda, Kei Nakayama, Tomoyuki Shikata, Fumio Takahashi, Haruo Yamaguchi, Setsuko Skamoto, Mineo Yamaguchi, Yuji Tomaru

    PloS one   10 ( 11 )   e0142731   2015年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PUBLIC LIBRARY SCIENCE  

    The dinoflagellate Karenia mikimotoi forms blooms in the coastal waters of temperate regions and occasionally causes massive fish and invertebrate mortality. This study aimed to elucidate the toxic effect of K. mikimotoi on marine organisms by using the genomics approach; RNA-sequence libraries were constructed, and data were analyzed to identify toxin-related genes. Next-generation sequencing produced 153,406 transcript contigs from the axenic culture of K. mikimotoi. BLASTX analysis against all assembled contigs revealed that 208 contigs were polyketide synthase (PKS) sequences. Thus, K. mikimotoi was thought to have several genes encoding PKS metabolites and to likely produce toxin-like polyketide molecules. Of all the sequences, approximately 30 encoded eight PKS genes, which were remarkably similar to those of Karenia brevis. Our phylogenetic analyses showed that these genes belonged to a new group of PKS type-I genes. Phylogenetic and active domain analyses showed that the amino acid sequence of four among eight Karenia PKS genes was not similar to any of the reported PKS genes. These PKS genes might possibly be associated with the synthesis of polyketide toxins produced by Karenia species. Further, a homology search revealed 10 contigs that were similar to a toxin gene responsible for the synthesis of saxitoxin (sxtA) in the toxic dinoflagellate Alexandrium fundyense. These contigs encoded A1-A3 domains of sxtA genes. Thus, this study identified some transcripts in K. mikimotoi that might be associated with several putative toxin-related genes. The findings of this study might help understand the mechanism of toxicity of K. mikimotoi and other dinoflagellates.

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  • Development of an International Glycan Structure Repository 査読

    Kiyoko Aoki-Kinoshita, Sanjay Agravat, Nobuyuki P. Aoki, Sena Arpinar, Richard D. Cummings, Akihiro Fujita, Noriaki Fujita, Gerald M. Hart, Stuart Haslam, Toshisuke Kawasaki, Masaaki Matsubara, Kelley W. Moreman, Hisashi Narimatsu, Shujiro Okuda, J. Michael Pierce, Rene Ranzinger, Toshihide Shikanai, Daisuke Shinmachi, Elena Solovieva, Yoshinori Suzuki, Shinichiro Tsuchiya, Issaku Yamada, William S. York, Joseph Zaia

    GLYCOBIOLOGY   24 ( 11 )   1106 - 1106   2014年11月

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    記述言語:英語   出版者・発行元:OXFORD UNIV PRESS INC  

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  • Next JCGGDB Plan for Semantic Web 査読

    Shikanai Toshihide, Fujita Noriaki, Suzuki Yoshinori, Solovieva Elena, Aoki-Kinoshita Kiyoko, Soyama Madoka, Kuno Atsushi, Kaji Hiroyuki, Shinmachi Daisuke, Yamada Issaku, Okuda Shujiro, Kawasaki Toshisuke, Narimatsu Hisashi

    GLYCOBIOLOGY   24 ( 11 )   1166 - 1167   2014年11月

  • Elucidation of the evolutionary expansion of phosphorylation signaling networks using comparative phosphomotif analysis. 査読 国際誌

    Hisayoshi Yoshizaki, Shujiro Okuda

    BMC genomics   15   546 - 546   2014年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:BIOMED CENTRAL LTD  

    BACKGROUND: Protein phosphorylation is catalyzed by kinases and is involved in the regulation of a wide range of processes. The phosphosites in protein sequence motifs determine the types of kinases involved. The development of phosphoproteomics has allowed the identification of huge numbers of phosphosites, some of which are not involved in physiological functions. RESULTS: We developed a method for extracting phosphosites with important roles in cellular functions and determined 178 phosphomotifs based on the analysis of 34,366 phosphosites. We compared the conservation of serine/threonine/tyrosine residues observed in humans and seven other species. Consequently, we identified 16 phosphomotifs, where the level of conservation increased among species. The highly conserved phosphomotifs in humans and the worm were kinase regulatory sites. The motifs present in the fly were novel phosphomotifs, including zinc finger motifs involved in the regulation of gene expression. Subsequently, we found that this zinc finger motif contributed to subcellular protein localization. The motifs identified in fish allowed us to detect the expansion of phosphorylation signals related to alternative splicing. We also showed that the motifs present in specific species functioned in an additional network that interacted directly with the core signaling network conserved from yeast to humans. CONCLUSIONS: Our method may facilitate the efficient extraction of novel phosphomotifs with physiological functions, thereby contributing greatly to the analysis of complex phosphorylation signaling cascades. Our study suggests that the phosphorylation networks acquired during evolution have added signaling network modules to the core signaling networks.

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  • BioHackathon series in 2011 and 2012: penetration of ontology and linked data in life science domains. 査読 国際誌

    Toshiaki Katayama, Mark D Wilkinson, Kiyoko F Aoki-Kinoshita, Shuichi Kawashima, Yasunori Yamamoto, Atsuko Yamaguchi, Shinobu Okamoto, Shin Kawano, Jin-Dong Kim, Yue Wang, Hongyan Wu, Yoshinobu Kano, Hiromasa Ono, Hidemasa Bono, Simon Kocbek, Jan Aerts, Yukie Akune, Erick Antezana, Kazuharu Arakawa, Bruno Aranda, Joachim Baran, Jerven Bolleman, Raoul Jp Bonnal, Pier Luigi Buttigieg, Matthew P Campbell, Yi-An Chen, Hirokazu Chiba, Peter Ja Cock, K Bretonnel Cohen, Alexandru Constantin, Geraint Duck, Michel Dumontier, Takatomo Fujisawa, Toyofumi Fujiwara, Naohisa Goto, Robert Hoehndorf, Yoshinobu Igarashi, Hidetoshi Itaya, Maori Ito, Wataru Iwasaki, Matúš Kalaš, Takeo Katoda, Taehong Kim, Anna Kokubu, Yusuke Komiyama, Masaaki Kotera, Camille Laibe, Hilmar Lapp, Thomas Lütteke, M Scott Marshall, Takaaki Mori, Hiroshi Mori, Mizuki Morita, Katsuhiko Murakami, Mitsuteru Nakao, Hisashi Narimatsu, Hiroyo Nishide, Yosuke Nishimura, Johan Nystrom-Persson, Soichi Ogishima, Yasunobu Okamura, Shujiro Okuda, Kazuki Oshita, Nicki H Packer, Pjotr Prins, Rene Ranzinger, Philippe Rocca-Serra, Susanna Sansone, Hiromichi Sawaki, Sung-Ho Shin, Andrea Splendiani, Francesco Strozzi, Shu Tadaka, Philip Toukach, Ikuo Uchiyama, Masahito Umezaki, Rutger Vos, Patricia L Whetzel, Issaku Yamada, Chisato Yamasaki, Riu Yamashita, William S York, Christian M Zmasek, Shoko Kawamoto, Toshihisa Takagi

    Journal of biomedical semantics   5 ( 1 )   5 - 5   2014年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Springer Science and Business Media LLC  

    The application of semantic technologies to the integration of biological data and the interoperability of bioinformatics analysis and visualization tools has been the common theme of a series of annual BioHackathons hosted in Japan for the past five years. Here we provide a review of the activities and outcomes from the BioHackathons held in 2011 in Kyoto and 2012 in Toyama. In order to efficiently implement semantic technologies in the life sciences, participants formed various sub-groups and worked on the following topics: Resource Description Framework (RDF) models for specific domains, text mining of the literature, ontology development, essential metadata for biological databases, platforms to enable efficient Semantic Web technology development and interoperability, and the development of applications for Semantic Web data. In this review, we briefly introduce the themes covered by these sub-groups. The observations made, conclusions drawn, and software development projects that emerged from these activities are discussed.

    DOI: 10.1186/2041-1480-5-5

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  • Enhanced translocation and growth of Rhodococcus erythropolis PR4 in the alkane phase of aqueous-alkane two phase cultures were mediated by GroEL2 overexpression. 査読

    Hayato Takihara, Jun Ogihara, Takao Yoshida, Shujiro Okuda, Mutsuyasu Nakajima, Noriyuki Iwabuchi, Michio Sunairi

    Microbes and environments   29 ( 4 )   346 - 52   2014年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:JAPANESE SOC MICROBIAL ECOLOGY, DEPT BIORESOURCE SCIENCE  

    We previously reported that R. erythropolis PR4 translocated from the aqueous to the alkane phase, and then grew in two phase cultures to which long-chain alkanes had been added. This was considered to be beneficial for bioremediation. In the present study, we investigated the proteins involved in the translocation of R. erythropolis PR4. The results of our proteogenomic analysis suggested that GroEL2 was upregulated more in cells that translocated inside of the pristane (C19) phase than in those located at the aqueous-alkane interface attached to the n-dodecane (C12) surface. PR4 (pK4-EL2-1) and PR4 (pK4-ΔEL2-1) strains were constructed to confirm the effects of the upregulation of GroEL2 in translocated cells. The expression of GroEL2 in PR4 (pK4-EL2-1) was 15.5-fold higher than that in PR4 (pK4-ΔEL2-1) in two phase cultures containing C12. The growth and cell surface lipophilicity of PR4 were enhanced by the introduction of pK4-EL2-1. These results suggested that the plasmid overexpression of groEL2 in PR4 (pK4-EL2-1) led to changes in cell localization, enhanced growth, and increased cell surface lipophilicity. Thus, we concluded that the overexpression of GroEL2 may play an important role in increasing the organic solvent tolerance of R. erythropolis PR4 in aqueous-alkane two phase cultures.

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  • The Fifth ACGG-DB Meeting Report: Towards an International Glycan Structure Repository 査読

    Kiyoko F. Aoki-Kinoshita, Hiromichi Sawaki, Hyun Joo An, Matthew Campbell, Qichen Cao, Richard Cummings, Daniel K. Hsu, Masaki Kato, Toshisuke Kawasaki, Kay-Hooi Khoo, Jaehan Kim, Daniel Kolarich, Xianyu Li, Mingqi Liu, Masaaki Matsubara, Shujiro Okuda, Nicolle H. Packer, Rene Ranzinger, Huali Shen, Toshihide Shikanai, Daisuke Shinmachi, Philip Toukach, Issaku Yamada, Yoshiki Yamaguchi, Pengyuan Yang, Wantao Ying, Jong Shin Yoo, Yan Zhang, Yang Zhang, Hisashi Narimatsu

    GLYCOBIOLOGY   23 ( 12 )   1422 - 1424   2013年12月

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    記述言語:英語   出版者・発行元:OXFORD UNIV PRESS INC  

    DOI: 10.1093/glycob/cwt084

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  • Introducing glycomics data into the Semantic Web. 査読 国際誌

    Kiyoko F Aoki-Kinoshita, Jerven Bolleman, Matthew P Campbell, Shin Kawano, Jin-Dong Kim, Thomas Lütteke, Masaaki Matsubara, Shujiro Okuda, Rene Ranzinger, Hiromichi Sawaki, Toshihide Shikanai, Daisuke Shinmachi, Yoshinori Suzuki, Philip Toukach, Issaku Yamada, Nicolle H Packer, Hisashi Narimatsu

    Journal of biomedical semantics   4 ( 1 )   39 - 39   2013年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:BIOMED CENTRAL LTD  

    BACKGROUND: Glycoscience is a research field focusing on complex carbohydrates (otherwise known as glycans)a, which can, for example, serve as "switches" that toggle between different functions of a glycoprotein or glycolipid. Due to the advancement of glycomics technologies that are used to characterize glycan structures, many glycomics databases are now publicly available and provide useful information for glycoscience research. However, these databases have almost no link to other life science databases. RESULTS: In order to implement support for the Semantic Web most efficiently for glycomics research, the developers of major glycomics databases agreed on a minimal standard for representing glycan structure and annotation information using RDF (Resource Description Framework). Moreover, all of the participants implemented this standard prototype and generated preliminary RDF versions of their data. To test the utility of the converted data, all of the data sets were uploaded into a Virtuoso triple store, and several SPARQL queries were tested as "proofs-of-concept" to illustrate the utility of the Semantic Web in querying across databases which were originally difficult to implement. CONCLUSIONS: We were able to successfully retrieve information by linking UniCarbKB, GlycomeDB and JCGGDB in a single SPARQL query to obtain our target information. We also tested queries linking UniProt with GlycoEpitope as well as lectin data with GlycomeDB through PDB. As a result, we have been able to link proteomics data with glycomics data through the implementation of Semantic Web technologies, allowing for more flexible queries across these domains.

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  • The Third ACGG-DB Meeting Report: Towards an international collaborative infrastructure for glycobioinformatics. 査読 国際誌

    Kiyoko F Aoki-Kinoshita, Hiromichi Sawaki, Hyun Joo An, Jin Won Cho, Daniel Hsu, Masaki Kato, Shin Kawano, Toshisuke Kawasaki, Kay-Hooi Khoo, Jaehan Kim, Jin-Dong Kim, Xianyu Li, Thomas Lütteke, Shujiro Okuda, Nicolle H Packer, James C Paulson, Rahul Raman, René Ranzinger, Huali Shen, Toshihide Shikanai, Issaku Yamada, Pengyuan Yang, Yoshiki Yamaguchi, Wantao Ying, Jong Shin Yoo, Yang Zhang, Hisashi Narimatsu

    Glycobiology   23 ( 2 )   144 - 6   2013年2月

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    記述言語:英語   出版者・発行元:OXFORD UNIV PRESS INC  

    DOI: 10.1093/glycob/cws167

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  • KEGG OC: a large-scale automatic construction of taxonomy-based ortholog clusters. 査読 国際誌

    Akihiro Nakaya, Toshiaki Katayama, Masumi Itoh, Kazushi Hiranuka, Shuichi Kawashima, Yuki Moriya, Shujiro Okuda, Michihiro Tanaka, Toshiaki Tokimatsu, Yoshihiro Yamanishi, Akiyasu C Yoshizawa, Minoru Kanehisa, Susumu Goto

    Nucleic acids research   41 ( Database issue )   D353-7 - D357   2013年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:OXFORD UNIV PRESS  

    The identification of orthologous genes in an increasing number of fully sequenced genomes is a challenging issue in recent genome science. Here we present KEGG OC (http://www.genome.jp/tools/oc/), a novel database of ortholog clusters (OCs). The current version of KEGG OC contains 1 176 030 OCs, obtained by clustering 8 357 175 genes in 2112 complete genomes (153 eukaryotes, 1830 bacteria and 129 archaea). The OCs were constructed by applying the quasi-clique-based clustering method to all possible protein coding genes in all complete genomes, based on their amino acid sequence similarities. It is computationally efficient to calculate OCs, which enables to regularly update the contents. KEGG OC has the following two features: (i) It consists of all complete genomes of a wide variety of organisms from three domains of life, and the number of organisms is the largest among the existing databases; and (ii) It is compatible with the KEGG database by sharing the same sets of genes and identifiers, which leads to seamless integration of OCs with useful components in KEGG such as biological pathways, pathway modules, functional hierarchy, diseases and drugs. The KEGG OC resources are accessible via OC Viewer that provides an interactive visualization of OCs at different taxonomic levels.

