2023/09/22 更新

写真a

オオノ キンジ
大野 欽司
OHNO, Kinji
所属
大学院医学系研究科 附属神経疾患・腫瘍分子医学研究センター 神経疾患病態統御部門 教授
大学院担当
大学院医学系研究科
学部担当
医学部
職名
教授

学位 1

  1. 医学博士 ( 1992年3月   名古屋大学 ) 

研究キーワード 1

  1. ゲノム、脳神経疾患、遺伝子、神経科学、蛋白質、脳・神経、遺伝子変異、Pre-mRNAスプライシング機構、既認可薬スクリーニング、インシリコ解析

研究分野 2

  1. その他 / その他  / 応用ゲノム科学

  2. その他 / その他  / 神経内科学

経歴 9

  1. 名古屋大学大学院医学系研究科・神経遺伝情報学・教授

    2004年9月 - 現在

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    国名:日本国

  2. 名古屋大学医学系研究科・副研究科長

    2009年4月 - 2020年3月

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    国名:日本国

  3. Senior Research Associate, Dept of Neurology, Mayo Clinic

    2001年4月 - 2004年8月

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    国名:アメリカ合衆国

  4. Assistant Professor, Mayo Medical School

    1998年4月 - 2004年8月

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    国名:アメリカ合衆国

  5. Research Associate, Dept of Neurology, Mayo Clinic

    1996年4月 - 2001年3月

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    国名:アメリカ合衆国

  6. Research Fellow, Dept of Neurology, Mayo Clinic

    1993年4月 - 1996年3月

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    国名:アメリカ合衆国

  7. 日本学術振興会特別研究員(名古屋大学医学部第2生化学)

    1992年4月 - 1993年3月

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    国名:日本国

  8. 国立名古屋病院神経内科レジデント及びスタッフ

    1985年4月 - 1988年3月

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    国名:日本国

  9. 国立名古屋病院研修医

    1983年6月 - 1985年3月

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    国名:日本国

▼全件表示

学歴 2

  1. 名古屋大学   医学系研究科   神経内科学

    1988年4月 - 1992年3月

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    国名: 日本国

  2. 名古屋大学   医学部   医学科

    1977年4月 - 1983年3月

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    国名: 日本国

所属学協会 9

  1. Society for Neuroscience

  2. American Society of Human Genetics

  3. RNA Society

  4. 日本分子生物学会

  5. 日本神経学会   評議員

  6. 日本内科学会

  7. 日本RNA学会

  8. 分子状水素医学シンポジウム   評議員

  9. 日本神経化学会   評議員

▼全件表示

受賞 1

  1. Neurology Research Award

    1995年   Mayo Clinic  

 

論文 172

  1. Fusobacterium infection facilitates the development of endometriosis through the phenotypic transition of endometrial fibroblasts. 査読有り

    Muraoka A, Suzuki M, Hamaguchi T, Watanabe S, Iijima K, Murofushi Y, Shinjo K, Osuka S, Hariyama Y, Ito M, Ohno K, Kiyono T, Kyo S, Iwase A, Kikkawa F, Kajiyama H, Kondo Y

    Science translational medicine   15 巻 ( 700 ) 頁: eadd1531   2023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: 10.1126/scitranslmed.add1531

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  2. Gastrointestinal disorders in Parkinson's disease and other Lewy body diseases. 査読有り

    Hirayama M, Nishiwaki H, Hamaguchi T, Ohno K

    NPJ Parkinson's disease   9 巻 ( 1 ) 頁: 71   2023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: 10.1038/s41531-023-00511-2

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  3. Impaired gating of γ- and ε-AChR respectively causes Escobar syndrome and fast-channel myasthenia. 査読有り

    Shen XM, Nakata T, Mizuno S, Imoto I, Selcen D, Ohno K, Engel AG

    Annals of clinical and translational neurology   10 巻 ( 5 ) 頁: 732 - 743   2023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: 10.1002/acn3.51756

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  4. A mutation in DOK7 in congenital myasthenic syndrome forms aggresome in cultured cells, and reduces DOK7 expression and MuSK phosphorylation in patient-derived iPS cells. 査読有り

    Zhang S, Ohkawara B, Ito M, Huang Z, Zhao F, Nakata T, Takeuchi T, Sakurai H, Komaki H, Kamon M, Araki T, Ohno K

    Human molecular genetics   32 巻 ( 9 ) 頁: 1511 - 1523   2023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)  

    DOI: 10.1093/hmg/ddac306

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  5. Neural Isoforms of Agrin Are Generated by Reduced PTBP1-RNA Interaction Network Spanning the Neuron-Specific Splicing Regions in AGRN. 査読有り

    Bushra S, Lin YN, Joudaki A, Ito M, Ohkawara B, Ohno K, Masuda A

    International journal of molecular sciences   24 巻 ( 8 )   2023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)  

    DOI: 10.3390/ijms24087420

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  6. Machine learning models predict delayed hyponatremia post-transsphenoidal surgery using clinically available features. 査読有り

    Fuse Y, Takeuchi K, Nishiwaki H, Imaizumi T, Nagata Y, Ohno K, Saito R

    Pituitary   26 巻 ( 2 ) 頁: 237 - 249   2023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)  

    DOI: 10.1007/s11102-023-01311-w

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  7. Activated FGFR3 suppresses bone regeneration and bone mineralization in an ovariectomized mouse model. 査読有り

    Kawashima I, Matsushita M, Mishima K, Kamiya Y, Osawa Y, Ohkawara B, Ohno K, Kitoh H, Imagama S

    BMC musculoskeletal disorders   24 巻 ( 1 ) 頁: 200   2023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)  

    DOI: 10.1186/s12891-023-06318-9

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  8. Evaluation of Human-Induced Pluripotent Stem Cells Derived from a Patient with Schwartz-Jampel Syndrome Revealed Distinct Hyperexcitability in the Skeletal Muscles. 査読有り

    Yamashita Y, Nakada S, Nakamura K, Sakurai H, Ohno K, Goto T, Mabuchi Y, Akazawa C, Hattori N, Arikawa-Hirasawa E

    Biomedicines   11 巻 ( 3 )   2023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)  

    DOI: 10.3390/biomedicines11030814

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  9. Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes-A Comprehensive Review. 査読有り

    Ohno K, Ohkawara B, Shen XM, Selcen D, Engel AG

    International journal of molecular sciences   24 巻 ( 4 )   2023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: 10.3390/ijms24043730

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  10. Effects of Pesticide Intake on Gut Microbiota and Metabolites in Healthy Adults. 査読有り

    Ueyama J, Hayashi M, Hirayama M, Nishiwaki H, Ito M, Saito I, Tsuboi Y, Isobe T, Ohno K

    International journal of environmental research and public health   20 巻 ( 1 )   2022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: 10.3390/ijerph20010213

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  11. Gut microbiota in dementia with Lewy bodies. 査読有り

    Nishiwaki H, Ueyama J, Kashihara K, Ito M, Hamaguchi T, Maeda T, Tsuboi Y, Katsuno M, Hirayama M, Ohno K

    NPJ Parkinson's disease   8 巻 ( 1 ) 頁: 169   2022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: 10.1038/s41531-022-00428-2

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  12. Efficacy of soluble lansoprazole-impregnated beta-tricalcium phosphate for bone regeneration. 査読有り

    Mishima K, Okabe YT, Mizuno M, Ohno K, Kitoh H, Imagama S

    Scientific reports   12 巻 ( 1 ) 頁: 20550   2022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: 10.1038/s41598-022-25184-4

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  13. Electrolyzed-Reduced Water: Review I. Molecular Hydrogen Is the Exclusive Agent Responsible for the Therapeutic Effects. 査読有り

    LeBaron TW, Sharpe R, Ohno K

    International journal of molecular sciences   23 巻 ( 23 )   2022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: 10.3390/ijms232314750

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  14. Electrolyzed-Reduced Water: Review II: Safety Concerns and Effectiveness as a Source of Hydrogen Water. 査読有り

    LeBaron TW, Sharpe R, Ohno K

    International journal of molecular sciences   23 巻 ( 23 )   2022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: 10.3390/ijms232314508

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  15. Short chain fatty acids-producing and mucin-degrading intestinal bacteria predict the progression of early Parkinson's disease. 査読有り 国際誌

    Nishiwaki H, Ito M, Hamaguchi T, Maeda T, Kashihara K, Tsuboi Y, Ueyama J, Yoshida T, Hanada H, Takeuchi I, Katsuno M, Hirayama M, Ohno K

    NPJ Parkinson's disease   8 巻 ( 1 ) 頁: 65 - 65   2022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: 10.1038/s41531-022-00328-5

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  16. Reply to the Letter to the Editor "The Microbiota in Parkinson's Disease: Ranking the Risk of Heart Disease". 査読有り

    Hirayama M, Ohno K

    Annals of nutrition & metabolism   78 巻 ( 2 ) 頁: 119 - 120   2022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:Annals of Nutrition and Metabolism  

    DOI: 10.1159/000521993

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  17. IntSplice2: Prediction of the Splicing Effects of Intronic Single-Nucleotide Variants Using LightGBM Modeling. 査読有り 国際誌

    Takeda JI, Fukami S, Tamura A, Shibata A, Ohno K

    Frontiers in genetics   12 巻   頁: 701076 - 701076   2021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:Frontiers in Genetics  

    Prediction of the effect of a single-nucleotide variant (SNV) in an intronic region on aberrant pre-mRNA splicing is challenging except for an SNV affecting the canonical GU/AG splice sites (ss). To predict pathogenicity of SNVs at intronic positions −50 (Int-50) to −3 (Int-3) close to the 3’ ss, we developed light gradient boosting machine (LightGBM)-based IntSplice2 models using pathogenic SNVs in the human gene mutation database (HGMD) and ClinVar and common SNVs in dbSNP with 0.01 ≤ minor allelic frequency (MAF) < 0.50. The LightGBM models were generated using features representing splicing cis-elements. The average recall/sensitivity and specificity of IntSplice2 by fivefold cross-validation (CV) of the training dataset were 0.764 and 0.884, respectively. The recall/sensitivity of IntSplice2 was lower than the average recall/sensitivity of 0.800 of IntSplice that we previously made with support vector machine (SVM) modeling for the same intronic positions. In contrast, the specificity of IntSplice2 was higher than the average specificity of 0.849 of IntSplice. For benchmarking (BM) of IntSplice2 with IntSplice, we made a test dataset that was not used to train IntSplice. After excluding the test dataset from the training dataset, we generated IntSplice2-BM and compared it with IntSplice using the test dataset. IntSplice2-BM was superior to IntSplice in all of the seven statistical measures of accuracy, precision, recall/sensitivity, specificity, F1 score, negative predictive value (NPV), and matthews correlation coefficient (MCC). We made the IntSplice2 web service at https://www.med.nagoya-u.ac.jp/neurogenetics/IntSplice2.