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  • A metagenome-wide association study of gut microbiota in type 2 diabetes. 査読 国際誌

    Junjie Qin, Yingrui Li, Zhiming Cai, Shenghui Li, Jianfeng Zhu, Fan Zhang, Suisha Liang, Wenwei Zhang, Yuanlin Guan, Dongqian Shen, Yangqing Peng, Dongya Zhang, Zhuye Jie, Wenxian Wu, Youwen Qin, Wenbin Xue, Junhua Li, Lingchuan Han, Donghui Lu, Peixian Wu, Yali Dai, Xiaojuan Sun, Zesong Li, Aifa Tang, Shilong Zhong, Xiaoping Li, Weineng Chen, Ran Xu, Mingbang Wang, Qiang Feng, Meihua Gong, Jing Yu, Yanyan Zhang, Ming Zhang, Torben Hansen, Gaston Sanchez, Jeroen Raes, Gwen Falony, Shujiro Okuda, Mathieu Almeida, Emmanuelle LeChatelier, Pierre Renault, Nicolas Pons, Jean-Michel Batto, Zhaoxi Zhang, Hua Chen, Ruifu Yang, Weimou Zheng, Songgang Li, Huanming Yang, Jian Wang, S Dusko Ehrlich, Rasmus Nielsen, Oluf Pedersen, Karsten Kristiansen, Jun Wang

    Nature   490 ( 7418 )   55 - 60   2012年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATURE PUBLISHING GROUP  

    Assessment and characterization of gut microbiota has become a major research area in human disease, including type 2 diabetes, the most prevalent endocrine disease worldwide. To carry out analysis on gut microbial content in patients with type 2 diabetes, we developed a protocol for a metagenome-wide association study (MGWAS) and undertook a two-stage MGWAS based on deep shotgun sequencing of the gut microbial DNA from 345 Chinese individuals. We identified and validated approximately 60,000 type-2-diabetes-associated markers and established the concept of a metagenomic linkage group, enabling taxonomic species-level analyses. MGWAS analysis showed that patients with type 2 diabetes were characterized by a moderate degree of gut microbial dysbiosis, a decrease in the abundance of some universal butyrate-producing bacteria and an increase in various opportunistic pathogens, as well as an enrichment of other microbial functions conferring sulphate reduction and oxidative stress resistance. An analysis of 23 additional individuals demonstrated that these gut microbial markers might be useful for classifying type 2 diabetes.

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  • Virtual metagenome reconstruction from 16S rRNA gene sequences. 査読 国際誌

    Shujiro Okuda, Yuki Tsuchiya, Chiho Kiriyama, Masumi Itoh, Hisao Morisaki

    Nature communications   3   1203 - 1203   2012年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATURE PUBLISHING GROUP  

    Microbial ecologists have investigated roles of species richness and diversity in a wide variety of ecosystems. Recently, metagenomics have been developed to measure functions in ecosystems, but this approach is cost-intensive. Here we describe a novel method for the rapid and efficient reconstruction of a virtual metagenome in environmental microbial communities without using large-scale genomic sequencing. We demonstrate this approach using 16S rRNA gene sequences obtained from denaturing gradient gel electrophoresis analysis, mapped to fully sequenced genomes, to reconstruct virtual metagenome-like organizations. Furthermore, we validate a virtual metagenome using a published metagenome for cocoa bean fermentation samples, and show that metagenomes reconstructed from biofilm formation samples allow for the study of the gene pool dynamics that are necessary for biofilm growth.

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  • The 2nd DBCLS BioHackathon: interoperable bioinformatics Web services for integrated applications. 査読 国際誌

    Toshiaki Katayama, Mark D Wilkinson, Rutger Vos, Takeshi Kawashima, Shuichi Kawashima, Mitsuteru Nakao, Yasunori Yamamoto, Hong-Woo Chun, Atsuko Yamaguchi, Shin Kawano, Jan Aerts, Kiyoko F Aoki-Kinoshita, Kazuharu Arakawa, Bruno Aranda, Raoul Jp Bonnal, José M Fernández, Takatomo Fujisawa, Paul Mk Gordon, Naohisa Goto, Syed Haider, Todd Harris, Takashi Hatakeyama, Isaac Ho, Masumi Itoh, Arek Kasprzyk, Nobuhiro Kido, Young-Joo Kim, Akira R Kinjo, Fumikazu Konishi, Yulia Kovarskaya, Greg von Kuster, Alberto Labarga, Vachiranee Limviphuvadh, Luke McCarthy, Yasukazu Nakamura, Yunsun Nam, Kozo Nishida, Kunihiro Nishimura, Tatsuya Nishizawa, Soichi Ogishima, Tom Oinn, Shinobu Okamoto, Shujiro Okuda, Keiichiro Ono, Kazuki Oshita, Keun-Joon Park, Nicholas Putnam, Martin Senger, Jessica Severin, Yasumasa Shigemoto, Hideaki Sugawara, James Taylor, Oswaldo Trelles, Chisato Yamasaki, Riu Yamashita, Noriyuki Satoh, Toshihisa Takagi

    Journal of biomedical semantics   2   4 - 4   2011年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: The interaction between biological researchers and the bioinformatics tools they use is still hampered by incomplete interoperability between such tools. To ensure interoperability initiatives are effectively deployed, end-user applications need to be aware of, and support, best practices and standards. Here, we report on an initiative in which software developers and genome biologists came together to explore and raise awareness of these issues: BioHackathon 2009. RESULTS: Developers in attendance came from diverse backgrounds, with experts in Web services, workflow tools, text mining and visualization. Genome biologists provided expertise and exemplar data from the domains of sequence and pathway analysis and glyco-informatics. One goal of the meeting was to evaluate the ability to address real world use cases in these domains using the tools that the developers represented. This resulted in i) a workflow to annotate 100,000 sequences from an invertebrate species; ii) an integrated system for analysis of the transcription factor binding sites (TFBSs) enriched based on differential gene expression data obtained from a microarray experiment; iii) a workflow to enumerate putative physical protein interactions among enzymes in a metabolic pathway using protein structure data; iv) a workflow to analyze glyco-gene-related diseases by searching for human homologs of glyco-genes in other species, such as fruit flies, and retrieving their phenotype-annotated SNPs. CONCLUSIONS: Beyond deriving prototype solutions for each use-case, a second major purpose of the BioHackathon was to highlight areas of insufficiency. We discuss the issues raised by our exploration of the problem/solution space, concluding that there are still problems with the way Web services are modeled and annotated, including: i) the absence of several useful data or analysis functions in the Web service "space"; ii) the lack of documentation of methods; iii) lack of compliance with the SOAP/WSDL specification among and between various programming-language libraries; and iv) incompatibility between various bioinformatics data formats. Although it was still difficult to solve real world problems posed to the developers by the biological researchers in attendance because of these problems, we note the promise of addressing these issues within a semantic framework.

    DOI: 10.1186/2041-1480-2-4

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  • Electrophoretic mobility of Bacillus subtilis knockout mutants with and without flagella. 査読 国際誌

    Shujiro Okuda, Ryosuke Igarashi, Yusuke Kusui, Yasuhiro Kasahara, Hisao Morisaki

    Journal of bacteriology   185 ( 13 )   3711 - 7   2003年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER SOC MICROBIOLOGY  

    Mutants of Bacillus subtilis 168 strain were obtained by inactivation of a specific gene by homologous recombination with the plasmid pMutinT3. The cell surface properties of these strains were characterized by measuring the electrophoretic mobility of the cells as a function of pH and ionic strength. The surface properties were different for the strains possessing flagella on their cells and strain FlgB, having no flagellum, due to knockout of the corresponding gene. The cell surface properties of the strains possessing flagella become similar to those of strain FlgB after acid treatment. It was confirmed that the acid treatment degraded the flagella without causing any apparent structural change on the cell surface via observations made using atomic force microscopy, transmission electron microscopy, and scanning electron microscopy. These results indicate that the flagella are a key factor influencing cell surface properties.

    DOI: 10.1128/JB.185.13.3711.3717.2003

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  • The electrophoretic mobility of Bacillus subtilis knockout mutants with and without flagella. 査読

    Okuda, S, R. Igarashi, Y. Kusui, Y. Kasahara, H. Morisaki

    J. Bacteriology   149   2501 - 2511   2003年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

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  • The GlyCosmos portal as a partner in the GlySpace Alliance to provide access to integrated glycan-related data resources

    Issaku Yamada, Masaaki Shiota, Daisuke Shimachi, Tamiko Ono, Shinichiro Tsuchiya, Masaaki Matsubara, Masae Hosoda, Akihiro Fujita, Nobuyuki P. Aoki, Yu Watanabe, Noriaki Fujita, Kiyohiko Angata, Hiroyuki Kaji, Hisashi Narimatsu, Shujiro Okuda, Kiyoko F. Aoki-Kinoshita

    GLYCOBIOLOGY   30 ( 12 )   1023 - 1023   2020年12月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:OXFORD UNIV PRESS INC  

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  • プロテオゲノミクスのための解析プラットフォーム開発

    上村駿人, 吉沢明康, 杉山直幸, 奥田修二郎, 石濱泰

    日本分析化学会年会講演要旨集(Web)   68th   2019年

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  • プロテオームおよび糖鎖関連の質量分析データリポジトリの開発

    渡辺由, 木下聖子, 石濱泰, 奥田修二郎

    質量分析総合討論会講演要旨集   67th   2019年

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  • Gifu嫌気性培地を用いたヒト腸内常在菌叢最優勢32種の培養および短鎖脂肪酸発酵特性に基づくその評価

    後藤愛那, 後藤愛那, 阪中幹祥, 阪中幹祥, 片山高嶺, 片山高嶺, 栗原新, 栗原新, 杉山友太, 奈良未沙希, 南博道, 谷内寛之, 北方彩, 中川明, 奥田修二郎, 加藤紀彦

    Institute for Fermentation, Osaka. Research Communications   ( 33 )   2019年

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  • プロテオーム統合データベースの機能深化

    守屋勇樹, 河野信, 奥田修二郎, 渡辺由, 松本雅記, 高見知代, 小林大樹, 山ノ内祥訓, 荒木令江, 吉沢明康, 田畑剛, 岩崎未央, 杉山直幸, 田中聡, 五斗進, 石濱泰

    第41回日本分子生物学会   2018年

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  • Metadata Curation for fully utilizing raw MS data in jPOST repository

    Kobayashi, D, Araki, N, Okuda, S, Watanabe, Y, Moriya, Y, Kawano, S, Yamamoto, T, Matsumoto, T, Takami, T, Yoshizawa, A.C, Tabata, T, Iwasaki, M, Sugiyama, N, Tanaka, S, Goto, S, Ishihama, Y

    Mass Spectrometry and Proteomics 2018 (MSP2018)(日本質量分析学会・日本プロテオーム学会 2018年合同大会)   2018年

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  • jPOST統合環境の開発

    奥田修二郎, 渡辺由, 守屋勇樹, 河野信, 松本雅記, 高見知代, 小林大樹, 山ノ内祥訓, 荒木令江, 吉沢明康, 田畑剛, 岩崎未央, 杉山直幸, 田中聡, 五斗進, 石濱泰

    トーゴ―の日2018シンポジウム   2018年

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  • jPOSTプロジェクトが提供するプロテオミクスデータとその解析ツール

    五斗進, 守屋勇樹, 河野信, 奥田修二郎, 渡辺由, 松本雅記, 高見知代, 小林大樹, 山ノ内祥訓, 荒木令江, 吉沢明康, 田畑剛, 岩崎未央, 杉山直幸, 田中聡, 石濱泰

    第41回日本分子生物学会   2018年

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  • 糖鎖関連生命情報を統合化するGlyCosmos Portalの構築

    塩田正明, 土屋伸一郎, 小野多美子, 李宣明, KUOKA Thukaa, 三浦信明, 平木愛子, 山田一作, 新町大輔, 青木ポール信行, 金進東, 渡邉由, 奥田修二郎, 鈴木芳典, 藤田典昭, 安形清彦, 成松久, 木下聖子

    日本分子生物学会年会プログラム・要旨集(Web)   41st   ROMBUNNO.1PW2‐09‐2 (WEB ONLY)   2018年

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  • jPOST 同定結果のFDR改善を目指す再解析プロトコルの開発

    吉沢 明康, 田畑 剛, 守屋 勇樹, 河野 信, 奥田 修二郎, 渡辺 由, 山本 格, 松本 雅記, 高見 知代, 小林 大樹, 荒木 令江, 杉山 直幸, 田中 聡, 五斗 進, 石濱 泰

    生命科学系学会合同年次大会   2017年度   [3P - 0172]   2017年12月

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    記述言語:日本語   出版者・発行元:生命科学系学会合同年次大会運営事務局  

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  • jPOST プロテオームデータベースの開発

    守屋 勇樹, 河野 信, 奥田 修二郎, 渡辺 由, 山本 格, 松本 雅記, 高見 知代, 小林 大樹, 荒木 令江, 吉沢 明康, 田畑 剛, 杉山 直幸, 田中 聡, 五斗 進, 石濱 泰

    生命科学系学会合同年次大会   2017年度   [3P - 0173]   2017年12月

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    記述言語:日本語   出版者・発行元:生命科学系学会合同年次大会運営事務局  

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  • jPOST プロテオーム統合データベースプロジェクト

    奥田 修二郎, 渡辺 由, 守屋 勇樹, 河野 信, 山本 格, 松本 雅記, 高見 知代, 小林 大樹, 荒木 令江, 吉沢 明康, 田畑 剛, 杉山 直幸, 田中 聡, 五斗 進, 石濱 泰

    生命科学系学会合同年次大会   2017年度   [3P - 0171]   2017年12月

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    記述言語:日本語   出版者・発行元:生命科学系学会合同年次大会運営事務局  

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  • PDCD11遺伝子の稀な変異と統合失調症の発症リスク 罹患同胞対家系の全エクソーム解析、ターゲットリシーケンス、および症例・対照研究

    保谷 智史, 渡部 雄一郎, 菱本 明豊, 布川 綾子, 金子 尚史, 村竹 辰之, 新名 尚史, 大塚 郁夫, 奥田 修二郎, 井上 絵美子, 井桁 裕文, 澁谷 雅子, 江川 純, 折目 直樹, 曽良 一郎, 染矢 俊幸

    日本生物学的精神医学会・日本神経精神薬理学会合同年会プログラム・抄録集   39回・47回   177 - 177   2017年9月

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    記述言語:日本語   出版者・発行元:日本生物学的精神医学会・日本神経精神薬理学会  

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  • Controlling false discovery rate in accumulated public proteome dataset

    Akiyasu C. Yoshizawa, Tsuyoshi Tabata, Yuki Moriya, Shin Kawano, Shujiro Okuda, Yu Watanabe, Tadashi Yamamoto, Masaki Matsumoto, Tomoyo Takami, Daiki Kobayashi, Norie Araki, Naoyuki Sugiyama, Satoshi Tanaka, Susumu Goto, Yasushi Ishihama

    65th ASMS   65th   MP321   2017年6月

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  • データベース検索エンジンを用いたタンパク質同定における特異性向上

    吉沢明康, 田畑剛, 守屋勇樹, 河野信, 奥田修二郎, 渡辺由, 山本格, 松本雅記, 高見知代, 小林大樹, 荒木令江, 杉山直幸, 田中聡, 五斗進, 石濱泰

    質量分析総合討論会講演要旨集   65th   107   2017年5月

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  • Genomic overview of right-sided and left-sided colorectal cancer using comprehensive genomic sequencing.

    Yoshifumi Shimada, Hitoshi Kameyama, Masayuki Nagahashi, Hiroshi Ichikawa, Ryoma Yagi, Yosuke Tajima, Kizuki Yuza, Masato Nakano, Masato Nakajima, Takashi Ishikawa, Jun Sakata, Takashi Kobayashi, Hitoshi Nogami, Satoshi Maruyama, Yasumasa Takii, Jennifer E. Ring, Stephen Lyle, Shujiro Okuda, Kazuaki Takabe, Toshifumi Wakai

    JOURNAL OF CLINICAL ONCOLOGY   35   2017年5月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER SOC CLINICAL ONCOLOGY  

    DOI: 10.1200/JCO.2017.35.15_suppl.e15101

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  • Association of activin type II receptor mutation with microsatellite instability in gastric cancer.

    Kizuki Yuza, Masayuki Nagahashi, Hiroshi Ichikawa, Masato Nakajima, Takaaki Hanyu, Takashi Ishikawa, Yoshifumi Shimada, Jun Sakata, Hitoshi Kameyama, Takashi Kobayashi, Satoru Nakagawa, Nobuaki Sato, Keiichi Honma, Takashi Kawasaki, Shujiro Okuda, Kazuaki Takabe, Toshifumi Wakai

    JOURNAL OF CLINICAL ONCOLOGY   35   2017年5月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER SOC CLINICAL ONCOLOGY  

    DOI: 10.1200/JCO.2017.35.15_suppl.e23191

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  • Identification of a novel causative gene responsible for autosomal recessive congenital ichthyosis

    Y. Shigehara, S. Okuda, R. Hayashi, H. Nakai, R. Abe, A. Ghani Kibbi, M. Kurban, Y. Shimomura

    JOURNAL OF INVESTIGATIVE DERMATOLOGY   137 ( 5 )   S85 - S85   2017年5月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:ELSEVIER SCIENCE INC  

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  • Comprehensive genomic sequencing for triple negative breast cancer in Japan.

    Masayuki Nagahashi, Tetsu Hayashida, Yuko Kitagawa, Manabu Futamura, Kazuhiro Yoshida, Takashi Kuwayama, Seigo Nakamura, Chie Toshikawa, Hideko Yamauchi, Koji Kaneko, Nobuaki Sato, Junko Tsuchida, Kizuki Yuza, Yoshifumi Shimada, Hiroshi Ichikawa, Jennifer E. Ring, Stephen Lyle, Shujiro Okuda, Kazuaki Takabe, Toshifumi Wakai

    JOURNAL OF CLINICAL ONCOLOGY   35   2017年5月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER SOC CLINICAL ONCOLOGY  

    DOI: 10.1200/JCO.2017.35.15_suppl.e23122

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  • Genomic profiling using a 435-gene panel provides a vision for precision medicine in Japanese gastric cancer.

    Hiroshi Ichikawa, Masayuki Nagahashi, Yuko Kitagawa, Kazuhiro Yoshida, Eiji Oki, Hiroshi Yabusaki, Satoru Nakagawa, Nobuaki Sato, Takaaki Hanyu, Takashi Ishikawa, Yusuke Muneoka, Kizuki Yuza, Yoshifumi Shimada, Jennifer E. Ring, Alexei Protopopov, Stephen Lyle, Yiwei Ling, Shujiro Okuda, Kazuaki Takabe, Toshifumi Wakai

    JOURNAL OF CLINICAL ONCOLOGY   35   2017年5月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER SOC CLINICAL ONCOLOGY  

    DOI: 10.1200/JCO.2017.35.15_suppl.e15592

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  • jPOST: Development of reanalysis protocol toward control of false discovery rate in peptide identification

    Akiyasu C. Yoshizawa, Tsuyoshi Tabata, Mio Iwasaki, Yuki Moriya, Shin Kawano, Shujiro Okuda, Yu Watanabe, Tadashi Yamamoto, Masaki Matsumoto, Tomoyo Takami, Daiki Kobayashi, Norie Araki, Naoyuki Sugiyama, Satoshi Tanaka, Susumu Goto, Yasushi Ishihama

    ConBio2017   2017年

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  • プロテオーム統合データベースjPOST:質量分析データ・リポジトリ

    奥田修二郎, 渡辺由, 守屋勇樹, 河野信, 山本格, 松本雅記, 高見知代, 小林大樹, 荒木令江, 吉沢明康, 田畑剛, 杉山直幸, 田中聡, 五斗進, 石濱泰

    日本プロテオーム学会大会プログラム・抄録集   2017 ( 0 )   114 - 197   2017年

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    記述言語:日本語   出版者・発行元:日本プロテオーム学会(日本ヒトプロテオーム機構)  

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  • jPOST再解析プロトコル:偽陽性と偽陰性の同時減少を目指す

    吉沢明康, 田畑剛, 守屋勇樹, 河野信, 奥田修二郎, 渡辺由, 山本格, 松本雅記, 高見知代, 小林大樹, 荒木令江, 杉山直幸, 田中聡, 五斗進, 石濱泰

    日本プロテオーム学会大会プログラム・抄録集   2017 ( 0 )   115 - 115   2017年

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    記述言語:日本語   出版者・発行元:日本プロテオーム学会(日本ヒトプロテオーム機構)  

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  • jPOST:プロテオーム統合データベースの開発

    守屋勇樹, 河野信, 奥田修二郎, 渡辺由, 山本格, 松本雅記, 高見知代, 小林大樹, 荒木令江, 吉沢明康, 田畑剛, 杉山直幸, 田中聡, 五斗進, 石澤泰

    日本プロテオーム学会大会プログラム・抄録集   2017   116   2017年

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  • 生後の抑制性介在ニューロン発達におけるホメオタンパク質Otx2の網羅的ターゲット解析

    酒井晶子, 中戸隆一郎, LING Yiwei, HOU Xubin, 原範和, 飯島友也, 柳川右千夫, 桑野良三, 奥田修二郎, 白髭克彦, 杉山清佳

    エピゲノムはどこまで操れるようになったか 第11回日本エピジェネティクス研究会年会プログラム集 理研シンポジウム 平成29年   105   2017年

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  • Reducing false positive identifications for proteome datasets accumulated in jPOST repository

    Yoshizawa A, Tabata T, Moriya Y, Kawano S, Okuda S, Watanabe Y, Yamamoto T, Matsumoto M, Takami T, Kobayashi D, Araki N, Sugiyama N, Tanaka S, Goto S, Ishihama Y

    16th Human Proteome Organization World Congress (HUPO2017)   2017年

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  • jPOST:再解析プロトコルによる同定結果の質的向上

    吉沢明康, 田畑剛, 守屋勇樹, 河野信, 奥田修二郎, 渡辺由, 山本格, 松本雅記, 高見知代, 小林大樹, 荒木令江, 杉山直幸, 田中聡, 五斗進, 石濱泰

    トーゴ―の日シンポジウム2017   2017年

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  • 国際糖鎖構造リポジトリGlyTouCanの新バージョンToco

    木下聖子, 木下聖子, 新町大輔, 青木信行, 藤田晶大, 土屋伸一郎, 松原正陽, 藤田典昭, 鈴木芳典, SOLOVIEVA Elena, 鹿内俊秀, 奥田修二郎, 川嵜敏祐, 山田一作, 成松久

    日本糖質学会年会要旨集   35th   72‐73   2016年8月

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  • 質量スペクトルはデータベース検索“グレーゾーン”を明瞭化するか

    吉沢明康, 田畑剛, 守屋勇樹, 河野信, 奥田修二郎, 山本格, 松本雅記, 小林大樹, 荒木令江, 杉山直幸, 五斗進, 石濱泰

    質量分析総合討論会講演要旨集   64th   15   2016年5月

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  • Large-scale genomic sequencing of colorectal cancer in the Japanese population

    Toshifumi Wakai, Masayuki Nagahashi, Yoshifumi Shimada, Hiroshi Ichikawa, Hitoshi Kameyama, Takashi Kobayashi, Jun Sakata, Nobuaki Sato, Hiroshi Izutsu, Keisuke Kodama, Mitsutaka Nakada, Meaghan Russell, Joerg Heyer, Winslow Powers, Ruobai Sun, Jennifer E. Ring, Shujiro Okuda, Kazuaki Takabe, Alexei Protopopov, Stephen Lyle

    JOURNAL OF CLINICAL ONCOLOGY   34 ( 15 )   2016年5月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER SOC CLINICAL ONCOLOGY  

    DOI: 10.1200/JCO.2016.34.15_suppl.e15121

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  • Large panel genomic profiling using CancerPlex to reveal candidates for HER2 targeted therapies in colorectal cancer.

    Hiroshi Ichikawa, Yoshifumi Shimada, Masayuki Nagahashi, Hitoshi Kameyama, Jun Sakata, Takuma Okamura, Yosuke Tajima, Ryoma Yagi, Nobuaki Sato, Yasumasa Takii, Satoshi Maruyama, Hitoshi Nogami, Keiichi Honma, Takashi Kawasaki, Taro Inada, Shujiro Okuda, Alexei Protopopov, Stephen Lyle, Kazuaki Takabe, Toshifumi Wakai

    JOURNAL OF CLINICAL ONCOLOGY   34 ( 15 )   2016年5月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER SOC CLINICAL ONCOLOGY  

    DOI: 10.1200/JCO.2016.34.15_suppl.e13125

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  • ヒト腸内細菌の代謝反応データベース構築

    佃直紀, 山本希, 東光一, 入江満, 五斗進, 奥田修二郎, 守屋勇樹, 森宙史, 黒川顕, 山田拓司

    日本ゲノム微生物学会年会要旨集   10th   88   2016年

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  • プロテオーム統合データベースjPOST:質量分析データ・リポジトリの公開

    奥田修二郎, 渡辺由, 守屋勇樹, 河野信, 山本格, 松本雅記, 高見知世, 小林大樹, 荒木令江, 吉沢明康, 田畑剛, 杉山直幸, 五斗進, 石濱泰

    日本分子生物学会年会プログラム・要旨集(Web)   39th   ROMBUNNO.1PS7‐4(2P‐0039) (WEB ONLY)   2016年

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  • jPOST:プロテオームデータベースプロジェクト

    守屋勇樹, 河野信, 奥田修二郎, 渡辺由, 山本格, 松本雅記, 高見知世, 小林大樹, 荒木令江, 吉沢明康, 田畑剛, 杉山直幸, 五斗進, 石濱泰

    日本分子生物学会年会プログラム・要旨集(Web)   39th   ROMBUNNO.1P‐0076 (WEB ONLY)   2016年

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  • プロテオーム統合データベースjPOSTの開発

    五斗進, 奥田修二郎, 渡邉由, 守屋勇樹, 河野信, 山本格, 松本雅記, 高見知代, 小林大樹, 荒木令江, 吉沢明康, 田畑剛, 杉山直幸, 石濱泰

    日本プロテオーム学会大会プログラム・抄録集   2016   88   2016年

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  • プロテオーム統合データベースjPOST:再解析プロトコルの開発

    吉沢明康, 田畑剛, 守屋勇樹, 河野信, 奥田修二郎, 渡辺由, 山本格, 松本雅記, 高見知世, 小林大樹, 荒木令江, 杉山直幸, 五斗進, 石濱泰

    日本分子生物学会年会プログラム・要旨集(Web)   39th   ROMBUNNO.3P‐0880 (WEB ONLY)   2016年

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  • プロテオーム統合データベースjPOST:再解析プロトコルの開発

    吉沢明康, 田畑剛, 守屋勇樹, 河野信, 奥田修二郎, 渡邉由, 山本格, 松本雅記, 高見知世, 小林大樹, 荒木令江, 杉山直幸, 五斗進, 石濱泰

    日本プロテオーム学会大会プログラム・抄録集   2016   177   2016年

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  • jPOST:プロテオーム解析ワークフローの標準化

    守屋勇樹, 河野信, 奥田修二郎, 山本格, 松本雅記, 小林大樹, 荒木令江, 吉沢明康, 五斗進, 田畑剛, 杉山直幸, 石濱泰

    日本生化学会大会(Web)   88th   3P0417 (WEB ONLY) - [3P0417]   2015年12月

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    記述言語:日本語   出版者・発行元:(公社)日本生化学会  