    DOI: 10.3389/fgene.2021.701076

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  18. Short-Chain Fatty Acid-Producing Gut Microbiota Is Decreased in Parkinson's Disease but Not in Rapid-Eye-Movement Sleep Behavior Disorder. 査読有り 国際誌

    Nishiwaki H, Hamaguchi T, Ito M, Ishida T, Maeda T, Kashihara K, Tsuboi Y, Ueyama J, Shimamura T, Mori H, Kurokawa K, Katsuno M, Hirayama M, Ohno K

    mSystems   5 巻 ( 6 )   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)   出版者・発行元:mSystems  

    Gut dysbiosis has been repeatedly reported in Parkinson's disease (PD) but only once in idiopathic rapid-eye-movement sleep behavior disorder (iRBD) from Germany. Abnormal aggregation of a-synuclein fibrils causing PD possibly starts from the intestine, although this is still currently under debate. iRBD patients frequently develop PD. Early-stage gut dysbiosis that is causally associated with PD is thus expected to be observed in iRBD. We analyzed gut microbiota in 26 iRBD patients and 137 controls by 16S rRNA sequencing (16S rRNA-seq). Our iRBD data set was meta-analyzed with the German iRBD data set and was compared with gut microbiota in 223 PD patients. Unsupervised clustering of gut microbiota by LIGER, a topic model-based tool for single-cell RNA sequencing (RNA-seq) analysis, revealed four enterotypes in controls, iRBD, and PD. Short-chain fatty acid (SCFA)-producing bacteria were conserved in an enterotype observed in controls and iRBD, whereas they were less conserved in enterotypes observed in PD. Genus Akkermansia and family Akkermansiaceae were consistently increased in both iRBD in two countries and PD in five countries. Short-chain fatty acid (SCFA)-producing bacteria were not significantly decreased in iRBD in two countries. In contrast, we previously reported that recognized or putative SCFA-producing genera Faecalibacterium, Roseburia, and Lachnospiraceae ND3007 group were consistently decreased in PD in five countries. In a-synucleinopathy, increase of mucin-layer-degrading genus Akkermansia is observed at the stage of iRBD, whereas decrease of SCFA-producing genera becomes obvious with development of PD. IMPORTANCE Twenty studies on gut microbiota in PD have been reported, whereas only one study has been reported on iRBD from Germany. iRBD has the highest likelihood ratio to develop PD. Our meta-analysis of iRBD in Japan and Germany revealed increased mucin-layer-degrading genus Akkermansia in iRBD. Genus Akkermansia may increase the intestinal permeability, as we previously observed in PD patients, and may make the intestinal neural plexus exposed to oxidative stress, which can lead to abnormal aggregation of prion-like a-synuclein fibrils in the intestine. In contrast to PD, SCFA-producing bacteria were not decreased in iRBD. As SCFA induces regulatory T (Treg) cells, a decrease of SCFA-producing bacteria may be a prerequisite for the development of PD. We propose that prebiotic and/or probiotic therapeutic strategies to increase the intestinal mucin layer and to increase intestinal SCFA potentially retard the development of iRBD and PD.

    DOI: 10.1128/mSystems.00797-20

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  19. Editorial: RNA Diseases in Humans-From Fundamental Research to Therapeutic Applications. 査読有り 国際誌

    Kataoka N, Mayeda A, Ohno K

    Frontiers in molecular biosciences   6 巻   頁: 53 - 53   2019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:Frontiers in Molecular Biosciences  

    DOI: 10.3389/fmolb.2019.00053

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  20. Inhalation of hydrogen gas elevates urinary 8-hydroxy-2'-deoxyguanine in Parkinson's disease. 査読有り

    Hirayama M, Ito M, Minato T, Yoritaka A, LeBaron TW, Ohno K

    Medical gas research   8 巻 ( 4 ) 頁: 144 - 149   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)   出版者・発行元:Medical Gas Research  

    Hyposmia is one of the earliest and the most common symptoms in Parkinson's disease (PD). The benefits of hydrogen water on motor deficits have been reported in animal PD models and PD patients, but the effects of hydrogen gas on PD patients have not been studied. We evaluated the effect of inhalation of hydrogen gas on olfactory function, non-motor symptoms, activities of daily living, and urinary 8-hydroxy-2′-deoxyguanine (8-OHdG) levels by a randomized, double-blinded, placebo-controlled, crossover trial with an 8-week washout period in 20 patients with PD. Patients inhaled either 1.2-1.4% hydrogen-air mixture or placebo for 10 minutes twice a day for 4 weeks. Inhalation of low dose hydrogen did not significantly influence the PD clinical parameters, but it did increase urinary 8-OHdG levels by 16%. This increase in 8-OHdG is markedly less than the over 300% increase in diabetes, and is more comparable to the increase after a bout of strenuous exercise. Although increased reactive oxygen species is often associated with toxicity and disease, they also play essential roles in mediating cytoprotective cellular adaptations in a process known as hormesis. Increases of oxidative stress by hydrogen have been previously reported, along with its ability to activate the Nrf2, NF-κB pathways, and heat shock responses. Although we did not observe any beneficial effect of hydrogen in our short trial, we propose that the increased 8-OHdG and other reported stress responses from hydrogen may indicate that its beneficial effects are partly or largely mediated by hormetic mechanisms. The study was approved by the ethics review committee of Nagoya University Graduate School of Medicine (approval number 2015-0295). The clinical trial was registered at the University Hospital Medical Information Network (identifier UMIN000019082).

    DOI: 10.4103/2045-9912.248264

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  21. Randomized, double-blind, multicenter trial of hydrogen water for Parkinson's disease. 査読有り 国際誌

    Yoritaka A, Ohtsuka C, Maeda T, Hirayama M, Abe T, Watanabe H, Saiki H, Oyama G, Fukae J, Shimo Y, Hatano T, Kawajiri S, Okuma Y, Machida Y, Miwa H, Suzuki C, Kazama A, Tomiyama M, Kihara T, Hirasawa M, Shimura H, Oda E, Ito M, Ohno K, Hattori N

    Movement disorders : official journal of the Movement Disorder Society   33 巻 ( 9 ) 頁: 1505 - 1507   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)   出版者・発行元:Movement Disorders  

    DOI: 10.1002/mds.27472

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  22. Loss of Sfpq Causes Long-Gene Transcriptopathy in the Brain. 査読有り 国際誌

    Takeuchi A, Iida K, Tsubota T, Hosokawa M, Denawa M, Brown JB, Ninomiya K, Ito M, Kimura H, Abe T, Kiyonari H, Ohno K, Hagiwara M

    Cell reports   23 巻 ( 5 ) 頁: 1326 - 1341   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:Cell Reports  

    Genes specifically expressed in neurons contain members with extended long introns. Longer genes present a problem with respect to fulfilment of gene length transcription, and evidence suggests that dysregulation of long genes is a mechanism underlying neurodegenerative and psychiatric disorders. Here, we report the discovery that RNA-binding protein Sfpq is a critical factor for maintaining transcriptional elongation of long genes. We demonstrate that Sfpq co-transcriptionally binds to long introns and is required for sustaining long-gene transcription by RNA polymerase II through mediating the interaction of cyclin-dependent kinase 9 with the elongation complex. Phenotypically, Sfpq disruption caused neuronal apoptosis in developing mouse brains. Expression analysis of Sfpq-regulated genes revealed specific downregulation of developmentally essential neuronal genes longer than 100 kb in Sfpq-disrupted brains; those genes are enriched in associations with neurodegenerative and psychiatric diseases. The identified molecular machinery yields directions for targeted investigations of the association between long-gene transcriptopathy and neuronal diseases. It has been a long-standing question how mammalian neuronal cells achieve full gene length transcription of extra-long genes. Takeuchi et al. show that RNA-binding protein Sfpq sustains long-gene transcription through Pol II-CTD activation. Loss of Sfpq caused long-gene transcriptopathy, which could be the cause of neurodegenerative and psychiatric disorders.

    DOI: 10.1016/j.celrep.2018.03.141

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  23. Rare loss of function mutations in N-methyl-D-aspartate glutamate receptors and their contributions to schizophrenia susceptibility. 査読有り 国際誌

    Yu Y, Lin Y, Takasaki Y, Wang C, Kimura H, Xing J, Ishizuka K, Toyama M, Kushima I, Mori D, Arioka Y, Uno Y, Shiino T, Nakamura Y, Okada T, Morikawa M, Ikeda M, Iwata N, Okahisa Y, Takaki M, Sakamoto S, Someya T, Egawa J, Usami M, Kodaira M, Yoshimi A, Oya-Ito T, Aleksic B, Ohno K, Ozaki N

    Translational psychiatry   8 巻 ( 1 ) 頁: 12 - 12   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:Translational Psychiatry  

    In schizophrenia (SCZ) and autism spectrum disorder (ASD), the dysregulation of glutamate transmission through N-methyl-d-aspartate receptors (NMDARs) has been implicated as a potential etiological mechanism. Previous studies have accumulated evidence supporting NMDAR-encoding genes' role in etiology of SCZ and ASD. We performed a screening study for exonic regions of GRIN1, GRIN2A, GRIN2C, GRIN2D, GRIN3A, and GRIN3B, which encode NMDAR subunits, in 562 participates (370 SCZ and 192 ASD). Forty rare variants were identified including 38 missense, 1 frameshift mutation in GRIN2C and 1 splice site mutation in GRIN2D. We conducted in silico analysis for all variants and detected seven missense variants with deleterious prediction. De novo analysis was conducted if pedigree samples were available. The splice site mutation in GRIN2D is predicted to result in intron retention by minigene assay. Furthermore, the frameshift mutation in GRIN2C and splice site mutation in GRIN2D were genotyped in an independent sample set comprising 1877 SCZ cases, 382 ASD cases, and 2040 controls. Both of them were revealed to be singleton. Our study gives evidence in support of the view that ultra-rare variants with loss of function (frameshift, nonsense or splice site) in NMDARs genes may contribute to possible risk of SCZ.