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  • GlyTouCan:国際糖鎖構造リポジトリの開発

    新町大輔, 青木ポール信行, 藤田晶大, 土屋伸一郎, 松原正陽, 藤田典昭, 鈴木芳典, SOLOVIEVA Elena, 鹿内俊秀, 奥田修二郎, 川嵜敏祐, 山田一作

    日本糖質学会年会要旨集   34th   207   2015年7月

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  • 日本発の高品質プロテオームデータベース:jPOST

    守屋勇樹, 河野信, 奥田修二郎, 山本格, 松本雅記, 小林大樹, 荒木令江, 吉沢明康, 五斗進, 田畑剛, 杉山直幸, 石濱泰

    日本プロテオーム学会大会プログラム・抄録集   2015 (Web)   2015年

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  • 国際糖鎖構造リポジトリの開発

    木下聖子, 山田一作, 藤田晶大, 土屋伸一郎, 新町大輔, 青木ポール信行, 松原正陽, 藤田典昭, 鈴木芳典, SOLOVIEVA Elena, 鹿内俊秀, 奥田修二郎, 川嵜敏祐, 成松久

    日本糖質学会年会要旨集   33rd   83   2014年7月

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  • GlycoRDF:糖鎖オントロジーによる糖鎖関連データのRDF化

    RANZINGER Rene, 木下聖子, CAMPBELL Matthew P, 河野信, LUETTEKE Thomas, 奥田修二郎, 新町大輔, 鹿内俊秀, 澤木弘道, TOUKACH Philip, 松原正陽, 山田一作, 成松久

    日本糖質学会年会要旨集   33rd   158   2014年7月

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  • ヒト腸内細菌叢代謝経路データベース

    山田拓司, 佃直紀, 高橋知紀, 森宙史, 黒川顕, 守屋勇樹, 奥田修二郎, 五斗進

    腸内細菌学雑誌   28 ( 2 )   (JA)59,(EN)60   2014年4月

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  • JCGGDB および国際糖鎖構造リポジトリの開発

    木下 聖子, 鹿内 俊秀, 奥田 修二郎, 川㟢 敏祐, 成松 久, 新町 大輔, 藤田 晶大, 土屋 伸一郎, 藤田 典昭, 鈴木 芳典, ソロビヨワ イェレナ, 松原 正陽, 山田 一作

    日本プロテオーム学会大会要旨集   2014 ( 0 )   27 - 27   2014年

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    記述言語:日本語   出版者・発行元:日本プロテオーム学会(日本ヒトプロテオーム機構)  

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  • 国際標準化糖鎖構造表記法WURCSの開発

    山田 一作, ソロビヨワ イェレナ, 藤田 典昭, 奥田 修二郎, 川嵜 敏祐, 成松 久, 木下 聖子, 松原 正陽, 土屋 伸一郎, 新町 大輔, 藤田 晶大, 青木 信幸, 鹿内 俊秀, 鈴木 芳典

    情報化学討論会講演要旨集   2014 ( 0 )   O10 - O10   2014年

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    記述言語:日本語   出版者・発行元:公益社団法人 日本化学会・情報化学部会  

    糖鎖研究において産出された糖鎖データには様々な表現方法が存在しており、このことは近年のウェブ技術を利用したライフサイエンスデータベース間の連携の妨げとなっていた。そこで我々は、糖鎖構造に対する新たな表記法としてWURCS(Web3 Unique Representation of Carbohydrate Structures)を開発した。WURCSは、曖昧さを含むあらゆる糖鎖構造を一意に表せる線形表記法であり、URIとして利用可能である。併せて、糖鎖データベースの構造データからWURCSに変換するソフトウェアを開発した。これにより共通の糖鎖構造を含む分子の横断検索が可能となる。また、WURCS普及促進のためのWURCSWorkingGroupを組織し、国際標準化に向けた活動を行っている。

    DOI: 10.11545/ciqs.2014.0_O10

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  • ヒト腸内細菌代謝経路データベースの構築

    山田拓司, 佃直紀, 森宙史, 黒川顕, 黒川顕, 守屋勇樹, 奥田修二郎, 五斗進

    日本臨床腸内微生物学会誌   17 ( 1 )   18   2014年

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  • ヒト腸内細菌叢解析のためのパスウェイデータベース構築

    奥田修二郎, 佃直紀, 山本希, 西本悠一郎, 高橋知紀, 森宙史, 黒川顕, 守屋勇樹, 五斗進, 山田拓司

    日本分子生物学会年会プログラム・要旨集(Web)   37th   WEB ONLY 3W18-5(3P-0945)   2014年

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  • 渦鞭毛藻Karenia mikimotoiの網羅的遺伝子発現解析に基づく毒素生合成関連遺伝子群の探索

    木村圭, 木村圭, 奥田修二郎, 仲山慶, 高橋文雄, 山口晴生, 紫加田知幸, 坂本節子, 山口峰生, 外丸裕司

    日本水産学会大会講演要旨集   2014   2014年

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  • バクテリア存在下で誘導される,珪藻Caetoceros tenuissimusのウイルス抵抗性

    木村圭, 木村圭, 奥田修二郎, 外丸裕司

    日本ベントス学会・日本プランクトン学会合同大会講演要旨集   2013   2013年

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  • JCGGDBの活動報告

    鹿内俊秀, 梶裕之, 鈴木芳典, 藤田典昭, 前田真砂子, WEN Hongling, 石崎円, 澤木弘道, 奥田修二郎, 鴨さおり, 中尾広美, 石水毅, 川嵜伸子, 川嵜敏祐, 山田一作, 本庄秀之, 森昌子, 弘瀬友理子, 水野真盛, 加藤雅樹, 菅秋次, 山口芳樹, 木下聖子, 河野信, 成松久

    日本糖質学会年会要旨集   31st   89   2012年8月

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  • 糖鎖データの標準化に向けた試み

    河野信, CAMPBELL Matthew, 藤田典昭, 加藤雅樹, 木下聖子, LUETTEKE Thomas, 成松久, 奥田修二郎, RANZINGER Rene, 澤木弘道, 鹿内俊秀, 鈴木芳典, TOUKACH Philip V, 山田一作

    日本糖質学会年会要旨集   31st   87   2012年8月

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  • KEGG OC:系統関係に基づいた大規模オーソログクラスタの自動生成

    守屋勇樹, 中谷明弘, 片山俊明, 伊藤真純, 平糠和志, 川島秀一, 奥田修二郎, 田中道廣, 時松敏明, 山西芳裕, 吉沢明康, 金久實, 五斗進

    日本分子生物学会年会プログラム・要旨集(Web)   35th   3P-0075 (WEB ONLY)   2012年

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  • In silico study on the substrate binding manner in human myo-inositol monophosphatase 2. 国際誌

    Seisuke Fujita, Tetsuo Ohnishi, Shujiro Okuda, Ryo Kobayashi, Satoshi Fukuno, Daisuke Furuta, Takeshi Kikuchi, Takeo Yoshikawa, Norihisa Fujita

    Journal of molecular modeling   17 ( 10 )   2559 - 67   2011年10月

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    記述言語:英語   出版者・発行元:SPRINGER  

    The human IMPA2 gene encoding myo-inositol monophosphatase 2 is highly implicated with bipolar disorder but the substrates and the reaction mechanism of myo-inositol monophosphatase 2 have not been well elucidated.9 In the present study, we constructed 3D models of three- and two-Mg(2+)-ion bound myo-inositol monophosphatase 2, and studied substrate-binding manners using the docking program AutoDock3. The subsequent study showed that the three-metal-ion model could interact with myo-inositol monophosphates, as follows: The phosphate moiety coordinated three Mg(2+) ions, and the inositol ring formed hydrogen bonds with the amino acids conserved in the family. Furthermore, the OH group vicinal to the phosphate group formed a hydrogen bond with a non-bridging oxygen atom of the phosphate. These interactions have been proposed as crucial for forming the transitional state, bipyramidal structure in the bovine myo-inositol monophosphatase. We therefore propose that the human myo-inositol monophosphatase 2 interacts with myo-inositol monophosphates in the three-metal-ion bound form, and proceeds the dephosphorylation through the three-metal-ion theory.

    DOI: 10.1007/s00894-010-0937-8

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  • iPath2.0: interactive pathway explorer. 国際誌

    Takuji Yamada, Ivica Letunic, Shujiro Okuda, Minoru Kanehisa, Peer Bork

    Nucleic acids research   39 ( Web Server issue )   W412-5 - W415   2011年7月

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    記述言語:英語   出版者・発行元:OXFORD UNIV PRESS  

    iPath2.0 is a web-based tool (http://pathways.embl.de) for the visualization and analysis of cellular pathways. Its primary map summarizes the metabolism in biological systems as annotated to date. Nodes in the map correspond to various chemical compounds and edges represent series of enzymatic reactions. In two other maps, iPath2.0 provides an overview of secondary metabolite biosynthesis and a hand-picked selection of important regulatory pathways and other functional modules, allowing a more general overview of protein functions in a genome or metagenome. iPath2.0's main interface is an interactive Flash-based viewer, which allows users to easily navigate and explore the complex pathway maps. In addition to the default pre-computed overview maps, iPath offers several data mapping tools. Users can upload various types of data and completely customize all nodes and edges of iPath2.0's maps. These customized maps give users an intuitive overview of their own data, guiding the analysis of various genomics and metagenomics projects.

    DOI: 10.1093/nar/gkr313

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  • ODB: a database for operon organizations, 2011 update. 国際誌

    Shujiro Okuda, Akiyasu C Yoshizawa

    Nucleic acids research   39 ( Database issue )   D552-5 - D555   2011年1月

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    記述言語:英語   出版者・発行元:OXFORD UNIV PRESS  

    ODB (Operon DataBase) aims to collect data of all known and conserved operons in completely sequenced genomes. Three newly updated features of this database have been added as follows: (i) Data from included operons were updated. The genome-wide analysis of transcription and transcriptional units has become popular recently and ODB successfully integrates these high-throughput operon data, including genome-wide transcriptional units of five prokaryotes and two eukaryotes. The current version of our database contains information from about 10,000 known operons in more than 50 genomes, and more than 400,000 conserved operons obtained from more than 1000 bacterial genomes. (ii) ODB proposes the idea of reference operons as a new operon prediction tool. A reference operon, a set of possible orthologous genes that organize operons, is defined by clustering all known operons. A large number of known operons, including the recently added genome-wide analysis of operons, allowed us to define more reliable reference operons. (iii) ODB also provides new graphical interfaces. One is for comparative analyses of operon structures in multiple genomes. The other is for visualization of possible operons in multiple genomes obtained from the reference operons. The 2011 updated version of ODB is now available at http://operondb.jp/.

    DOI: 10.1093/nar/gkq1090

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  • Direct observation and analysis of bacterial growth on an antimicrobial surface. 国際誌

    Hiroyuki Yamada, Nobuyuki Takahashi, Shujiro Okuda, Yuki Tsuchiya, Hisao Morisaki

    Applied and environmental microbiology   76 ( 16 )   5409 - 14   2010年8月

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    記述言語:英語   出版者・発行元:AMER SOC MICROBIOLOGY  

    Cells of Escherichia coli NBRC 3972 and Staphylococcus aureus NBRC 12732 were inoculated onto an agar (1.5%) medium varying in nutrient concentration from full strength of the nutrient broth (NB) to 1/10 NB. Immediately thereafter, the inoculated agar was placed on antimicrobial and nonantimicrobial surfaces in such a way that the microbial cells came into contact with these surfaces. Cell growth was directly observed under a microscope, and the growth rate constant of the cells was measured based on the increase in the area of the colonies formed by the growing cells. On the antimicrobial surface, the growth rate constant decreased at lower nutrient concentrations for both E. coli and S. aureus cells, whereas it showed little change on the nonantimicrobial surface. It was supposed that either the nutrient uptake or the nutrient utilization efficiency was retarded by the antimicrobial surface. At the lowest nutrient concentration examined in the present study, 1/10 NB, the cells could hardly grow on the antimicrobial surface, indicating that the surface would be sufficiently active in preventing bacterial growth under normal usage conditions, such as the wet areas of a kitchen. It was also revealed that the antimicrobial surface could prevent the division of cells either during the growth stage or before the onset of growth.

    DOI: 10.1128/AEM.00576-10

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  • 日本糖鎖科学コンソーシアムのデータベース

    鹿内俊秀, 新間陽一, 鈴木芳典, 藤田典昭, 梶裕之, 佐藤隆, 栂谷内晶, 亀山昭彦, 舘野浩章, 平林淳, 奥田修二郎, 川嵜敏祐, 高橋禮子, 加藤晃一, 古川鋼一, 八杉悦子, 西島正弘, 木下聖子, 西原祥子, 山田一作, 水野真盛, 白井孝, 加藤雅樹, 山口芳樹, 萩谷恵里子, 吉田圭一, 谷口直之, 成松久

    生化学   ROMBUNNO.4P-183   2009年9月

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  • 日本糖鎖科学コンソーシアムのデータベース

    鹿内俊秀, 新間陽一, 鈴木芳典, 藤田典昭, 梶裕之, 佐藤隆, 栂谷内晶, 亀山昭彦, 舘野浩章, 平林淳, 奥田修二郎, 川嵜敏祐, 高橋禮子, 加藤晃一, 古川鋼一, 八杉悦子, 西島正弘, 木下聖子, 西原祥子, 山田一作, 水野真盛, 白井孝, 加藤雅樹, 山口芳樹, 萩谷恵里子, 吉田圭一, 谷口直之, 成松久

    日本糖質学会年会要旨集   29th   120   2009年8月

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  • Comprehensive analysis of glycosyltransferases in eukaryotic genomes for structural and functional characterization of glycans. 国際誌

    Kosuke Hashimoto, Toshiaki Tokimatsu, Shin Kawano, Akiyasu C Yoshizawa, Shujiro Okuda, Susumu Goto, Minoru Kanehisa

    Carbohydrate research   344 ( 7 )   881 - 7   2009年5月

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    記述言語:英語   出版者・発行元:ELSEVIER SCI LTD  

    Glycosyltransferases comprise highly divergent groups of enzymes, which play a central role in the synthesis of complex glycans. Because the repertoire of glycosyltransferases in the genome determines the range of synthesizable glycans, and because the increasing amount of genome sequence data is now available, it is essential to examine these enzymes across organisms to explore possible structures and functions of the glycoconjugates. In this study, we systematically investigated 36 eukaryotic genomes and obtained 3426 glycosyltransferase homologs for biosynthesis of major glycans, classified into 53 families based on sequence similarity. The families were further grouped into six functional categories based on the biosynthetic pathways, which revealed characteristic patterns among organism groups in the degree of conservation and in the number of paralogs. The results also revealed a strong correlation between the number of glycosyltransferases and the number of coding genes in each genome. We then predicted the ability to synthesize major glycan structures including N-glycan precursors and GPI-anchors in each organism from the combination of the glycosyltransferase families. This indicates that not only parasitic protists but also some algae are likely to synthesize smaller structures than the structures known to be conserved among a wide range of eukaryotes. Finally we discuss the functions of two large families, sialyltransferases and beta 4-glycosyltransferases, by performing finer classifications into subfamilies. Our findings suggest that universality and diversity of glycans originate from two types of evolution of glycosyltransferase families, namely conserved families with few paralogs and diverged families with many paralogs.

    DOI: 10.1016/j.carres.2009.03.001

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  • Extraction and analysis of chemical modification patterns in drug development. 国際誌

    Daichi Shigemizu, Michihiro Araki, Shujiro Okuda, Susumu Goto, Minoru Kanehisa

    Journal of chemical information and modeling   49 ( 4 )   1122 - 9   2009年4月

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    記述言語:英語   出版者・発行元:AMER CHEMICAL SOC  

    Most drugs have been continuously modified from prototypic compounds in the drug development process. Such chemical modifications in the history of drug development are expected to contain a wealth of medicinal chemists' knowledge, and the KEGG DRUG structure maps have been compiled to capture this knowledge. Here we attempted to extract the information on the chemical modification patterns from 3745 approved drugs in the KEGG DRUG database and 255 drug pairs in the KEGG DRUG structure maps. We first identified 236 core structures and 506 peripheral fragments from the KEGG DRUG database using bit-represented fingerprints and hierarchical clustering of similar structures. We then examined position-dependent relationships between core structures and peripheral fragments, which revealed the tendency of specific fragments connected to specific modification sites on the core structures. Next we converted the drug pairs into 204 peripheral fragment changes at the modification sites. Each change was represented by the transformation profile defined as a difference of fingerprint bit patterns, and the hierarchical clustering of similar transformation profiles was performed. We thus identified 125 chemical modification patterns that characterize the KEGG DRUG structure maps. These patterns were further applied to the reconstruction of a new structure map. The approach presented here may be applicable to systematic in silico drug modifications.

    DOI: 10.1021/ci8003804

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  • KEGG Atlas mapping for global analysis of metabolic pathways. 国際誌

    Shujiro Okuda, Takuji Yamada, Masami Hamajima, Masumi Itoh, Toshiaki Katayama, Peer Bork, Susumu Goto, Minoru Kanehisa

    Nucleic acids research   36 ( Web Server issue )   W423-6 - W426   2008年7月

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    記述言語:英語   出版者・発行元:OXFORD UNIV PRESS  

    KEGG Atlas is a new graphical interface to the KEGG suite of databases, especially to the systems information in the PATHWAY and BRITE databases. It currently consists of a single global map and an associated viewer for metabolism, covering about 120 KEGG metabolic pathway maps and about 10 BRITE hierarchies. The viewer allows the user to navigate and zoom the global map under the Ajax technology. The mapping of high-throughput experimental data onto the global map is the main use of KEGG Atlas. In the global metabolism map, the node (circle) is a chemical compound and the edge (line) is a set of reactions linked to a set of KEGG Orthology (KO) entries for enzyme genes. Once gene identifiers in different organisms are converted to the K number identifiers in the KO system, corresponding line segments can be highlighted in the global map, allowing the user to view genome sequence data as organism-specific pathways, gene expression data as up- or down-regulated pathways, etc. Once chemical compounds are converted to the C number identifiers in KEGG, metabolomics data can also be displayed in the global map. KEGG Atlas is available at http://www.genome.jp/kegg/atlas/.

    DOI: 10.1093/nar/gkn282

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  • KEGG for linking genomes to life and the environment. 国際誌

    Minoru Kanehisa, Michihiro Araki, Susumu Goto, Masahiro Hattori, Mika Hirakawa, Masumi Itoh, Toshiaki Katayama, Shuichi Kawashima, Shujiro Okuda, Toshiaki Tokimatsu, Yoshihiro Yamanishi

    Nucleic acids research   36 ( Database issue )   D480-4 - D484   2008年1月

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    記述言語:英語   出版者・発行元:OXFORD UNIV PRESS  

    KEGG (http://www.genome.jp/kegg/) is a database of biological systems that integrates genomic, chemical and systemic functional information. KEGG provides a reference knowledge base for linking genomes to life through the process of PATHWAY mapping, which is to map, for example, a genomic or transcriptomic content of genes to KEGG reference pathways to infer systemic behaviors of the cell or the organism. In addition, KEGG provides a reference knowledge base for linking genomes to the environment, such as for the analysis of drug-target relationships, through the process of BRITE mapping. KEGG BRITE is an ontology database representing functional hierarchies of various biological objects, including molecules, cells, organisms, diseases and drugs, as well as relationships among them. KEGG PATHWAY is now supplemented with a new global map of metabolic pathways, which is essentially a combined map of about 120 existing pathway maps. In addition, smaller pathway modules are defined and stored in KEGG MODULE that also contains other functional units and complexes. The KEGG resource is being expanded to suit the needs for practical applications. KEGG DRUG contains all approved drugs in the US and Japan, and KEGG DISEASE is a new database linking disease genes, pathways, drugs and diagnostic markers.

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  • The repertoire of desaturases and elongases reveals fatty acid variations in 56 eukaryotic genomes. 国際誌

    Kosuke Hashimoto, Akiyasu C Yoshizawa, Shujiro Okuda, Keiichi Kuma, Susumu Goto, Minoru Kanehisa

    Journal of lipid research   49 ( 1 )   183 - 91   2008年1月

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    記述言語:英語   出版者・発行元:AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC  

    The repertoire of biosynthetic enzymes found in an organism is an important clue for elucidating the chemical structural variations of various compounds. In the case of fatty acids, it is essential to examine key enzymes that are desaturases and elongases, whose combination determine the range of fatty acid structures. We systematically investigated 56 eukaryotic genomes to obtain 275 desaturase and 265 elongase homologs. Phylogenetic and motif analysis indicated that the desaturases consisted of four functionally distinct subfamilies and the elongases consisted of two subfamilies. From the combination of the subfamilies, we then predicted the ability to synthesize six types of fatty acids. Consequently, we found that the ranges of synthesizable fatty acids were often different even between closely related organisms. The reason is that, as well as diverging into subfamilies, the enzymes have functionally diverged within the individual subfamilies. Finally, we discuss how the adaptation to individual environments and the ability to synthesize specific metabolites provides some explanation for the diversity of enzyme functions. This study provides an example of a potent strategy to bridge the gap from genomic knowledge to chemical knowledge.

    DOI: 10.1194/jlr.M700377-JLR200

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  • 医薬品添付文書に基づく薬物相互作用の網羅的解析

    財部将孝, 奥田修二郎, 伊藤真純, 時松敏明, 五斗進, 金久實

    生化学   4P-0977   2008年

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  • Network analysis of adverse drug interactions.

    Masataka Takarabe, Shujiro Okuda, Masumi Itoh, Tosihaki Tokimatsu, Susumu Goto, Minoru Kanehisa

    Genome informatics. International Conference on Genome Informatics   20   252 - 9   2008年

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    記述言語:英語  

    Harmful effects associated with use of drugs are caused as a result of their side effects and combined use of different drugs. These drug interactions result in increased or decreased drug effects, or produce other new unwanted effects and are serious problems for medical institutions and pharmaceutical companies. In this study, we created a drug-drug interaction network from drug package inserts and characterized drug interactions. The known information about the potential risk of drug interactions is described in drug package inserts. Japanese drug package inserts are stored in the JAPIC (Japan Pharmaceutical Information Center) database and GenomeNet provides the GenomeNet pharmaceutical products database, which integrate the JAPIC and KEGG databases. We extracted drug interaction data from GenomeNet, where interactions are classified according to risks, contraindications or cautions for coadministration, and some entries include information about enzymes metabolizing the drugs. We defined drug target and drug-metabolizing enzymes as interaction factors using information on them in KEGG DRUG, and classified drugs into pharmacological/chemical subgroups. In the resulting drug-drug interaction network, the drugs that are associated with the same interaction factors are closely interconnected. Mechanisms of these interactions were then identified by each interaction factor. To characterize other interactions without interaction factors, we used the ATC classification system and found an association between interaction mechanisms and pharmacological/chemical subgroups.

    DOI: 10.11234/gi1990.20.252

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  • KEGG OC:網羅的なオーソログクラスターの自動生成

    中谷明弘, 伊藤真純, 奥田修二郎, 川島秀一, 田中道廣, 時松敏明, 片山俊明, 平糠和志, 守屋勇樹, 山西芳裕, 吉沢明康, 金久實

    生化学   4P-0986   2008年

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    記述言語:日本語  

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  • KEGG OC:オーソログクラスターのマニュアルアノテーション

    川島秀一, 伊藤真純, 奥田修二郎, 片山俊明, 田中道廣, 時松敏明, 中谷明弘, 平糠和志, 守屋勇樹, 山西芳裕, 吉沢明康, 金久實

    生化学   4P-0987   2008年

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  • KEGG OC:全生物種ゲノムにおけるオーソログ遺伝子のバリエーションと高速検索技術

    片山俊明, 伊藤真純, 奥田修二郎, 川島秀一, 田中道廣, 時松敏明, 中谷明弘, 平糠和志, 守屋勇樹, 山西芳裕, 吉沢明康, 金久實

    生化学   4T9-4   2008年

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  • [Integrated drug information resource].

    Minoru Kanehisa, Masumi Itoh, Shujiro Okuda, Susumu Goto, Fukuko Ohta

    Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme   52 ( 12 )   1486 - 91   2007年10月

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    記述言語:日本語  

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  • KAAS: an automatic genome annotation and pathway reconstruction server. 国際誌

    Yuki Moriya, Masumi Itoh, Shujiro Okuda, Akiyasu C Yoshizawa, Minoru Kanehisa

    Nucleic acids research   35 ( Web Server issue )   W182-5 - W185   2007年7月

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    記述言語:英語   出版者・発行元:OXFORD UNIV PRESS  

    The number of complete and draft genomes is rapidly growing in recent years, and it has become increasingly important to automate the identification of functional properties and biological roles of genes in these genomes. In the KEGG database, genes in complete genomes are annotated with the KEGG orthology (KO) identifiers, or the K numbers, based on the best hit information using Smith-Waterman scores as well as by the manual curation. Each K number represents an ortholog group of genes, and it is directly linked to an object in the KEGG pathway map or the BRITE functional hierarchy. Here, we have developed a web-based server called KAAS (KEGG Automatic Annotation Server: http://www.genome.jp/kegg/kaas/) i.e. an implementation of a rapid method to automatically assign K numbers to genes in the genome, enabling reconstruction of KEGG pathways and BRITE hierarchies. The method is based on sequence similarities, bi-directional best hit information and some heuristics, and has achieved a high degree of accuracy when compared with the manually curated KEGG GENES database.

    DOI: 10.1093/nar/gkm321

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  • Characterization of relationships between transcriptional units and operon structures in Bacillus subtilis and Escherichia coli. 国際誌

    Shujiro Okuda, Shuichi Kawashima, Kazuo Kobayashi, Naotake Ogasawara, Minoru Kanehisa, Susumu Goto

    BMC genomics   8   48 - 48   2007年2月

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    記述言語:英語   出版者・発行元:BIOMED CENTRAL LTD  

    BACKGROUND: Operon structures play an important role in transcriptional regulation in prokaryotes. However, there have been fewer studies on complicated operon structures in which the transcriptional units vary with changing environmental conditions. Information about such complicated operons is helpful for predicting and analyzing operon structures, as well as understanding gene functions and transcriptional regulation. RESULTS: We systematically analyzed the experimentally verified transcriptional units (TUs) in Bacillus subtilis and Escherichia coli obtained from ODB and RegulonDB. To understand the relationships between TUs and operons, we defined a new classification system for adjacent gene pairs, divided into three groups according to the level of gene co-regulation: operon pairs (OP) belong to the same TU, sub-operon pairs (SOP) that are at the transcriptional boundaries within an operon, and non-operon pairs (NOP) belonging to different operons. Consequently, we found that the levels of gene co-regulation was correlated to intergenic distances and gene expression levels. Additional analysis revealed that they were also correlated to the levels of conservation across about 200 prokaryotic genomes. Most interestingly, we found that functional associations in SOPs were more observed in the environmental and genetic information processes. CONCLUSION: Complicated operon structures were correlated with genome organization and gene expression profiles. Such intricately regulated operons allow functional differences depending on environmental conditions. These regulatory mechanisms are helpful in accommodating the variety of changes that happen around the cell. In addition, such differences may play an important role in the evolution of gene order across genomes.

    DOI: 10.1186/1471-2164-8-48

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  • Extracting sequence motifs and the phylogenetic features of SNARE-dependent membrane traffic. 国際誌

    Akiyasu C Yoshizawa, Shuichi Kawashima, Shujiro Okuda, Masashi Fujita, Masumi Itoh, Yuki Moriya, Masahiro Hattori, Minoru Kanehisa

    Traffic (Copenhagen, Denmark)   7 ( 8 )   1104 - 18   2006年8月

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    記述言語:英語   出版者・発行元:WILEY-BLACKWELL  

    The SNARE proteins are required for membrane fusion during intracellular vesicular transport and for its specificity. Only the unique combination of SNARE proteins (cognates) can be bound and can lead to membrane fusion, although the characteristics of the possible specificity of the binding combinations encoded in the SNARE sequences have not yet been determined. We discovered by whole genome sequence analysis that sequence motifs (conserved sequences) in the SNARE motif domains for each protein group correspond to localization sites or transport pathways. We claim that these motifs reflect the specificity of the binding combinations of SNARE motif domains. Using these motifs, we could classify SNARE proteins from 48 organisms into their localization sites or transport pathways. The classification result shows that more than 10 SNARE subgroups are kingdom specific and that the SNARE paralogs involved in the plasma membrane-related transport pathways have developed greater variations in higher animals and higher plants than those involved in the endoplasmic reticulum-related transport pathways throughout eukaryotic evolution.