    DOI: 10.1038/s41398-017-0061-y

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  24. MYRF is associated with encephalopathy with reversible myelin vacuolization. 査読有り 国際誌

    Kurahashi H, Azuma Y, Masuda A, Okuno T, Nakahara E, Imamura T, Saitoh M, Mizuguchi M, Shimizu T, Ohno K, Okumura A

    Annals of neurology   83 巻 ( 1 ) 頁: 98 - 106   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:Annals of Neurology  

    Objective: Reversible myelin vacuolization is associated with variable conditions including mild encephalitis/encephalopathy with a reversible splenial lesion (MERS), which is characterized by mildly impaired consciousness and transient splenial lesion. Familial and/or recurrent cases with a clinical diagnosis of MERS suggest the presence of genetic factors. Methods: We examined a family in which the proband presented with a history of recurrent encephalopathy with extensive but reversible cerebral myelin vacuolization and neurological symptoms similar to those of MERS spanning 3 generations. Whole-exome sequencing was performed in family members. Results: Eight rare nonsynonymous single-nucleotide variants shared by all patients were identified. By filtering genes expressed in the corpus callosum, we identified a heterozygous c.1208A>G predicting p.Gln403Arg in the highly conserved DNA-binding domain in the myelin regulatory factor (MYRF) gene. We subsequently screened the coding regions of MYRF by Sanger sequencing in our cohort comprised of 33 sporadic cases with MERS and 3 cases in another family with extensive myelin vacuolization, and identified the same heterozygous c.1208A>G in all affected members in the second family. Luciferase assay revealed that transcriptional activity of the N-terminal region of MYRF was significantly diminished by introducing the c.1208A>G variant. Interpretation: MYRF is a transcriptional regulator that is necessary for oligodendrocyte differentiation and myelin maintenance. Functional defects of MYRF are likely to be causally associated with encephalopathy with extensive myelin vacuolization. We propose the term “MYRF-related mild encephalopathy with reversible myelin vacuolization.” Our findings provide a new perspective on the pathogenesis of myelin vacuolization. Ann Neurol 2018;83:98–106.

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  25. Activated FGFR3 promotes bone formation via accelerating endochondral ossification in mouse model of distraction osteogenesis. 査読有り 国際誌

    Osawa Y, Matsushita M, Hasegawa S, Esaki R, Fujio M, Ohkawara B, Ishiguro N, Ohno K, Kitoh H

    Bone   105 巻 ( - ) 頁: 42 - 49   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)   出版者・発行元:Bone  

    Achondroplasia (ACH) is one of the most common short-limbed skeletal dysplasias caused by gain-of-function mutations in the fibroblast growth factor receptors 3 (FGFR3) gene. Distraction osteogenesis (DO) is a treatment option for short stature in ACH in some countries. Although the patients with ACH usually show faster healing in DO, details of the newly formed bone have not been examined. We have developed a mouse model of DO and analyzed new bone regenerates of the transgenic mice with ACH (Fgfr3ach mice) histologically and morphologically. We established two kinds of DO protocols, the short-DO consisted of 5 days of latency period followed by 5 days of distraction with a rate of 0.4 mm per 24 h, and the long-DO consisted of the same latency period followed by 7 days of distraction with a rate of 0.3 mm per 12 h. The callus formation was evaluated radiologically by bone fill score and quantified by micro-CT scan in both protocols. The histomorphometric analysis was performed in the short-DO protocol by various stainings, including Villanueva Goldner, Safranin-O/Fast green, tartrate-resistant acid phosphatase, and type X collagen. Bone fill scores were significantly higher in Fgfr3ach mice than in wild-type mice in both protocols. The individual bone parameters, including bone volume and bone volume/tissue volume, were also significantly higher in Fgfr3ach mice than in wild-type mice in both protocols. The numbers of osteoblasts, as well as osteoclasts, around the trabecular bone were increased in Fgfr3ach mice. Cartilaginous tissues of the distraction region rapidly disappeared in Fgfr3ach mice compared to wild-type mice during the consolidation phase. Similarly, type X collagen-positive cells were markedly decreased in Fgfr3ach mice during the same period. Fgfr3ach mice exhibited accelerated bone regeneration after DO. Accelerated endochondral ossification could contribute to faster healing in Fgfr3ach mice.

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  26. Promethazine Hydrochloride Inhibits Ectopic Fat Cell Formation in Skeletal Muscle. 査読有り 国際誌

    Kasai T, Nakatani M, Ishiguro N, Ohno K, Yamamoto N, Morita M, Yamada H, Tsuchida K, Uezumi A

    The American journal of pathology   187 巻 ( 12 ) 頁: 2627 - 2634   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)   出版者・発行元:American Journal of Pathology  

    Fatty degeneration of skeletal muscle leads to muscle weakness and loss of function. Preventing fatty degeneration in skeletal muscle is important, but no drug has been used clinically. In this study, we performed drug repositioning using human platelet-derived growth factor receptor α (PDGFRα)-positive mesenchymal progenitors that have been proved to be an origin of ectopic adipocytes in skeletal muscle. We found that promethazine hydrochloride (PH) inhibits adipogenesis in a dose-dependent manner without cell toxicity. PH inhibited expression of adipogenic markers and also suppressed phosphorylation of cAMP response-element binding protein, which was reported to be a primary regulator of adipogenesis. We established a mouse model of tendon rupture with intramuscular fat deposition and confirmed that emerged ectopic adipocytes are derived from PDGFRα+ cells using lineage tracing mice. When these injured mice were treated with PH, formation of ectopic adipocytes was suppressed significantly. Our results show that PH inhibits PDGFRα+ mesenchymal progenitor-dependent ectopic adipogenesis in skeletal muscle and suggest that treatment with PH can be a promising approach to prevent fatty degeneration of skeletal muscle.

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  27. An ENU-induced splice site mutation of mouse Col1a1 causing recessive osteogenesis imperfecta and revealing a novel splicing rescue. 査読有り 国際誌

    Tabeta K, Du X, Arimatsu K, Yokoji M, Takahashi N, Amizuka N, Hasegawa T, Crozat K, Maekawa T, Miyauchi S, Matsuda Y, Ida T, Kaku M, Hoebe K, Ohno K, Yoshie H, Yamazaki K, Moresco EMY, Beutler B

    Scientific reports   7 巻 ( 1 ) 頁: 11717 - 11717   2017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:Scientific Reports  

    GU-AG consensus sequences are used for intron recognition in the majority of cases of pre-mRNA splicing in eukaryotes. Mutations at splice junctions often cause exon skipping, short deletions, or insertions in the mature mRNA, underlying one common molecular mechanism of genetic diseases. Using N-ethyl-N-nitrosourea, a novel recessive mutation named seal was produced, associated with fragile bones and susceptibility to fractures (spine and limbs). A single nucleotide transversion (T → A) at the second position of intron 36 of the Col1a1 gene, encoding the type I collagen, α1 chain, was responsible for the phenotype. Col1a1 seal mRNA expression occurred at greatly reduced levels compared to the wild-type transcript, resulting in reduced and aberrant collagen fibers in tibiae of seal homozygous mice. Unexpectedly, splicing of Col1a1 seal mRNA followed the normal pattern despite the presence of the donor splice site mutation, likely due to the action of a putative intronic splicing enhancer present in intron 25, which appeared to function redundantly with the splice donor site of intron 36. Seal mice represent a model of human osteogenesis imperfecta, and reveal a previously unknown mechanism for splicing "rescue.".

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  28. Six GU-rich (6GU(R)) FUS-binding motifs detected by normalization of CLIP-seq by Nascent-seq. 査読有り

    Takeda JI, Masuda A, Ohno K

    Gene   618 巻 ( - ) 頁: 57 - 64   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:Gene  

    FUS, an RNA-binding protein (RBP), is mutated or abnormally regulated in neurodegenerative disorders. FUS regulates various aspects of RNA metabolisms. FUS-binding sites are rich in GU contents and are highly degenerative. FUS-binding motifs of GGU, GGUG, GUGGU and CGCGC have been previously reported. These motifs, however, are applicable to a small fraction of FUS-binding sites. As CLIP-seq tags are enriched in genes that are highly expressed, we normalized CLIP-seq tags by Nascent-seq tags or RNA-seq tags of mouse N2a cells. Nascent-seq identifies nascent transcripts before being processed for splicing and polyadenylation. We extracted frequently observed 4-nt motifs from Nascent-seq-normalized CLIP regions, RNA-seq-normalized CLIP regions, and native CLIP regions. Specific GU-rich motifs were best detected in Nascent-seq-normalized CLIP regions. Analysis of structural motifs using Nascent-seq-normalized CLIP regions also predicted GU-rich sequence forming a stem structure. Sensitivity and specificity were calculated by examining whether the extracted motifs were present at the cross-linking-induced mutation sites (CIMS), where FUS was directly bound. We found that a combination of six motifs (UGUG, CUGG, UGGU, GCUG, GUGG, and UUGG), which were extracted from Nascent-seq-normalized CLIP-regions, had a better discriminative power than (i) motifs extracted from RNA-seq-normalized CLIP regions, (ii) motifs extracted from native CLIP regions, (iii) previously reported individual motifs, or (iv) 15 motifs in SpliceAid 2. Validation of the 6 GU-rich (6GUR) motifs using CLIP-seq of the cerebrum and the whole brain showed that the 6GUR motifs were specifically enriched in CIMS. The number of the 6GUR motifs in an uninterrupted region was counted and multiplied by four to calculate the area, which was defined as the 6GUR-Score. The 6GUR-Score of 8 or more best discriminated CIMS from CIMS-flanking regions. We propose that the 6GUR motifs predict FUS-binding sites more efficiently than previously reported individual motifs or 15 motifs in SpliceAid 2.

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  29. Wnt/β-catenin signaling suppresses expressions of Scx, Mkx, and Tnmd in tendon-derived cells. 査読有り

    Kishimoto Y, Ohkawara B, Sakai T, Ito M, Masuda A, Ishiguro N, Shukunami C, Docheva D, Ohno K

    PloS one   12 巻 ( 7 ) 頁: e0182051 - -   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:PLoS ONE  

    After tendon injuries, biomechanical properties of the injured tendon are not fully recovered in most cases. Modulation of signaling pathways, which are involved in tendon development and tendon repair, is one of attractive modalities to facilitate proper regeneration of the injured tendon. The roles of TGF-β signaling in tendon homeostasis and tendon development have been elucidated. In contrast, the roles of Wnt/β-catenin signaling in tendon remain mostly elusive. We found that the number of β-catenin-positive cells was increased at the injured site, suggesting involvement of Wnt/β-catenin signaling in tendon healing. Activation of Wnt/β-catenin signaling suppressed expressions of tenogenic genes of Scx, Mkx, and Tnmd in rat tendon-derived cells (TDCs) isolated from the Achilles tendons of 6-week old rats. Additionally, activation of Wnt/β-catenin reduced the amounts of Smad2 and Smad3, which are intracellular mediators for TGF-β signaling, and antagonized upregulation of Scx induced by TGF-β signaling in TDCs. We found that Wnt/β-catenin decreased Mkx and Tnmd expressions without suppressing Scx expression in Scx-programmed tendon progenitors. Our studies suggest that Wnt/β-catenin signaling is a repressor for tenogenic gene expressions.

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  30. Is the serum creatine kinase level elevated in congenital myasthenic syndrome? 査読有り

    Ohno Kinji

    JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY   87 巻 ( 8 ) 頁: 801 - 801   2016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:Journal of Neurology, Neurosurgery and Psychiatry  

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  31. Global identification of hnRNP A1 binding sites for SSO-based splicing modulation. 査読有り

    Bruun GH, Doktor TK, Borch-Jensen J, Masuda A, Krainer AR, Ohno K, Andresen BS

    BMC biology   14 巻 ( 1 ) 頁: 54 - -   2016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:BMC Biology  

    Background: Many pathogenic genetic variants have been shown to disrupt mRNA splicing. Besides splice mutations in the well-conserved splice sites, mutations in splicing regulatory elements (SREs) may deregulate splicing and cause disease. A promising therapeutic approach is to compensate for this deregulation by blocking other SREs with splice-switching oligonucleotides (SSOs). However, the location and sequence of most SREs are not well known. Results: Here, we used individual-nucleotide resolution crosslinking immunoprecipitation (iCLIP) to establish an in vivo binding map for the key splicing regulatory factor hnRNP A1 and to generate an hnRNP A1 consensus binding motif. We find that hnRNP A1 binding in proximal introns may be important for repressing exons. We show that inclusion of the alternative cassette exon 3 in SKA2 can be significantly increased by SSO-based treatment which blocks an iCLIP-identified hnRNP A1 binding site immediately downstream of the 5' splice site. Because pseudoexons are well suited as models for constitutive exons which have been inactivated by pathogenic mutations in SREs, we used a pseudoexon in MTRR as a model and showed that an iCLIP-identified hnRNP A1 binding site downstream of the 5' splice site can be blocked by SSOs to activate the exon. Conclusions: The hnRNP A1 binding map can be used to identify potential targets for SSO-based therapy. Moreover, together with the hnRNP A1 consensus binding motif, the binding map may be used to predict whether disease-associated mutations and SNPs affect hnRNP A1 binding and eventually mRNA splicing.

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  32. R-spondin 2 promotes acetylcholine receptor clustering at the neuromuscular junction via Lgr5. 査読有り

    Nakashima H, Ohkawara B, Ishigaki S, Fukudome T, Ito K, Tsushima M, Konishi H, Okuno T, Yoshimura T, Ito M, Masuda A, Sobue G, Kiyama H, Ishiguro N, Ohno K

    Scientific reports   6 巻 ( - ) 頁: 28512 - -   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:Scientific Reports  

    At the neuromuscular junction (NMJ), acetylcholine receptor (AChR) clustering is mediated by spinal motor neuron (SMN)-derived agrin and its receptors on the muscle, the low-density lipoprotein receptor-related protein 4 (LRP4) and muscle-specific receptor tyrosine kinase (MuSK). Additionally, AChR clustering is mediated by the components of the Wnt pathway. Laser capture microdissection of SMNs revealed that a secreted activator of Wnt signaling, R-spondin 2 (Rspo2), is highly expressed in SMNs. We found that Rspo2 is enriched at the NMJ, and that Rspo2 induces MuSK phosphorylation and AChR clustering. Rspo2 requires Wnt ligands, but not agrin, for promoting AChR clustering in cultured myotubes. Leucine-rich repeat-containing G-protein coupled receptor 5 (Lgr5), an Rspo2 receptor, is also accumulated at the NMJ, and is associated with MuSK via LRP4. Lgr5 is required for Rspo2-mediated AChR clustering in myotubes. In Rspo2-knockout mice, the number and density of AChRs at the NMJ are reduced. The Rspo2-knockout diaphragm has an altered ultrastructure with widened synaptic clefts and sparse synaptic vesicles. Frequency of miniature endplate currents is markedly reduced in Rspo2-knockout mice. To conclude, we demonstrate that Rspo2 and its receptor Lgr5 are Wnt-dependent and agrin-independent regulators of AChR clustering at the NMJ.

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  33. Phenylbutazone induces expression of MBNL1 and suppresses formation of MBNL1-CUG RNA foci in a mouse model of myotonic dystrophy. 査読有り

    Chen G, Masuda A, Konishi H, Ohkawara B, Ito M, Kinoshita M, Kiyama H, Matsuura T, Ohno K

    Scientific reports   6 巻 ( - ) 頁: 25317 - -   2016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:Scientific Reports  

    Myotonic dystrophy type 1 (DM1) is caused by abnormal expansion of CTG repeats in the 3′ untranslated region of the DMPK gene. Expanded CTG repeats are transcribed into RNA and make an aggregate with a splicing regulator, MBNL1, in the nucleus, which is called the nuclear foci. The nuclear foci sequestrates and downregulates availability of MBNL1. Symptomatic treatments are available for DM1, but no rational therapy is available. In this study, we found that a nonsteroidal anti-inflammatory drug (NSAID), phenylbutazone (PBZ), upregulated the expression of MBNL1 in C2C12 myoblasts as well as in the HSA LR mouse model for DM1. In the DM1 mice model, PBZ ameliorated aberrant splicing of Clcn1, Nfix, and Rpn2. PBZ increased expression of skeletal muscle chloride channel, decreased abnormal central nuclei of muscle fibers, and improved wheel-running activity in HSA LR mice. We found that the effect of PBZ was conferred by two distinct mechanisms. First, PBZ suppressed methylation of an enhancer region in Mbnl1 intron 1, and enhanced transcription of Mbnl1 mRNA. Second, PBZ attenuated binding of MBNL1 to abnormally expanded CUG repeats in cellulo and in vitro. Our studies suggest that PBZ is a potent therapeutic agent for DM1 that upregulates availability of MBNL1.

    DOI: 10.1038/srep25317

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  34. Serum Tyrosine-to-Phenylalanine Ratio is Low in Parkinson's Disease. 査読有り

    Hirayama M, Tsunoda M, Yamamoto M, Tsuda T, Ohno K

    Journal of Parkinson's disease   6 巻 ( 2 ) 頁: 423 - 31   2016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:Journal of Parkinson's Disease  

    Background: Noninvasive biomarkers for Parkinson's disease (PD) are currently unavailable. Objective: To search for a biomarker unique to PD in sweat and serum. Methods: Sweat samples in 42 PD patients and 16 controls were analyzed using liquid chromatography/mass spectrometry (LC/MS). The principal component analysis (PCA) and the orthogonal projections to latent structures (OPLS) analysis were employed. Serum Phe and Tyr levels were determined using the HPLC-fluorescence detection system in 28 de novo PD patients, 52 L-Dopa-treated PD patients, and 27 controls. Results: PCA and OPLS analyses of LC/MS of sweat samples revealed that Tyr, Phe, Leu (Ile), and Asp have high effect sizes to differentiate PD and controls. As Phe and Tyr are precursors of dopamine, we quantified the serum Phe and Tyr levels in de novo and treated PD patients, as well as in controls. Phe was high in de novo patients, but not in treated patients. In contrast, Tyr tended to be low in treated patients, but not in de novo patients. Tyr/Phe ratios were lower in both de novo and treated patients than in controls. The Tyr/Phe ratios were all higher than 0.82 in controls, whereas 49% of the de novo and treated patients had Tyr/Phe ratios less than 0.82. The low Tyr/Phe ratios were associated with male patients and low doses of entacapone. However, Tyr/Phe ratios were not different between male and female patients, and between patients with and without entacapone. Conclusions: The low serum Tyr/Phe ratio differentiates PD from controls with sensitivity = 0.49, specificity = 1.00, positive predictive value = 1.00, and negative predictive value = 0.40.

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  35. A missense mutation in domain III in HSPG2 in Schwartz-Jampel syndrome compromises secretion of perlecan into the extracellular space. 査読有り

    Iwata S, Ito M, Nakata T, Noguchi Y, Okuno T, Ohkawara B, Masuda A, Goto T, Adachi M, Osaka H, Nonaka R, Arikawa-Hirasawa E, Ohno K

    Neuromuscular disorders : NMD   25 巻 ( 8 ) 頁: 667 - 71   2015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:Neuromuscular Disorders  

    Schwartz-Jampel syndrome (SJS) type 1 is characterized by short stature, myotonia, and chondrodysplasia, and is caused by partial loss-of-function mutations in HSPG2 encoding perlecan. Six missense mutations have been reported in SJS to date and only one has been characterized using a recombinant protein. We report an 11-year-old Japanese boy with SJS, who shows "rigid" walking with less flexion of knees/ankles and protruded mouth. His intelligence is normal. We identified by whole genome resequencing a heterozygous missense p.Leu1088Pro in domain III-2 and a heterozygous nonsense p.Gln3061Ter in domain IV of perlecan. Expression studies revealed that p.Leu1088Pro markedly reduces the cellular expression of domain III-2 and almost nullifies its secretion into the culture medium. As five of the seven missense mutations in SJS affect domain III of perlecan, domain III is likely to be essential for secretion of perlecan into the extracellular space.