    DOI: 10.1111/j.1600-0854.2006.00451.x

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  • ODB: a database of operons accumulating known operons across multiple genomes. 国際誌

    Shujiro Okuda, Toshiaki Katayama, Shuichi Kawashima, Susumu Goto, Minoru Kanehisa

    Nucleic acids research   34 ( Database issue )   D358-62 - D362   2006年1月

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    記述言語:英語   出版者・発行元:OXFORD UNIV PRESS  

    Operon structures play an important role in co-regulation in prokaryotes. Although over 200 complete genome sequences are now available, databases providing genome-wide operon information have been limited to certain specific genomes. Thus, we have developed an ODB (Operon DataBase), which provides a data retrieval system of known operons among the many complete genomes. Additionally, putative operons that are conserved in terms of known operons are also provided. The current version of our database contains about 2000 known operon information in more than 50 genomes and about 13 000 putative operons in more than 200 genomes. This system integrates four types of associations: genome context, gene co-expression obtained from microarray data, functional links in biological pathways and the conservation of gene order across the genomes. These associations are indicators of the genes that organize an operon, and the combination of these indicators allows us to predict more reliable operons. Furthermore, our system validates these predictions using known operon information obtained from the literature. This database integrates known literature-based information and genomic data. In addition, it provides an operon prediction tool, which make the system useful for both bioinformatics researchers and experimental biologists. Our database is accessible at http://odb.kuicr.kyoto-u.ac.jp/.

    DOI: 10.1093/nar/gkj037

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  • Analysis of the differences in metabolic network expansion between prokaryotes and eukaryotes.

    Michihiro Tanaka, Takuji Yamada, Masumi Itoh, Shujiro Okuda, Susumu Goto, Minoru Kanehisa

    Genome informatics. International Conference on Genome Informatics   17 ( 1 )   230 - 9   2006年

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    記述言語:英語  

    Recent evidence points to the existence of scale-free properties in many biological networks. By topological analysis, several models including preferential attachment and hierarchical modules have been proposed to explain how these networks are organized. On the other hand, analyses using dynamics have suggested that gene expression and metabolic networks have been organized with the scale-free property by the other models such as "rich-travel-more" and "log-normal dynamics." Because most of these approaches are based on comparative genomics of extant species, and did not consider evolutionary events such as horizontal gene transfer, gene loss and gene gain, we have analyzed transition of metabolic networks from the vertical point of view of evolution. First, to identify metabolic networks of common ancestors, we applied a parsimony algorithm for the enzymatic reaction set. Then by comparing the estimated metabolic networks among common ancestors, we investigated the transition of metabolic networks along the evolutionary process. As a result, we estimated enzymatic reaction contents of 227 common ancestors from 228 extant species, and found that links of several specific metabolites have frequently changed during the course of evolution.

    DOI: 10.11234/gi1990.17.230

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  • Conservation of gene co-regulation between two prokaryotes: Bacillus subtilis and Escherichia coli.

    Shujiro Okuda, Shuichi Kawashima, Susumu Goto, Minoru Kanehisa

    Genome informatics. International Conference on Genome Informatics   16 ( 1 )   116 - 24   2005年

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    記述言語:英語  

    We measured conservation of gene co-regulation between two distantly related prokaryotes, B. subtilis and E. coli. The co-regulation between genes was extracted from knowledge of regulation of genes stored in databases. For B. subtilis operons, we obtained the data set from ODB which we have developed and, for the regulons, we used DBTBS. For E. coli data set, we used known regulons derived from RegulonDB. We obtained a reliable data set of co-regulated genes in B. subtilis and E. coli. About 60-80 % of gene pairs conserved co-regulation relationships, so co-regulation between genes are highly conserved even between distantly related species. To measure the functional relationship between these conserved genes, we used KEGG PATHWAY and COG. When two co-regulated genes are in the same biological pathway in KEGG or share the same functional category in COG, we assume that they have the same function. As a result, we also found that many conserved co-regulated gene pairs share the same functions. These observations would help to predict gene co-regulation and protein functions.

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  • Electrophoretic mobility of Bacillus subtilis knockout mutants with and without flagella

    S Okuda, R Igarashi, Y Kusui, Y Kasahara, H Morisaki

    JOURNAL OF BACTERIOLOGY   185 ( 13 )   3711 - 3717   2003年7月

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    記述言語:英語   出版者・発行元:AMER SOC MICROBIOLOGY  

    Mutants of Bacillus subtilis 168 strain were obtained by inactivation of a specific gene by homologous recombination with the plasmid pMutinT3. The cell surface properties of these strains were characterized by measuring the electrophoretic mobility of the cells as a function of pH and ionic strength. The surface properties were different for the strains possessing flagella on their cells and strain FlgB, having no flagellum, due to knockout of the corresponding gene. The cell surface properties of the strains possessing flagella become similar to those of strain FlgB after acid treatment. It was confirmed that the acid treatment degraded the flagella without causing any apparent structural change on the cell surface via observations made using atomic force microscopy, transmission electron microscopy, and scanning electron microscopy. These results indicate that the flagella are a key factor influencing cell surface properties.

    DOI: 10.1128/JB.185.13.3711.3717.2003

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講演・口頭発表等

  • Computational Methods for the Interpretation of Clinical Meta­Omics Data: from a ‘Bag of Genes’ to Ecosystem Networks and Clinical Markers.

    International Human microbiome Congress  2011年 

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  • From Parts Lists to Ecosystem Networks: Development of a 2nd Generation Toolkit for Meta­Omics Analysis.

    Human Microbiome Research Conference  2010年 

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  • iPath: Interactive Pathways Explorer.

    ECCB 2010  2010年 

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  • From Parts Lists to Ecosystem Networks: Development of a 2nd Generation Toolkit for Meta­Omics Analysis.

    Human Microbiome Research Conference  2010年 

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  • Network analysis of adverse drug interactions.

    IBSB 2008  2008年 

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  • A systems biology approach to elucidating mechanisms underlying smog-induced airway inflammation.

    8th Siena Meeting  2008年 

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  • Analysis of Tissue Specific Expression Patterns of Metabolic Pathway.

    IBSB 2007  2007年 

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  • Pseudo-clique extraction method towards comprehensive clustering of orthologous genes in KEGG.

    JSBI 2007  2007年 

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  • Analysis of Tissue Specific Expression Patterns of Isozymes.

    GIW 2006  2006年 

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  • Construction of the drug substructure library from the KEGG DRUG database.

    IBSB 2006  2006年 

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  • Analysis of the differences in metabolic network expansion between prokaryotes and eukaryotes.

    IBSB 2006  2006年 

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  • Conservation of gene co-regulation between two prokaryotes: Bacillus subtilis and Escherichia coli.

    IBSB 2005  2005年 

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  • KAAS: KEGG Automatic Annotation Server.

    GIW 2005  2005年 

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  • Analysis of the bacterial mRNAs recognized by RNA-binding proteins and compounds.

    IBSB 2005  2005年 

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  • Determining the Evolutionary direction of Protein Domain-Fusion Using Genomic Fusion Flux.

    ISMB 2005  2005年 

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  • Automatic generation of KEGG OC (Ortholog Cluster) and its assignment to draft genomes.

    GIW 2004  2004年 

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  • Functional categorization of multiple genomes using KEGG OC in the genome indices.

    GIW 2004  2004年 

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  • Analysis of the bacterial sequences recognized by RNA-binding proteins and compounds.

    GIW 2004  2004年 

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  • Functional classification of coiled-coil proteins in multiple genomes.

    GIW 2004  2004年 

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  • Integration of biological features of multiple genomes: the construction of "Genome Indices" database.

    IBSB 2004  2004年 

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  • Prediction and Comparison of Coiled-Coil Proteins in Multiple Genomes.

    IBSB 2004  2004年 

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  • Comprehensive survey of intracellular transport system-related proteins in complete genomes and draft genomes.

    GIW 2003  2003年 

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  • Analysis of domain combinations in eukaryotic genomes.

    GIW 2003  2003年 

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  • Database of operons in Bacillus subtilis.

    GIW 2002  2002年 

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産業財産権

  • 高頻度変異型癌の判別システム、プログラム及び方法

    若井 俊文, 奥田 修二郎, 島田 能史, 井筒 浩, 兒玉 啓輔

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    出願人:国立大学法人 新潟大学

    出願番号:JP2019004499  出願日:2019年2月

    公表番号:WO2019-159821  公表日:2019年8月

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共同研究・競争的資金等の研究

  • 潰瘍性大腸炎術後回腸嚢炎の発症機序解明:腸内細菌叢および脂質メディエーターの解析

    研究課題/領域番号:20K09074  2020年4月 - 2023年3月

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    亀山 仁史, 奥田 修二郎, 廣瀬 雄己, 島田 能史, 中野 麻恵, 竹内 志穂, 中野 雅人, 小柳 英人, 永橋 昌幸, 田島 陽介

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    配分額:4290000円 ( 直接経費:3300000円 、 間接経費:990000円 )

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  • 消化器領域におけるヒト共生細菌叢と宿主の癌遺伝子異常との相互作用の解明

    研究課題/領域番号:19K22651  2019年6月 - 2022年3月

    日本学術振興会  科学研究費助成事業 挑戦的研究(萌芽)  挑戦的研究(萌芽)

    若井 俊文, 奥田 修二郎, 坂田 純, 島田 能史, 永橋 昌幸, 市川 寛, 廣瀬 雄己, 油座 築

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    配分額:6370000円 ( 直接経費:4900000円 、 間接経費:1470000円 )

    本研究の目的は、「癌遺伝子変異データ、細菌叢ゲノムデータを高次元解析し、癌と関連する細菌叢バイオマーカー及び薬物療法における治療効果の予測が可能となる細菌叢バイオマーカー同定すること」である。臨床応用に向けたMicrobiome-based Precision Medicine(細菌叢を基盤とした精密医療)という新たな治療体系の礎を築くことを目指す。
    消化器癌と細菌叢との類似研究における未解明な課題として、細菌叢と宿主(ヒト)の癌遺伝子異常との相互作用があげられる。本研究の意義は、癌における遺伝子異常と癌に共生する細菌(叢)とを同時にゲノム解析することにより、細菌叢と宿主(ヒト)の癌遺伝子異常との相互作用を究明できる点にある。
    2019年度は、大腸癌および周囲の非癌粘膜内の腸内細菌叢を16S RNA遺伝子解析し、大腸癌における遺伝子異常との関連性をバイオインフォマティクスによる高次元解析により解析を行っている。宿主(ヒト)における各種体液(唾液、胃液、胆汁、膵液、腸液、糞便)中の細菌叢もターゲットにして、胆道癌、膵癌における各種体液(唾液、胃液、胆汁、膵液、腸液、糞便)中の細菌叢を16S RNA遺伝子解析した。

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  • 炎症の進展と寛解に関与する好中球サブセット同定への挑戦

    研究課題/領域番号:19K22706  2019年6月 - 2021年3月

    日本学術振興会  科学研究費助成事業 挑戦的研究(萌芽)  挑戦的研究(萌芽)

    前川 知樹, 奥田 修二郎, 土門 久哲, 寺尾 豊

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    配分額:6500000円 ( 直接経費:5000000円 、 間接経費:1500000円 )

    歯周炎は,歯周病原細菌の感染に伴う正常な歯周組織からの病的な発展である.歯周病原細菌の感染初期には,好中球が主な防御機構を司っており,感染細菌を貪食するとともに,炎症性サイトカインを産生し,感染組織への炎症性細胞誘導を引き起こす.その後は,T細胞とB細胞の組織浸潤が認められ,歯周炎は慢性化へと展開していく.炎症寛解期に浸潤する好中球を単離し,機能解析したところ,歯周炎期の好中球と異なり,オプソニン化した細菌に対する反応性が減弱し,IL-10やTGF-β等の抗炎症性サイトカインを産生することが示された.加えて,歯牙結紮除去後に誘導される好中球を抑制すると,抗炎症性サイトカインのIL-10産生が減少し,歯周炎によって破壊された組織の修復が遅延することを見出した.これまで好中球とされていた分画に,炎症の進展に関与する“貪食”好中球と,炎症の寛解に関与する“抗炎症”好中球の2つのサブセットが存在する可能性がある.そこで①桿状核球から貪食好中球および抗炎症好中球の分化に必要な因子を解明すること,②貪食好中球から抗炎症好中球への転換が可塑性に起きている場合に,転換の鍵となる因子を解明することを目的とした.
    令和元年度は,貪食好中球と抗炎症好中球の機能解析を行った.マウスの背部に滅菌チタンコイルチャンバーを留置するマウスチャンバーモデルを用い,チャンバーの留置から1~3日後の炎症初期に浸潤する好中球およびチャンバー内の浸出液を採取した.続いて,創が閉鎖する留置14日後のチャンバーからも同様に好中球と浸出液を採取した.採取した好中球は,細菌に対する貪食能,サイトカイン産生能および好中球エラスターゼ活性を比較解析した.さらにサイトカインをLuminexにて測定した.炎症初期と後期に採取された好中球に表現型としての差異を認めたため,歯肉組織からも好中球を単離して解析を行なっている.