    DOI: 10.1016/j.nmd.2015.05.002

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  36. Position-specific binding of FUS to nascent RNA regulates mRNA length. 査読有り

    Masuda A, Takeda J, Okuno T, Okamoto T, Ohkawara B, Ito M, Ishigaki S, Sobue G, Ohno K

    Genes & development   29 巻 ( 10 ) 頁: 1045 - 57   2015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:Genes and Development  

    More than half of all human genes produce prematurely terminated polyadenylated short mRNAs. However, the underlying mechanisms remain largely elusive. CLIP-seq (cross-linking immunoprecipitation [CLIP] combined with deep sequencing) of FUS (fused in sarcoma) in neuronal cells showed that FUS is frequently clustered around an alternative polyadenylation (APA) site of nascent RNA. ChIP-seq (chromatin immunoprecipitation [ChIP] combined with deep sequencing) of RNA polymerase II (RNAP II) demonstrated that FUS stalls RNAP II and prematurely terminates transcription. When an APA site is located upstream of an FUS cluster, FUS enhances polyadenylation by recruiting CPSF160 and up-regulates the alternative short transcript. In contrast, when an APA site is located downstream from an FUS cluster, polyadenylation is not activated, and the RNAP II-suppressing effect of FUS leads to down-regulation of the alternative short transcript. CAGE-seq (cap analysis of gene expression [CAGE] combined with deep sequencing) and PolyA-seq (a strand-specific and quantitative method for high-throughput sequencing of 3’ ends of polyadenylated transcripts) revealed that position-specific regulation of mRNA lengths by FUS is operational in two-thirds of transcripts in neuronal cells, with enrichment in genes involved in synaptic activities.

    DOI: 10.1101/gad.255737.114

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  37. FUS regulates AMPA receptor function and FTLD/ALS-associated behaviour via GluA1 mRNA stabilization. 査読有り

    Udagawa T, Fujioka Y, Tanaka M, Honda D, Yokoi S, Riku Y, Ibi D, Nagai T, Yamada K, Watanabe H, Katsuno M, Inada T, Ohno K, Sokabe M, Okado H, Ishigaki S, Sobue G

    Nature communications   6 巻 ( - ) 頁: 7098 - -   2015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:Nature Communications  

    FUS is an RNA/DNA-binding protein involved in multiple steps of gene expression and is associated with amyotrophic lateral sclerosis (ALS) and fronto-temporal lobar degeneration (FTLD). However, the specific disease-causing and/or modifying mechanism mediated by FUS is largely unknown. Here we evaluate intrinsic roles of FUS on synaptic functions and animal behaviours. We find that FUS depletion downregulates GluA1, a subunit of AMPA receptor. FUS binds GluA1 mRNA in the vicinity of the 3′ terminus and controls poly (A) tail maintenance, thus regulating stability. GluA1 reduction upon FUS knockdown reduces miniature EPSC amplitude both in cultured neurons and in vivo. FUS knockdown in hippocampus attenuates dendritic spine maturation and causes behavioural aberrations including hyperactivity, disinhibition and social interaction defects, which are partly ameliorated by GluA1 reintroduction. These results highlight the pivotal role of FUS in regulating GluA1 mRNA stability, post-synaptic function and FTLD-like animal behaviours.

    DOI: 10.1038/ncomms8098

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  38. Simultaneous oral and inhalational intake of molecular hydrogen additively suppresses signaling pathways in rodents 査読有り

    Sobue Sayaka, Yamai Kazuaki, Ito Mikako, Ohno Kinji, Ito Masafumi, Iwamoto Takashi, Qiao Shanlou, Ohkuwa Tetsuo, Ichihara Masatoshi

    MOLECULAR AND CELLULAR BIOCHEMISTRY   403 巻 ( 1-2 ) 頁: 231 - 241   2015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:Molecular and Cellular Biochemistry  

    Molecular hydrogen (H2) is an agent with potential applications in oxidative stress-related and/or inflammatory disorders. H2 is usually administered by inhaling H2-containing air (HCA) or by oral intake of H2-rich water (HRW). Despite mounting evidence, the molecular mechanism underlying the therapeutic effects and the optimal method of H2 administration remain unclear. Here, we investigated whether H2 affects signaling pathways and gene expression in a dosage- or dose regimen-dependent manner. We first examined the H2 concentrations in blood and organs after its administration and found that oral intake of HRW rapidly but transiently increased H2 concentrations in the liver and atrial blood, while H2 concentrations in arterial blood and the kidney were one-tenth of those in the liver and atrial blood. In contrast, inhalation of HCA increased H2 equally in both atrial and arterial blood. We next examined whether H2 alters gene expression in normal mouse livers using DNA microarray analysis after administration of HCA and HRW. Ingenuity Pathway Analysis revealed that H2 suppressed the expression of nuclear factor-kappa B (NF-κB)-regulated genes. Western blot analysis showed that H2 attenuated ERK, p38 MAPK, and NF-κB signaling in mouse livers. Finally, we evaluated whether the changes in gene expression were influenced by the route of H2 administration and found that the combination of both HRW and HCA had the most potent effects on signaling pathways and gene expression in systemic organs, suggesting that H2 may act not only through a dose-dependent mechanism but also through a complex molecular network.

    DOI: 10.1007/s11010-015-2353-y

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  39. Noninvasive monitoring of plasma L-dopa concentrations using sweat samples in Parkinson's disease. 査読有り

    Tsunoda M, Hirayama M, Tsuda T, Ohno K

    Clinica chimica acta; international journal of clinical chemistry   442 巻 ( - ) 頁: 52 - 5   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:Clinica Chimica Acta  

    Background: l-dopa (l-3,4-dihydroxyphenylalanine) is commonly used for treating Parkinson's disease (PD). However, regardless of its prominent effect, therapeutic range of l-dopa narrows down with disease progression, which leads to development of motor complications including wearing off and dyskinesias. In addition, intestinal absorption of l-dopa is inversely correlated with the amount of oral protein intake, and shows intra- and inter-day variability. Hence, frequent monitoring of plasma l-dopa concentrations is beneficial, but frequent venipuncture imposes physical and psychological burdens on patients with PD. Methods: We investigated the usefulness of sweat samples instead of plasma samples for monitoring l-dopa concentrations. With a monolithic silica disk-packed spin column and the high-performance liquid chromatography-electrochemical detection system, l-dopa in sweat samples was successfully quantified and analyzed in 23 PD patients. Results: We found that the Pearson's correlation coefficient of the plasma and sweat l-dopa concentrations was 0.678. Although the disease durations and severities were not correlated with the deviation of the actual sweat l-dopa concentrations from the fitted line, acquisition of the sweat samples under a stable condition was technically difficult in severely affected patients. The deviations may also be partly accounted for by skin permeability of l-dopa. Conclusions: Measuring l-dopa concentrations in sweat is suitable to get further insights into the l-dopa metabolism.

    DOI: 10.1016/j.cca.2014.12.032

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  40. CHCHD2 mutations in autosomal dominant late-onset Parkinson's disease: a genome-wide linkage and sequencing study. 査読有り

    Funayama M, Ohe K, Amo T, Furuya N, Yamaguchi J, Saiki S, Li Y, Ogaki K, Ando M, Yoshino H, Tomiyama H, Nishioka K, Hasegawa K, Saiki H, Satake W, Mogushi K, Sasaki R, Kokubo Y, Kuzuhara S, Toda T, Mizuno Y, Uchiyama Y, Ohno K, Hattori N

    The Lancet. Neurology   14 巻 ( 3 ) 頁: 274 - 82   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:The Lancet Neurology  

    Background: Identification of causative genes in mendelian forms of Parkinson's disease is valuable for understanding the cause of the disease. We did genetic studies in a Japanese family with autosomal dominant Parkinson's disease to identify novel causative genes. Methods: We did a genome-wide linkage analysis on eight affected and five unaffected individuals from a family with autosomal dominant Parkinson's disease (family A). Subsequently, we did exome sequencing on three patients and whole-genome sequencing on one patient in family A. Variants were validated by Sanger sequencing in samples from patients with autosomal dominant Parkinson's disease, patients with sporadic Parkinson's disease, and controls. Participants were identified from the DNA bank of the Comprehensive Genetic Study on Parkinson's Disease and Related Disorders (Juntendo University School of Medicine, Tokyo, Japan) and were classified according to clinical information obtained by neurologists. Splicing abnormalities of CHCHD2 mutants were analysed in SH-SY5Y cells. We used the Fisher's exact test to calculate the significance of allele frequencies between patients with sporadic Parkinson's disease and unaffected controls, and we calculated odds ratios and 95% CIs of minor alleles. Findings: We identified a missense mutation (. CHCHD2, 182C>T, Thr61Ile) in family A by next-generation sequencing. We obtained samples from a further 340 index patients with autosomal dominant Parkinson's disease, 517 patients with sporadic Parkinson's disease, and 559 controls. Three CHCHD2 mutations in four of 341 index cases from independent families with autosomal dominant Parkinson's disease were detected by CHCHD2 mutation screening: 182C>T (Thr61Ile), 434G>A (Arg145Gln), and 300+5G>A. Two single nucleotide variants (-9T>G and 5C>T) in CHCHD2 were confirmed to have different frequencies between sporadic Parkinson's disease and controls, with odds ratios of 2·51 (95% CI 1·48-4·24; p=0·0004) and 4·69 (1·59-13·83, p=0·0025), respectively. One single nucleotide polymorphism (rs816411) was found in CHCHD2 from a previously reported genome-wide association study; however, there was no significant difference in its frequency between patients with Parkinson's disease and controls in a previously reported genome-wide association study (odds ratio 1·17, 95% CI 0·96-1·19; p=0·22). In SH-SY5Y cells, the 300+5G>A mutation but not the other two mutations caused exon 2 skipping. Interpretation: CHCHD2 mutations are associated with, and might be a cause of, autosomal dominant Parkinson's disease. Further genetic studies in other populations are needed to confirm the pathogenicity of CHCHD2 mutations in autosomal dominant Parkinson's disease and susceptibility for sporadic Parkinson's disease, and further functional studies are needed to understand how mutant CHCHD2 might play a part in the pathophysiology of Parkinson's disease.