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  • 胃癌マイクロサテライト不安定性評価の検証と薬物治療における臨床的意義の解明

    研究課題/領域番号:19K09165  2019年4月 - 2022年3月

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    羽入 隆晃, 奥田 修二郎, 永橋 昌幸, 市川 寛, 石川 卓, 小杉 伸一, 加納 陽介

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    配分額:4290000円 ( 直接経費:3300000円 、 間接経費:990000円 )

    本研究の目的は、「胃癌における癌遺伝子解析パネルを用いたMSI 解析の精度、およびその臨床的意義を明らかにすることで、MSI を基軸とした胃癌薬物治療発展への足がかりとすること」である。本年度は、癌遺伝子パネルによるMSI解析結果と、ミスマッチ修復遺伝子発現の相関とMSI解析の精度を明らかにすることを目的に実験を行った。
    癌遺伝子パネルによる遺伝子解析を施行した胃癌切除検体27例(MSI-high: 13例、MSI-low/MSS: 14例)を対象とした。原発巣におけるミスマッチ修復(MMR)タンパク質(MLH1, PMS2, MSH2, MSH6)発現を免疫組織化学(IHC)で評価した。MSI-highの13例中、10例でMLH1及びPMS2のlossを、2例でPMS2のlossを認め、1例でMMRタンパク質発現が全て保たれていた。MSI-low/MSSの14例では、全例でMMRタンパク質発現が保たれていた。MSI-high胃癌抽出において、MLH1及びPMS2のIHCによるMMR遺伝子異常評価の感度は92%、特異度は100%であった。
    また、MSI-highの13例を対象として、臨床検査であるマイクロサテライト不安定性(MSI)検査(BAT25、BAT26、NR21、NR24、MONO27 の5マーカー)を施行した。13例全てで5マーカーにMSI陽性を認め、MSI-highと判定された。
    癌遺伝子パネルで同定されたMSI-high胃癌では、従来の報告通りMLH1またはPMS2発現の欠失が多く認められる。癌遺伝子パネルによるMSI評価の精度は高く、胃癌におけるPembrolizumab療法適応症例の選択に有用である可能性が示唆された。

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  • 経験による大脳抑制性ニューロンの形態形成と機能分化メカニズムの解析

    研究課題/領域番号:19H03322  2019年4月 - 2022年3月

    日本学術振興会  科学研究費助成事業 基盤研究(B)  基盤研究(B)

    杉山 清佳, 奥田 修二郎, 高田 美絵子

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    配分額:17290000円 ( 直接経費:13300000円 、 間接経費:3990000円 )

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  • HER2陽性胃癌における遺伝子異常の包括的評価と臨床的意義の解明

    研究課題/領域番号:19K09117  2019年4月 - 2022年3月

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    臼井 賢司, 奥田 修二郎, 島田 能史, 永橋 昌幸, 若井 俊文, 羽入 隆晃, 市川 寛, 石川 卓, 小杉 伸一

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    配分額:4290000円 ( 直接経費:3300000円 、 間接経費:990000円 )

    本研究の目的は、「胃癌における癌遺伝子解析パネルを用いたERBB2 遺伝子異常評価の精度、および併存する遺伝子異常の臨床的意義を明らかにすることで、抗HER2療法を基軸とした胃癌薬物治療発展への足がかりとすること」である。本年度は、癌遺伝子パネルによるERBB2増幅とHER2発現の関係を明らかにすることを目的に実験を行った。胃癌切除検体130例の原発巣におけるHER2発現を臨床検査(HER2検査)に準じて免疫組織化学(IHC)やFISHで評価した。IHCにはヒストファイン HER2キット(MONO)ユニバーサルキット(ニチレイバイオサイエンス)を、FISHにはパスビジョンHER-2 DNAプローブキット(PathVysion;Abbott Molecular)用いた。IHCで3+、またはIHC2+でFISH陽性(HER2/CEP17比≧2.0)をHER2陽性と定義した。同一症例のERBB2増幅を癌遺伝子パネルで解析し、コピー数≧2.5倍を増幅と定義した。全例でIHCやFISHと癌遺伝子パネルは同一のホルマリン固定後パラフィン包埋(FFPE)ブロックを用いた。35例は癌遺伝子パネルとは異なるFFPEブロックを用いたHER2検査も臨床的に行われていた。
    130例中HER2陽性は16例(12.3%)であった。また、ERBB2増幅は11例(8.5%)に認められた。10例はHER2陽性かつERBB2増幅、113例はHER2陰性かつERBB2非増幅であり、HER2検査としての癌遺伝子パネルの精度は94.6%であった。癌遺伝子パネルに用いたFFPEブロックと異なる検体を用いたHER2検査の結果を検討したところ、癌遺伝子パネルの精度は80.0%と低下した。
    癌遺伝子パネルによるHER2検査の精度は高く、胃癌における抗HER2療法適応症例の選択に有用である可能性が示唆された。

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  • 乳癌免疫微小環境における脂質メディエーター分子の役割解明と治療応用を目指した研究

    研究課題/領域番号:19H03714  2019年4月 - 2022年3月

    日本学術振興会  科学研究費助成事業 基盤研究(B)  基盤研究(B)

    永橋 昌幸, 奥田 修二郎, 阿部 学, 諸 和樹, 崎村 建司, 若井 俊文, 土田 純子, 五十嵐 道弘

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    配分額:17550000円 ( 直接経費:13500000円 、 間接経費:4050000円 )

    近年、乳癌の転移・再発における腫瘍免疫微小環境の働きが注目されている。腫瘍免疫微小環境においては、癌を抑制する免疫細胞と、癌に対する免疫を抑制し癌の進展を促進する免疫細胞とが存在する。癌を抑制する免疫細胞として腫瘍浸潤リンパ球(TIL)があり、TILが多い癌では転移が抑制される。癌の免疫逃避に重要な役割を果たす免疫細胞には、制御性T細胞(Treg)や骨髄由来免疫抑制細胞(Myeloid derived suppressor cell; 以下、MDSC)等が知られ、癌の転移・再発を促進する。S1Pは腫瘍免疫微小環境において、癌細胞を制御するこれらの免疫細胞に影響を及ぼしている可能性が示唆され、本研究で追究する。申請者は、「乳癌患者の腫瘍免疫微小環境において脂質メディエーター・スフィンゴシン-1-リン酸(S1P)が重要な役割を担っている」と仮説を立て、本研究を企画した。本研究の目的は、腫瘍免疫微小環境におけるS1Pの役割を解明し、その臨床的意義を明らかにして治療応用のための研究基盤を築くことである。本研究課題では、SphK1KO細胞をSphK1KOマウスに移植する実験を行い、腫瘍微小環境におけるS1Pの重要性が示唆された。免疫微小環境におけるS1Pの作用機構について解析し、免疫逃避機構(PD-1、PD-L1発現)との関連について解析中である。また、患者検体でS1Pを含むリピドミクス解析を行い、臨床病理学的因子との関連を解析した。さらに、TCGA及び自験例におけるバイオインフォマティクス解析により、腫瘍関連免疫細胞とS1Pとの関連性を検証中である。

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  • S1Pの癌代謝制御機構に着眼したトリプルネガティブ乳癌の病態と薬剤耐性機序の解明

    研究課題/領域番号:18K19576  2018年6月 - 2021年3月

    日本学術振興会  科学研究費助成事業 挑戦的研究(萌芽)  挑戦的研究(萌芽)

    永橋 昌幸, 若井 俊文, 五十嵐 道弘, 崎村 建司, 阿部 学, 奥田 修二郎, 土田 純子

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    配分額:6240000円 ( 直接経費:4800000円 、 間接経費:1440000円 )

    トリプルネガティブ乳癌(TNBC)は生物学的に悪性度が高く、薬物療法への抵抗性を生じやすく予後不良である。近年の網羅的遺伝子解析にも関わらず、TNBCは発癌や癌の悪化に寄与するドライバー遺伝子変異に乏しく、その病態メカニズムは未だ不明の点が多い。スフィンゴシン-1-リン酸(S1P)は、脂質でありながらタンパク質と同じように情報伝達物質として働く脂質メディエーターであり、癌で重要な役割を担っている。私達は、「TNBCの高悪性度の病態は、遺伝子やタンパク質の異常だけでは説明がつかず、その背景には脂質メディエーターを介した癌代謝制御機構が関与している」と仮説を立て、本研究を企画した。本研究の目的は「脂質メディエーター・S1Pを介した癌代謝制御機構に着目してTNBCの病態メカニズムを解明し、新規治療法開発への研究基盤を確立すること」である。本研究実績として、TNBCマウスモデルを用いて、癌の発育進展においてS1Pが重要な役割を果たしていることが分かった。また臨床検体のリピドミクス解析により、TNBC患者におけるスフィンゴリン脂質の動態について明らかにした。さらに臨床病理学的因子との比較により、TNBCにおけるS1Pの臨床的意義を見出し、今後の治療開発へ向けた研究の礎となることが期待される。

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  • がんゲノム医療実現化に向けた高次元データ解析基盤構築

    研究課題/領域番号:18H04123  2018年4月 - 2021年3月

    日本学術振興会  科学研究費助成事業 基盤研究(A)  基盤研究(A)

    奥田 修二郎, 赤澤 宏平, 島田 能史, 永橋 昌幸, 若井 俊文, 市川 寛

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    配分額:45760000円 ( 直接経費:35200000円 、 間接経費:10560000円 )

    がんという病気は細胞中のDNAに損傷(変異)が起きること、その変異が長年の間修復されずに積み重なることにより発症する。これまで個人のがん組織における変異を全て同定するには膨大な費用がかかったが、現在では超ハイスループットDNAシーケンサーの発達により比較的安価に変異同定が可能になった。米国ではThe Cancer Genome Atlasなどのがんゲノムを網羅的に調べる大型プロジェクトが立ち上がり、数百・千人規模でのがん変異の情報が蓄積されている。これらの成果から、がん発症に関連する数百の遺伝子(ターゲット遺伝子)に絞り込みより深くシーケンスするターゲットシーケンス法により、遺伝子変異の同定効率は飛躍的に上昇し、実臨床としてがんゲノム医療が実現しようとしている。そこで重要となるのが、がんゲノム情報のデータ統合化とデータ解析基盤の構築である。 平成30年度は、大腸がん201症例、胃がん207症例、肺がん167症例、乳がん53症例を含め700症例以上の固形がんにおける遺伝子検査結果のデータベース化を実施した。また、がん化の原因の多くは、関連するシグナル伝達系の何処かに遺伝子変異が起きることで細胞増殖のサイクルが狂うことにあるため、シグナル伝達系を中心にがん関連パスウェイの情報のデータベース化を進めている。さらに医療情報とゲノム変異の情報を合わせてあらゆる条件で半自動的に様々な統計解析やグラフ化を実施できるシステムの開発を進めてきた。人工知能への応用として、病理画像の認識技術の開発も継続して進めている。これらの大規模なデータと解析システムを統合化したプラットフォームを構築している。

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  • 統合オーミクス解析に基づく口腸連関の解明-歯周病をモデルとした関連解析ー

    研究課題/領域番号:18H04067  2018年4月 - 2021年3月

    日本学術振興会  科学研究費助成事業 基盤研究(A)  基盤研究(A)

    山崎 和久, 大野 博司, 奥田 修二郎

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    配分額:44330000円 ( 直接経費:34100000円 、 間接経費:10230000円 )

    本研究は、歯周病の全身への影響メカニズムを口腔‐腸管連関に基づき各種オーミクス解析の統合的応用によって解明しことである。今年度は二つのモデルマウスの作成を行った。1)NASHモデル:C57BL/6マウスにコリン欠損高脂肪食餌(CDAHFD60)を与え、実験的NASH状態を作成し、さらに歯周病原細菌Porphyromonas gingivalis, Prevotella intermediaを口腔より投与するという、歯周炎患者の口腔状態を模したモデルである。予備実験としてCDAHFD60の投与期間(2週から12週)、細菌の投与時期と間隔等を検討した結果、順化後細菌を1週間に5回の頻度で投与し、投与開始1週後から餌をCDAHFD60に変更して2週間投与し、その間細菌投与を継続するというモデルが最適であることが明らかになった。このモデルを用い、順化後、細菌投与1週後、実験終了時糞便サンプルの採取、血清の採取、肝臓、腸管組織のサンプリングが終了し、解析を開始した。2)糞便移入モデル:2群のC57BL/6マウスにそれぞれHigh Fat Diet32 (HFD32)とNormal Chow (NC)を投与し、投与開始4週目以降の糞をプールする。別のマウスに順化後抗生物質のカクテルを1週間投与した後、プールした糞便をカニューレを用いて毎日1回5日間投与し、1週後にligature-induced periodontitisを惹起した。コントロールはNC投与、HFD32投与マウス糞便移植、Ligature (-)とした。Ligature開始1週後にサンプリングを行った。移入開始前、移入後、実験終了時の糞便を採取し、細菌叢の解析を開始している。
    並行してGerm-freeマウスにP. gingivalis, Lactobacillus salivarius投与実験を行い、データを得た。

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  • 発癌の分子メカニズムの違いに着目した大腸癌TGF-βシグナル伝達経路の新たな分類

    研究課題/領域番号:18K08612  2018年4月 - 2021年3月

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    島田 能史, 若井 俊文, 亀山 仁史, 永橋 昌幸, 市川 寛, 田島 陽介, 小林 隆, 奥田 修二郎

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    配分額:4420000円 ( 直接経費:3400000円 、 間接経費:1020000円 )

    申請者らは、TGF-βシグナル伝達経路に異常を有する大腸癌には、2つの異なる発癌の分子メカニズムが存在することに着目し、「TGF-βシグナル伝達経路に異常を有する大腸癌は、シグナルの受容体であるTGFBR2もしくはACVR2Aに遺伝子変異をもつ群(受容体変異群)と、細胞内におけるシグナル伝達の調節因子であるSMAD2もしくはSMAD4に遺伝子変異をもつ群(調節因子変異群)とに分類することができる」という仮説を立て、本研究を企画した。本研究の目的は、「受容体変異群と調節因子変異群について、病理像・臨床像・人種差・蛋白質発現を解析し、発癌の分子メカニズムの違いに着目した大腸癌TGF-βシグナル伝達経路の分類における研究基盤を確立すること」である。
    本年度は、散発性大腸癌におけるTGF-βシグナル伝達経路と、MAPK経路におけるBRAF V600E変異およびWnt経路におけるRNF43変異との関係を解析し、その結果を英文雑誌に投稿した。
    Matsumoto A, Shimada Y, et al. RNF43 mutation is associated with aggressive tumor biology along with BRAF V600E mutation in right-sided colorectal cancer. Oncol Rep. 2020 Mar 23.doi: 10.3892/or.2020.7561.