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  41. Intestinal Dysbiosis and Lowered Serum Lipopolysaccharide-Binding Protein in Parkinson's Disease. 査読有り

    Hasegawa S, Goto S, Tsuji H, Okuno T, Asahara T, Nomoto K, Shibata A, Fujisawa Y, Minato T, Okamoto A, Ohno K, Hirayama M

    PloS one   10 巻 ( 11 ) 頁: e0142164 - -   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:PLoS ONE  

    Background The intestine is one of the first affected organs in Parkinson’s disease (PD). PD subjects show abnormal staining for Escherichia coli and α-synuclein in the colon. Methods We recruited 52 PD patients and 36 healthy cohabitants. We measured serum markers and quantified the numbers of 19 fecal bacterial groups/genera/species by quantitative RT-PCR of 16S or 23S rRNA. Although the six most predominant bacterial groups/genera/species covered on average 71.3% of total intestinal bacteria, our analysis was not comprehensive compared to metagenome analysis or 16S rRNA amplicon sequencing. Results In PD, the number of Lactobacillus was higher, while the sum of analyzed bacteria, Clostridium coccoides group, and Bacteroides fragilis group were lower than controls. Additionally, the sum of putative hydrogen-producing bacteria was lower in PD. A linear regression model to predict disease durations demonstrated that C. coccoides group and Lactobacillus gasseri subgroup had the largest negative and positive coefficients, respectively. As a linear regression model to predict stool frequencies showed that these bacteria were not associated with constipation, changes in these bacteria were unlikely to represent worsening of constipation in the course of progression of PD. In PD, the serum lipopolysaccharide (LPS)- binding protein levels were lower than controls, while the levels of serum diamine oxidase, a marker for intestinal mucosal integrity, remained unchanged in PD. Conclusions The permeability to LPS is likely to be increased without compromising the integrity of intestinal mucosa in PD. The increased intestinal permeability in PD may make the patients susceptible to intestinal dysbiosis. Conversely, intestinal dysbiosis may lead to the increased intestinal permeability. One or both of the two mechanisms may be operational in development and progression of PD.

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  42. Beneficial biological effects and the underlying mechanisms of molecular hydrogen - comprehensive review of 321 original articles. 査読有り

    Ichihara M, Sobue S, Ito M, Ito M, Hirayama M, Ohno K

    Medical gas research   5 巻 ( 1 ) 頁: 12 - -   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:Medical Gas Research  

    Therapeutic effects of molecular hydrogen for a wide range of disease models and human diseases have been investigated since 2007. A total of 321 original articles have been published from 2007 to June 2015. Most studies have been conducted in Japan, China, and the USA. About three-quarters of the articles show the effects in mice and rats. The number of clinical trials is increasing every year. In most diseases, the effect of hydrogen has been reported with hydrogen water or hydrogen gas, which was followed by confirmation of the effect with hydrogen-rich saline. Hydrogen water is mostly given ad libitum. Hydrogen gas of less than 4 % is given by inhalation. The effects have been reported in essentially all organs covering 31 disease categories that can be subdivided into 166 disease models, human diseases, treatment-associated pathologies, and pathophysiological conditions of plants with a predominance of oxidative stress-mediated diseases and inflammatory diseases. Specific extinctions of hydroxyl radical and peroxynitrite were initially presented, but the radical-scavenging effect of hydrogen cannot be held solely accountable for its drastic effects. We and others have shown that the effects can be mediated by modulating activities and expressions of various molecules such as Lyn, ERK, p38, JNK, ASK1, Akt, GTP-Rac1, iNOS, Nox1, NF-κB p65, IκBα, STAT3, NFATc1, c-Fos, and ghrelin. Master regulator(s) that drive these modifications, however, remain to be elucidated and are currently being extensively investigated.

    DOI: 10.1186/s13618-015-0035-1

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  43. LDB3 splicing abnormalities are specific to skeletal muscles of patients with myotonic dystrophy type 1 and alter its PKC binding affinity. 査読有り

    Yamashita Y, Matsuura T, Kurosaki T, Amakusa Y, Kinoshita M, Ibi T, Sahashi K, Ohno K

    Neurobiology of disease   69 巻 ( - ) 頁: 200 - 5   2014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:Neurobiology of Disease  

    Myotonic dystrophy type 1 (DM1) is caused by transcription of CUG repeat RNA, which causes sequestration of muscleblind-like 1 (MBNL1) and upregulation of CUG triplet repeat RNA-binding protein (CUG-BP1). In DM1, dysregulation of these proteins contributes to many aberrant splicing events, causing various symptoms of the disorder. Here, we demonstrate the occurrence of aberrant splicing of LIM domain binding 3 (LDB3) exon 11 in DM1 skeletal muscle. Exon array surveys, RT-PCR, and western blotting studies demonstrated that exon 11 inclusion was DM1 specific and could be reproduced by transfection of a minigene containing the CTG repeat expansion. Moreover, we found that the LDB3 exon 11-positive isoform had reduced affinity for PKC compared to the exon 11-negative isoform. Since PKC exhibits hyperactivation in DM1 and stabilizes CUG-BP1 by phosphorylation, aberrant splicing of LDB3 may contribute to CUG-BP1 upregulation through changes in its affinity for PKC. © 2014 Elsevier Inc.

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  44. Mutation analysis of a large cohort of GNE myopathy reveals a diverse array of GNE mutations affecting sialic acid biosynthesis 査読有り

    Ohno Kinji

    JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY   85 巻 ( 8 ) 頁: 832 - 832   2014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:Journal of Neurology, Neurosurgery and Psychiatry  

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  45. Collagen Q is a Key Player for Developing Rational Therapy for Congenital Myasthenia and for Dissecting the Mechanisms of Anti-MuSK Myasthenia Gravis 査読有り

    Ohno Kinji, Ito Mikako, Kawakami Yu, Ohtsuka Kenji

    JOURNAL OF MOLECULAR NEUROSCIENCE   53 巻 ( 3 ) 頁: 359 - 361   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:Journal of Molecular Neuroscience  

    Acetylcholinesterase (AChE) at the neuromuscular junction (NMJ) is anchored to the synaptic basal lamina via a triple helical collagen Q (ColQ) in the form of asymmetric AChE (AChE/ColQ). We exploited the proprietary NMJ-targeting signals of ColQ to treat congenital myasthenia and to explore the mechanisms of autoimmune myasthenia gravis (MG). Mutations in COLQ cause congenital endplate AChE deficiency (CEAD). First, a single intravenous administration of adeno-associated virus serotype 8 (AAV8)-COLQ to Colq-/- mice normalized motor functions, synaptic transmission, and partly the NMJ ultrastructure. Additionally, injection of purified recombinant AChE/ColQ protein complex into gluteus maximus accumulated AChE in non-injected forelimbs. Second, MuSK antibody-positive MG accounts for 5-15 % of MG. In vitro overlay of AChE/ColQ to muscle sections of Colq-/- mice, as well as in vitro plate-binding of MuSK to ColQ, revealed that MuSK-IgG blocks binding of ColQ to MuSK in a dose-dependent manner. Passive transfer of MuSK-IgG to wild-type mice markedly reduced the size and intensity of ColQ signals at NMJs. MuSK-IgG thus interferes with binding of ColQ to MuSK. Elucidation of molecular mechanisms of specific binding of ColQ to NMJ enabled us to ameliorate devastating myasthenic symptoms of Colq-/- mice and also to reveal underlying mechanisms of anti-MuSK-MG. © 2013 Springer Science+Business Media.

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  46. A Kir3.4 mutation causes Andersen-Tawil syndrome by an inhibitory effect on Kir2.1. 査読有り

    Kokunai Y, Nakata T, Furuta M, Sakata S, Kimura H, Aiba T, Yoshinaga M, Osaki Y, Nakamori M, Itoh H, Sato T, Kubota T, Kadota K, Shindo K, Mochizuki H, Shimizu W, Horie M, Okamura Y, Ohno K, Takahashi MP

    Neurology   82 巻 ( 12 ) 頁: 1058 - 64   2014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:Neurology  

    Objective: To identify other causative genes for Andersen-Tawil syndrome, which is characterized by a triad of periodic paralysis, cardiac arrhythmia, and dysmorphic features. Andersen-Tawil syndrome is caused in amajority of cases bymutations in KCNJ2,which encodes the Kir2.1 subunit of the inwardly rectifying potassium channel. Methods: The proband exhibited episodic flaccid weakness and a characteristic TU-wave pattern, both suggestive of Andersen-Tawil syndrome, but did not harbor KCNJ2 mutations. We performed exome capture resequencing by restricting the analysis to genes that encode ion channels/associated proteins. The expression of gene products in heart and skeletalmuscle tissues was examined by immunoblotting. The functional consequences of the mutation were investigated using a heterologous expression system in Xenopus oocytes, focusing on the interaction with the Kir2.1 subunit. Results: We identified a mutation in the KCNJ5 gene, which encodes the G-protein-activated inwardly rectifying potassium channel 4 (Kir3.4). Immunoblotting demonstrated significant expression of the Kir3.4 protein in human heart and skeletal muscles. The coexpression of Kir2.1 and mutant Kir3.4 in Xenopus oocytes reduced the inwardly rectifying current significantly compared with that observed in the presence of wild-type Kir3.4. Conclusions: We propose that KCNJ5 is a second gene causing Andersen-Tawil syndrome. The inhibitory effects of mutant Kir3.4 on inwardly rectifying potassium channels may account for the clinical presentation in both skeletal and heart muscles. © 2014 American Academy of Neurology.

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  47. Clinical and genetic analysis of the first known Asian family with myotonic dystrophy type 2. 査読有り

    Nakayama T, Nakamura H, Oya Y, Kimura T, Imahuku I, Ohno K, Nishino I, Abe K, Matsuura T

    Journal of human genetics   59 巻 ( 3 ) 頁: 129 - 33   2014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:Journal of Human Genetics  

    Myotonic dystrophy type 2 (DM2) is more common than DM1 in Europe and is considered a rare cause of myotonic dystrophies in Asia. Its clinical course is also milder with more phenotypic variability than DM1. We herein describe the first known Asian family (three affected siblings) with DM2 based on clinical and genetic analyses. Notably, two of the affected siblings were previously diagnosed with limb-girdle muscular dystrophy. Myotonia (the inability of the muscle to relax) was absent or only faintly present in these individuals. The third sibling had grip myotonia and is the first known Asian DM2 patient. The three DM2 siblings share several systemic characteristics, including late-onset, proximal-dominant muscle weakness, diabetes, cataracts and asthma. Repeat-primed PCR across the DM2 repeat revealed a characteristic ladder pattern of a CCTG expansion in all siblings. Southern blotting analysis identified the presence of 3400 repeats. Further DM2 studies in Asian populations are needed to define the clinical presentation of Asian DM2 and as yet unidentified phenotypic differences from Caucasian patients. © 2014 The Japan Society of Human Genetics All rights reserved 1434-5161/14.

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  48. [Beneficial effects of 3,4-diaminopyridine in a 26-year-old woman with DOK7 congenital myasthenic syndrome who was originally diagnosed with facioscapulohumeral dystrophy].