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  • 線維化促進分泌型タンパクを介した、非アルコール性脂肪性肝炎の新たな発症機序の解明

    研究課題/領域番号:17K19648  2017年6月 - 2019年3月

    日本学術振興会  科学研究費助成事業 挑戦的研究(萌芽)  挑戦的研究(萌芽)

    清水 逸平, 南野 徹, 吉田 陽子, 奥田 修二郎, 崎村 建司, 寺井 崇二, 笹岡 俊邦, 中神 啓徳

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    配分額:6370000円 ( 直接経費:4900000円 、 間接経費:1470000円 )

    本研究の目的は肥満関連分泌型線維化促進分子(OAFP)を介した、非アルコール性脂肪性肝炎(NASH)の肝臓線維化促進機構を明らかにすることであった。肥満ストレス下で血液中で発現が上昇する線維化促進分泌型タンパク質「OAFP」に着目し、肥満→NASH→肝臓線維化→肝硬変という一連の病態にOAFPが関与するか検証した。マウスOAFP過剰発現モデルや、発現抑制モデルを作製し表現型を解析したところ、OAFPを介して肝臓の線維化が促進されることが明らかとなった。本検討により、NASHの病態において線維化促進分泌型タンパク質OAFPが重要な役割を果たす可能性が示唆された。

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  • 大規模菌叢解析データを用いた歯周病治療法の最適化クリティカルパスの開発

    研究課題/領域番号:17K19747  2017年6月 - 2019年3月

    日本学術振興会  科学研究費助成事業 挑戦的研究(萌芽)  挑戦的研究(萌芽)

    前川 知樹, 奥田 修二郎, 土門 久哲, 寺尾 豊, 米澤 大輔

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    配分額:6500000円 ( 直接経費:5000000円 、 間接経費:1500000円 )

    ヒト歯周炎罹患患者を侵襲性歯周炎,歯肉膿瘍を伴う歯周炎,慢性歯周炎に分類し,正常な細菌構成バランスを持つ正常な歯周状態の患者からの計57名の歯肉縁下プラークサンプルを採取した.採取したサンプルはメタゲノム解析のためのサンプル調整をおこない,次世代シークエンサーにて全細菌のメタゲノム解析と中心となって機能すると予想される細菌の同定を行った.中心となって機能している候補細菌の一つであるP. gは,免疫機能を減弱させることで,歯周炎を引き起こしていることが明らかになった.そこで同様のアプローチを新たに同定された疾患ごとの中心となって機能する細菌に対し行なっている.

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  • Precision medicineに向けたゲノム解析に基づく胃がん新分類の試み

    研究課題/領域番号:17H04280  2017年4月 - 2020年3月

    日本学術振興会  科学研究費助成事業 基盤研究(B)  基盤研究(B)

    吉田 和弘, 奥田 修二郎, 二村 学, 大島 貴, 北川 雄光, 沖 英次

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    配分額:17160000円 ( 直接経費:13200000円 、 間接経費:3960000円 )

    私達は日本人の胃癌ゲノムを次世代シークエンサーにて解明し日本人胃癌の特徴をもとに、臨床応用に繋げていくデータベースの構築を試みました。本邦の胃癌サンプル207例のゲノム解析を癌遺伝子パネル(CancerPlex)にて行い、93.7%で1つ以上の遺伝子異常が発見されました。米国のデータベースTCGAのサブタイプ4分類(EBV:9%,MSI:21%,CIN:50%,GS:20%)と比較して、EBV:4%, MSI:8%, CIN:58%, GS:30% でEBVやMSIの頻度が少なかった。これには日本ではEBウイルス感染が少なかったり、ピロリ菌感染が多かったりする環境要因の違いも示唆されます。

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  • 褐色脂肪由来物質を介した心筋代謝リモデリング機構の解明

    研究課題/領域番号:16H06244  2016年4月 - 2019年3月

    日本学術振興会  科学研究費助成事業 若手研究(A)  若手研究(A)

    清水 逸平, 南野 徹, 吉田 陽子, 曽我 朋義, 箕越 靖彦, 奥田 修二郎, 崎村 建司, 笹岡 俊邦

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    配分額:24050000円 ( 直接経費:18500000円 、 間接経費:5550000円 )

    本研究により、心不全の病態に伴い褐色脂肪不全が生じることが明らかとなった。褐色脂肪不全マウスでは心不全が増悪し、褐色脂肪機能活性化マウスでは心不全が抑制された。メタボローム解析の結果、心不全時に心臓の代謝不全を増悪させる代謝物質が全身に循環し、褐色脂肪不全によりそのレベルが上昇することが明らかとなった。この代謝物により、骨格筋の線維化と筋力低下も惹起される可能性が示唆されている。このような役割を担う代謝物質を「老化促進代謝物質」と捉え、その病的意義を心不全、サルコペニアモデルを用いて今後も明らかにしてゆきたいと考えている。

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  • 大動脈疾患における老化シグナルを介した血管リモデリング機構の解明

    研究課題/領域番号:16K10653  2016年4月 - 2019年3月

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    長澤 綾子, 清水 逸平, 土田 正則, 南野 徹, 奥田 修二郎, 曽我 朋義, 青木 淳賢, 早野 俊哉, 崎村 健司, 笹岡 俊邦

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    配分額:4680000円 ( 直接経費:3600000円 、 間接経費:1080000円 )

    今研究は大動脈疾患における細胞老化の果たす役割に解明が目的であり、12週齢野生型マウスに高容量AngIIを14日間投与した大動脈疾患モデルを作成し、老化マーカーを検証したところ、大動脈壁において蛋白レベルのp53上昇を認め、免疫染色で大動脈中膜へのp53の集積を確認した。次に平滑筋特異的細胞老化抑制・促進モデルマウスを作成し、高容量AngIIを投与して大動脈疾患の発症頻度を検証したところ、細胞老化モデルで有意に大動脈疾患発症率が低く、細胞老化抑制モデルの大動脈疾患発症率は有意に増加が見られた。以上より平滑筋の細胞老化は大動脈疾患発症に対して保護的であることが示唆され、さらなる研究が必要である。

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  • メタボロミクスを用いた心肺血管疾患における代謝リモデリングの解析

    研究課題/領域番号:16K09422  2016年4月 - 2019年3月

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    尾崎 和幸, 南野 徹, 小澤 拓也, 柳川 貴央, 保屋野 真, 田中 孔明, 清水 逸平, 高野 俊樹, 久保田 直樹, 崎村 建司, 奥田 修二郎, 曽我 朋義

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    配分額:4680000円 ( 直接経費:3600000円 、 間接経費:1080000円 )

    これまで、我々は138名の心肺血管疾患患者において探索的にメタボローム解析を行った。その結果、特に虚血性心筋症における低心機能患者において、ピルビン酸、乳酸の心臓への取り込みの減少等、いくつかの代謝産物に変化があることを確認した。さらに、非虚血性心筋症に伴う低心機能患者では、一部の代謝産物において虚血性心筋症とは異なる動態を示すことも判明しつつある。詳細な臨床データとの解析も現在進行中である。また、重要と思われる代謝産物では心不全モデルマウスでの検討も開始した。今後、さらなる症例の蓄積、フォローアップデータの解析を行う予定である。

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  • iPS細胞マーカーTRA-1-60はがん難治性の指標か?

    研究課題/領域番号:16K15245  2016年4月 - 2018年3月

    日本学術振興会  科学研究費助成事業 挑戦的萌芽研究  挑戦的萌芽研究

    近藤 英作, 奥田 修二郎, 阪口 政清

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    配分額:3640000円 ( 直接経費:2800000円 、 間接経費:840000円 )

    TRA-1-60は糖鎖修飾型PODXL1であることから、ヒト膵がん細胞株においてPODXL1ノックアウトクローンを作成し機能解析した。結果、MiaPaCa-2, AsPC1, Panc-1 PODXL1-KO(PODXL1 -/-)クローンは膵がん肝転移を劇的に抑制した。即ち、PODXL1は膵がんの転移能獲得に直接に機能していることが判明した。PODXL1は複数のサイトカイン受容体と結合能を持ち、がん組織内でこれら受容体の機能活性化に働いていることが判明した膵がん患者病理組織では、上記の遺伝子機能を反映し、腫瘍の浸潤先進部や肝転移巣で高発現していることが判明した。

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  • 難治性感染症の原因となる休止細菌の分子機構解明

    研究課題/領域番号:15K15134  2015年4月 - 2017年3月

    日本学術振興会  科学研究費助成事業 挑戦的萌芽研究  挑戦的萌芽研究

    常田 聡, 奥田 修二郎

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    配分額:3770000円 ( 直接経費:2900000円 、 間接経費:870000円 )

    代謝活性を止めている休止細菌は,抗生物質存在下において生存できるため,感染症難治化の原因となる。本研究では,細菌の細胞骨格であるFtsZに着目し,細胞分裂時のZ-ringの形成を蛍光共鳴エネルギー移動で検出する遺伝子組換え大腸菌株の開発を行った。その結果,セルソーターを用いることで休止細菌と分裂細菌の分離に成功し,休止細菌は抗生物質(オフロキサシン)に対して高い抵抗性を持つことがわかった。また,トランスクリプトーム解析の結果,休止細菌は乳酸デヒドロゲナーゼの遺伝子発現を亢進させていることがわかった。さらに,マイクロ流体デバイスを用いたシングルセル観察によっても上記の結果が支持された。

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  • ヒトマイクロバイオームによる疾患因子プロファイリング

    研究課題/領域番号:26700029  2014年4月 - 2018年3月

    日本学術振興会  科学研究費助成事業 若手研究(A)  若手研究(A)

    奥田 修二郎

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    配分額:24570000円 ( 直接経費:18900000円 、 間接経費:5670000円 )

    腸内細菌叢を始めとしたヒトマイクロバイオームの研究を推進する上で非常に重要なことが、どの細菌がどういう相互作用をしてその細菌叢を構築しているか、を推定することである。そのために必要となる基盤的手法の開発を実施した。細菌種間の相互作用を担う可能性の高い代謝系上の接点を推測し、これらの相互作用点を元に細菌種間相互作用ネットワークを推定する手法を開発した。これにより複雑なマイクロバイオーム内での細菌間の関係を解析および可視化できるようになる。

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  • 視覚からコミュニケーションへ:皮質脳波法で読み解く大脳神経回路の情報流

    研究課題/領域番号:26242088  2014年4月 - 2017年3月

    日本学術振興会  科学研究費助成事業 基盤研究(A)  基盤研究(A)

    長谷川 功, 奥田 修二郎, 谷川 久, 中原 潔, 神谷 之康, 河野 剛士, 鎌田 恭輔, 北村 秀明, 鈴木 隆文, 戸田 春男, 川嵜 圭祐, 飯島 淳彦, 西山 雄大

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    配分額:44850000円 ( 直接経費:34500000円 、 間接経費:10350000円 )

    種々の空間スケールで計測した皮質脳波信号の2次元格子パターンから視覚的コミュニケーションを担う階層的・分散的な大脳の情報流を定量化する手法を開発した。マカクザル下側頭皮質では視覚刺激提示後に順行性と逆行性の情報流が交互に現れ、トポロジーの分離・統合が起こることを見出した。内側側頭葉では図形の記憶がシータ波の空間パターンとして分散し、記憶の形成に伴って再編されることを示した。前頭皮質でも記号の変換に関わるシータ波信号の流れを同定し、また時空間二次元フーリエ変換により、ラット視覚野の周辺抑制の時空間特性を明らかにした。

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  • 海綿メタボロミクスを基盤とした希少海綿動物および微量天然物の有効利用

    研究課題/領域番号:25660163  2013年4月 - 2015年3月

    日本学術振興会  科学研究費助成事業 挑戦的萌芽研究  挑戦的萌芽研究

    高田 健太郎, 奥田 修二郎, 伊勢 優史

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    配分額:3900000円 ( 直接経費:3000000円 、 間接経費:900000円 )

    海洋天然物は多様な化学構造を持ち、また、興味深い生物活性を示すことから、医薬品の探索資源として利用されている。その中でも海綿動物は体内に数多くの共生微生物を持つことから、化合物の多様性に富む。本研究では、海綿動物の抽出物に対するメタボロミクスにより、各海綿動物の化合物プロファイルを明らかにし、未利用資源からの有用物質の探索研究に有効活用することを目的とした。その結果、約1500種の海綿動物の化合物プロファイルの構築とクラスター解析に成功し、さらに解析データを基に2種の海綿動物より生物活性物質の単離と構造決定に成功した。

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  • 環境ゲノムの機能多様性の解析

    研究課題/領域番号:21710212  2009年 - 2010年

    日本学術振興会  科学研究費助成事業 若手研究(B)  若手研究(B)

    奥田 修二郎

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    配分額:4550000円 ( 直接経費:3500000円 、 間接経費:1050000円 )

    本課題の目的としては、環境微生物のゲノム配列を利用して、環境の違いと微生物の機能との関係を明らかにすることである。さまざまな環境から得られる微生物の遺伝子配列を利用し比較解析を行った結果、代謝系のカテゴリにおける差は、大きくないことがわかったが、環境微生物では、より小さなサブネットワークが連結しやすいという傾向を発見した。このことにより、環境中の微生物は、代謝物質のやりとりにより相互作用している可能性が示唆された。

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  • ゲノムの多様性と環境との相互作用の解析

    研究課題/領域番号:20810039  2008年 - 2009年

    日本学術振興会  科学研究費助成事業 若手研究(スタートアップ)  若手研究(スタートアップ)

    奥田 修二郎

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    配分額:3302000円 ( 直接経費:2540000円 、 間接経費:762000円 )

    自然環境中には、未だゲノム配列の決まっていない生物種も含めて極めて多くの生物が、相互に影響を及ぼしながら棲息している。これまでのように単一生物種のゲノム配列決定だけでは、そういった生物間相互作用、あるいは生物と環境との相互作用を観察することは難しかった。しかしながら、近年、メタゲノム解析手法の発展とともに、ある環境サンプル中の生物が持つゲノム配列を網羅的に決めることができるようになった。この技術により、生物と環境との関係への理解が飛躍的に進むものと期待されている。本課題の目的としては、メタゲノム配列を利用して、環境の違いが、環境ゲノムの機能とどのような関係にあるのかを明らかにすることである。これまでに、論文として発表されているメタゲノムデータを収集し、データフォーマットの統一化を行った。これらのデータから、京都大学化学研究所にて提供されるKEGGデータベース内にある自動アノテーションツールKAASによって、システマティックにアノテーションを得ることが出来る。現在、このツールを利用して、メタゲノム配列の機能アノテーションを行っている。これによって、メタゲノム配列中の遺伝子に対して、KEGGデータベースで利用される遺伝子オーソロジー(KO)に基づいた、階層的な機能の分類を行うことが出来る。そのために必要とされる一連のプロセスを、可能な限りプログラムによって自動化できるようシステム構築を行っている。

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  • 生命システムと環境の相互作用の理解

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    資金種別:競争的資金

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  • Toward understanding interaction between life and the environment

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    資金種別:競争的資金

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