    Nishikawa A, Mori-Yoshimura M, Okamoto T, Oya Y, Nakata T, Ohno K, Murata M

    Rinsho shinkeigaku = Clinical neurology   54 巻 ( 7 ) 頁: 561 - 4   2014年

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Clinical Neurology  

    We report a 26-year-old woman who had respiratory dysfunction and muscle weakness at birth and was diagnosed with facioscapulohumeral dystrophy at the age of 5. The extent of muscle weakness fluctuated daily or weekly and deteriorated in menstrual periods. At the age of 12, she noted improvements in symptoms when taking procaterol hydrochloride and began to take it regularly. After that, her condition stabilized. At the age of 26, she visited our hospital presenting with ptosis, muscle weakness in the face, trunk, and proximal limbs, and easy fatigability. Serum CK was normal; anti-acetylcholine receptor and anti-muscle specific tyrosine kinase antibodies were negative. A repetitive stimulation test in the trapezius muscle showed a waning phenomenon. Gene analysis for congenital myasthenic syndrome (CMS) revealed a new mutation in the DOK7 gene; the diagnosis of CMS was confirmed. Her symptoms worsened with ambenonium chloride but improved with 3,4-diaminopyridine. Our findings suggest that daily or weekly fluctuation and worsening with a menses in muscle weakness is an important diagnostic feature of CMS.

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  49. Glycosylation defects as an emerging novel cause leading to a limb-girdle type of congenital myasthenic syndromes 査読有り

    Ohno Kinji

    JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY   84 巻 ( 10 ) 頁: 1064 - 1064   2013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:Journal of Neurology, Neurosurgery and Psychiatry  

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  50. Mutations in the C-terminal domain of ColQ in endplate acetylcholinesterase deficiency compromise ColQ-MuSK interaction. 査読有り

    Nakata T, Ito M, Azuma Y, Otsuka K, Noguchi Y, Komaki H, Okumura A, Shiraishi K, Masuda A, Natsume J, Kojima S, Ohno K

    Human mutation   34 巻 ( 7 ) 頁: 997 - 1004   2013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:Human Mutation  

    Acetylcholinesterase (AChE) at the neuromuscular junction (NMJ) is mostly composed of an asymmetric form in which three tetramers of catalytic AChE subunits are linked to a triple helical collagen Q (ColQ). Mutations in COLQ cause endplate AChE deficiency. We report three patients with endplate AChE deficiency with five recessive COLQ mutations. Sedimentation profiles showed that p.Val322Asp and p.Arg227X, but not p.Cys444Tyr, p.Asp447His, or p.Arg452Cys, inhibit formation of triple helical ColQ. In vitro overlay of mutant ColQ-tailed AChE on muscle sections of Colq-/- mice revealed that p.Cys444Tyr, p.Asp447His, and p.Arg452Cys in the C-terminal domain (CTD) abrogate anchoring ColQ-tailed AChE to the NMJ. In vitro plate-binding assay similarly demonstrated that the three mutants inhibit binding of ColQ-tailed AChE to MuSK. We also confirmed the pathogenicity of p.Asp447His by treating Colq-/- mice with adeno-associated virus serotype 8 carrying mutant COLQ-p.Asp447His. The treated mice showed no improvement in motor functions and no anchoring of ColQ-tailed AChE at the NMJ. Electroporation of mutant COLQ harboring p.Cys444Tyr, p.Asp447His, and p.Arg452Cys into anterior tibial muscles of Colq-/- mice similarly failed to anchor ColQ-tailed AChE at the NMJ. We proved that the missense mutations in ColQ-CTD cause endplate AChE deficiency by compromising ColQ-MuSK interaction at the NMJ. Missense mutations in COLQ encoding collagen Q (ColQ) compromise binding of ColQ to MuSK and lead to endplate acetylcholinesterase (AChE) deficiency. Defective binding has been proven by an in vitro overlay assay of mutant ColQ on skeletal muscle of Colq-/- mice and by an in vitro plate-binding assay on purified MuSK. We also confirmed that AAV8-mediated gene transfer of mutant ColQ into Colq-/- mice failed to express ColQ at the neuromuscular junction and to improve the motor deficits. © 2013 WILEY PERIODICALS, INC.

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  51. Exome sequencing of senescence-accelerated mice (SAM) reveals deleterious mutations in degenerative disease-causing genes 査読有り

    Tanisawa Kumpei, Mikami Eri, Fuku Noriyuki, Honda Yoko, Honda Shuji, Ohsawa Ikuro, Ito Masafumi, Endo Shogo, Ihara Kunio, Ohno Kinji, Kishimoto Yuki, Ishigami Akihito, Maruyama Naoki, Sawabe Motoji, Iseki Hiroyoshi, Okazaki Yasushi, Hasegawa-Ishii Sanae, Takei Shiro, Shimada Atsuyoshi, Hosokawa Masanori, Mori Masayuki, Higuchi Keiichi, Takeda Toshio, Higuchi Mitsuru, Tanaka Masashi

    BMC GENOMICS   14 巻 ( 1 ) 頁: 248 - -   2013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:BMC Genomics  

    Background: Senescence-accelerated mice (SAM) are a series of mouse strains originally derived from unexpected crosses between AKR/J and unknown mice, from which phenotypically distinct senescence-prone (SAMP) and -resistant (SAMR) inbred strains were subsequently established. Although SAMP strains have been widely used for aging research focusing on their short life spans and various age-related phenotypes, such as immune dysfunction, osteoporosis, and brain atrophy, the responsible gene mutations have not yet been fully elucidated.Results: To identify mutations specific to SAMP strains, we performed whole exome sequencing of 6 SAMP and 3 SAMR strains. This analysis revealed 32,019 to 38,925 single-nucleotide variants in the coding region of each SAM strain. We detected Ogg1 p.R304W and Mbd4 p.D129N deleterious mutations in all 6 of the SAMP strains but not in the SAMR or AKR/J strains. Moreover, we extracted 31 SAMP-specific novel deleterious mutations. In all SAMP strains except SAMP8, we detected a p.R473W missense mutation in the Ldb3 gene, which has been associated with myofibrillar myopathy. In 3 SAMP strains (SAMP3, SAMP10, and SAMP11), we identified a p.R167C missense mutation in the Prx gene, in which mutations causing hereditary motor and sensory neuropathy (Dejerine-Sottas syndrome) have been identified. In SAMP6 we detected a p.S540fs frame-shift mutation in the Il4ra gene, a mutation potentially causative of ulcerative colitis and osteoporosis.Conclusions: Our data indicate that different combinations of mutations in disease-causing genes may be responsible for the various phenotypes of SAMP strains. © 2013 Tanisawa et al.; licensee BioMed Central Ltd.

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  52. Clinically applicable antianginal agents suppress osteoblastic transformation of myogenic cells and heterotopic ossifications in mice. 査読有り

    Yamamoto R, Matsushita M, Kitoh H, Masuda A, Ito M, Katagiri T, Kawai T, Ishiguro N, Ohno K

    Journal of bone and mineral metabolism   31 巻 ( 1 ) 頁: 26 - 33   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:Journal of Bone and Mineral Metabolism  

    Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disorder characterized by progressive heterotopic ossification. FOP is caused by a gain-of-function mutation in ACVR1 encoding the bone morphogenetic protein type II receptor, ACVR1/ALK2. The mutant receptor causes upregulation of a transcriptional factor, Id1. No therapy is available to prevent the progressive heterotopic ossification in FOP. In an effort to search for clinically applicable drugs for FOP, we screened 1,040 FDA-approved drugs for suppression of the Id1 promoter activated by the mutant ACVR1/ALK2 in C2C12 cells. We found that that two antianginal agents, fendiline hydrochloride and perhexiline maleate, suppressed the Id1 promoter in a dose-dependent manner. The drugs also suppressed the expression of native Id1 mRNA and alkaline phosphatase in a dose-dependent manner. Perhexiline but not fendiline downregulated phosphorylation of Smad 1/5/8 driven by bone morphogenetic protein (BMP)-2. We implanted crude BMPs in muscles of ddY mice and fed them fendiline or perhexiline for 30 days. Mice taking perhexiline showed a 38.0 % reduction in the volume of heterotopic ossification compared to controls, whereas mice taking fendiline showed a slight reduction of heterotopic ossification. Fendiline, perhexiline, and their possible derivatives are potentially applicable to clinical practice to prevent devastating heterotopic ossification in FOP. © 2012 The Japanese Society for Bone and Mineral Research and Springer.

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  53. Protein-anchoring strategy for delivering acetylcholinesterase to the neuromuscular junction. 査読有り

    Ito M, Suzuki Y, Okada T, Fukudome T, Yoshimura T, Masuda A, Takeda S, Krejci E, Ohno K

    Molecular therapy : the journal of the American Society of Gene Therapy   20 巻 ( 7 ) 頁: 1384 - 92   2012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:Molecular Therapy  

    Acetylcholinesterase (AChE) at the neuromuscular junction (NMJ) is anchored to the synaptic basal lamina via a triple helical collagen Q (ColQ). Congenital defects of ColQ cause endplate AChE deficiency and myasthenic syndrome. A single intravenous administration of adeno-associated virus serotype 8 (AAV8)-COLQ to Colq-/- mice recovered motor functions, synaptic transmission, as well as the morphology of the NMJ. ColQ-tailed AChE was specifically anchored to NMJ and its amount was restored to 89% of the wild type. We next characterized the molecular basis of this efficient recovery. We first confirmed that ColQ-tailed AChE can be specifically targeted to NMJ by an in vitro overlay assay in Colq-/- mice muscle sections. We then injected AAV1-COLQ-IRES-EGFP into the left tibialis anterior and detected AChE in noninjected limbs. Furthermore, the in vivo injection of recombinant ColQ-tailed AChE protein complex into the gluteus maximus muscle of Colq -/- mice led to accumulation of AChE in noninjected forelimbs. We demonstrated for the first time in vivo that the ColQ protein contains a tissue-targeting signal that is sufficient for anchoring itself to the NMJ. We propose that the protein-anchoring strategy is potentially applicable to a broad spectrum of diseases affecting extracellular matrix molecules. © The American Society of Gene & Cell Therapy.

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  54. Four parameters increase the sensitivity and specificity of the exon array analysis and disclose 25 novel aberrantly spliced exons in myotonic dystrophy. 査読有り

    Yamashita Y, Matsuura T, Shinmi J, Amakusa Y, Masuda A, Ito M, Kinoshita M, Furuya H, Abe K, Ibi T, Sahashi K, Ohno K

    Journal of human genetics   57 巻 ( 6 ) 頁: 368 - 74   2012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:Journal of Human Genetics  

    Myotonic dystrophy type 1 (DM1) is an RNA gain-of-function disorder in which abnormally expanded CTG repeats of DMPK sequestrate a splicing trans-factor MBNL1 and upregulate another splicing trans-factor CUGBP1. To identify a diverse array of aberrantly spliced genes, we performed the exon array analysis of DM1 muscles. We analyzed 72 exons by RT-PCR and found that 27 were aberrantly spliced, whereas 45 were not. Among these, 25 were novel and especially splicing aberrations of LDB3 exon 4 and TTN exon 45 were unique to DM1. Retrospective analysis revealed that four parameters efficiently detect aberrantly spliced exons: (i) the signal intensity is high; (ii) the ratio of probe sets with reliable signal intensities (that is, detection above background P-value0.000) is high within a gene; (iii) the splice index (SI) is high; and (iv) SI is deviated from SIs of the other exons that can be estimated by calculating the deviation value (DV). Application of the four parameters gave rise to a sensitivity of 77.8% and a specificity of 95.6% in our data set. We propose that calculation of DV, which is unique to our analysis, is of particular importance in analyzing the exon array data. © 2012 The Japan Society of Human Genetics All rights reserved.

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  55. A novel mutation in SCN4A causes severe myotonia and school-age-onset paralytic episodes 査読有り

    Yoshinaga Harumi, Sakoda Shunichi, Good Jean-Marc, Takahashi Masanori P., Kubota Tomoya, Arikawa-Hirasawa Eri, Nakata Tomohiko, Ohno Kinji, Kitamura Tetsuro, Kobayashi Katsuhiro, Ohtsuka Yoko

    JOURNAL OF THE NEUROLOGICAL SCIENCES   315 巻 ( 1-2 ) 頁: 15 - 19   2012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:Journal of the Neurological Sciences  

    Mutations in the pore-forming subunit of the skeletal muscle sodium channel (SCN4A) are responsible for hyperkalemic periodic paralysis, paramyotonia congenita and sodium channel myotonia. These disorders are classified based on their cardinal symptoms, myotonia and/or paralysis. We report the case of a Japanese boy with a novel mutation of SCN4A, p.I693L, who exhibited severe episodic myotonia from infancy and later onset mild paralytic attack. He started to have apneic episodes with generalized hypertonia at age of 11 months, then developed severe episodic myotonia since 2 years of age. He presented characteristic generalized features which resembled Schwarz-Jampel syndrome. After 7 years old, paralytic episodes occurred several times a year. The compound muscle action potential did not change during short and long exercise tests. Functional analysis of the mutant channel expressed in cultured cell revealed enhancement of the activation and disruption of the slow inactivation, which were consistent with myotonia and paralytic attack. The severe clinical features in his infancy may correspond to myotonia permanence, however, he subsequently experienced paralytic attacks. This case provides an example of the complexity and overlap of the clinical features of sodium channel myotonic disorders. © 2011 Elsevier B.V. All rights reserved.

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  56. Myotonic dystrophy type 2 is rare in the Japanese population 査読有り

    Matsuura Tohru, Minami Narihiro, Arahata Hajime, Ohno Kinji, Abe Koji, Hayashi Yukiko K., Nishino Ichizo

    JOURNAL OF HUMAN GENETICS   57 巻 ( 3 ) 頁: 219 - 220   2012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:Journal of Human Genetics  

    DOI: 10.1038/jhg.2011.152

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  57. Position-dependent FUS-RNA interactions regulate alternative splicing events and transcriptions. 査読有り

    Ishigaki S, Masuda A, Fujioka Y, Iguchi Y, Katsuno M, Shibata A, Urano F, Sobue G, Ohno K

    Scientific reports   2 巻 ( - ) 頁: 529 - -   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:Scientific Reports  

    FUS is an RNA-binding protein that regulates transcription, alternative splicing, and mRNA transport. Aberrations of FUS are causally associated with familial and sporadic ALS/FTLD. We analyzed FUS-mediated transcriptions and alternative splicing events in mouse primary cortical neurons using exon arrays. We also characterized FUS-binding RNA sites in the mouse cerebrum with HITS-CLIP. We found that FUS-binding sites tend to form stable secondary structures. Analysis of position-dependence of FUS-binding sites disclosed scattered binding of FUS to and around the alternatively spliced exons including those associated with neurodegeneration such as Mapt, Camk2a, and Fmr1. We also found that FUS is often bound to the antisense RNA strand at the promoter regions. Global analysis of these FUS-tags and the expression profiles disclosed that binding of FUS to the promoter antisense strand downregulates transcriptions of the coding strand. Our analysis revealed that FUS regulates alternative splicing events and transcriptions in a position-dependent manner.

    DOI: 10.1038/srep00529

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  58. Molecular hydrogen as an emerging therapeutic medical gas for neurodegenerative and other diseases. 査読有り

    Ohno K, Ito M, Ichihara M, Ito M

    Oxidative medicine and cellular longevity   2012 巻 ( - ) 頁: 353152 - -   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:Oxidative Medicine and Cellular Longevity  

    Effects of molecular hydrogen on various diseases have been documented for 63 disease models and human diseases in the past four and a half years. Most studies have been performed on rodents including two models of Parkinson's disease and three models of Alzheimer's disease. Prominent effects are observed especially in oxidative stress-mediated diseases including neonatal cerebral hypoxia; Parkinson's disease; ischemia/reperfusion of spinal cord, heart, lung, liver, kidney, and intestine; transplantation of lung, heart, kidney, and intestine. Six human diseases have been studied to date: diabetes mellitus type 2, metabolic syndrome, hemodialysis, inflammatory and mitochondrial myopathies, brain stem infarction, and radiation-induced adverse effects. Two enigmas, however, remain to be solved. First, no dose-response effect is observed. Rodents and humans are able to take a small amount of hydrogen by drinking hydrogen-rich water, but marked effects are observed. Second, intestinal bacteria in humans and rodents produce a large amount of hydrogen, but an addition of a small amount of hydrogen exhibits marked effects. Further studies are required to elucidate molecular bases of prominent hydrogen effects and to determine the optimal frequency, amount, and method of hydrogen administration for each human disease. Copyright © 2012 Kinji Ohno et al.

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  59. The unstable CCTG repeat responsible for myotonic dystrophy type 2 originates from an AluSx element insertion into an early primate genome. 査読有り

    Kurosaki T, Ueda S, Ishida T, Abe K, Ohno K, Matsuura T

    PloS one   7 巻 ( 6 ) 頁: e38379 - -   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:PLoS ONE  

    Myotonic dystrophy type 2 (DM2) is a subtype of the myotonic dystrophies, caused by expansion of a tetranucleotide CCTG repeat in intron 1 of the zinc finger protein 9 (ZNF9) gene. The expansions are extremely unstable and variable, ranging from 75-11,000 CCTG repeats. This unprecedented repeat size and somatic heterogeneity make molecular diagnosis of DM2 difficult, and yield variable clinical phenotypes. To better understand the mutational origin and instability of the ZNF9 CCTG repeat, we analyzed the repeat configuration and flanking regions in 26 primate species. The 3′-end of an AluSx element, flanked by target site duplications (5′-ACTRCCAR-3′or 5′-ACTRCCARTTA-3′), followed the CCTG repeat, suggesting that the repeat was originally derived from the Alu element insertion. In addition, our results revealed lineage-specific repetitive motifs: pyrimidine (CT)-rich repeat motifs in New World monkeys, dinucleotide (TG) repeat motifs in Old World monkeys and gibbons, and dinucleotide (TG) and tetranucleotide (TCTG and/or CCTG) repeat motifs in great apes and humans. Moreover, these di- and tetra-nucleotide repeat motifs arose from the poly (A) tail of the AluSx element, and evolved into unstable CCTG repeats during primate evolution. Alu elements are known to be the source of microsatellite repeats responsible for two other repeat expansion disorders: Friedreich ataxia and spinocerebellar ataxia type 10. Taken together, these findings raise questions as to the mechanism(s) by which Alu-mediated repeats developed into the large, extremely unstable expansions common to these three disorders. © 2012 Kurosaki et al.

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  60. Anti-MuSK autoantibodies block binding of collagen Q to MuSK. 査読有り

    Kawakami Y, Ito M, Hirayama M, Sahashi K, Ohkawara B, Masuda A, Nishida H, Mabuchi N, Engel AG, Ohno K

    Neurology   77 巻 ( 20 ) 頁: 1819 - 26   2011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:Neurology  

    Objective: Muscle-specific receptor tyrosine kinase (MuSK) antibody-positive myasthenia gravis (MG) accounts for 5%-15% of autoimmune MG. MuSK mediates the agrin-signaling pathway and also anchors the collagenic tail subunit (ColQ) of acetylcholinesterase (AChE). The exact molecular target of MuSK-immunoglobulin G (IgG), however, remains elusive. As acetylcholine receptor (AChR) deficiency is typically mild and as cholinesterase inhibitors are generally ineffective, we asked if MuSK-IgG interferes with binding of ColQ to MuSK. Methods: We used 3 assays: in vitro overlay of the human ColQ-tailed AChE to muscle sections of Colq-/- mice; in vitro plate-binding assay to quantitate binding of MuSK to ColQ and to LRP4; and passive transfer of MuSK-IgG to mice. Results: The in vitro overlay assay revealed that MuSK-IgG blocks binding of ColQ to the neuromuscular junction. The in vitro plate-binding assay showed that MuSK-IgG exerts a dosedependent block of MuSK binding to ColQ by but not to LRP4. Passive transfer of MuSK-IgG to mice reduced the size and density of ColQ tõ10% of controls and had a lesser effect on the size and density of AChR and MuSK. Conclusions: As lack of ColQ compromises agrin-mediated AChR clustering in Colq-/- mice, a similar mechanism may lead to AChR deficiency in MuSK-MG patients. Our experiments also predict partial AChE deficiency in MuSK-MG patients, but AChE is not reduced in biopsied NMJs. In humans, binding of ColQ to MuSK may be dispensable for clustering ColQ, but is required for facilitating AChR clustering. Further studies will be required to elucidate the basis of this paradox. Copyright © 2011 by AAN Enterprises, Inc.

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    その他リンク: http://orcid.org/0000-0003-0092-7837

  61. Hyperuricemia cosegregating with osteogenesis imperfecta is associated with a mutation in GPATCH8. 査読有り

    Kaneko H, Kitoh H, Matsuura T, Masuda A, Ito M, Mottes M, Rauch F, Ishiguro N, Ohno K

    Human genetics   130 巻 ( 5 ) 頁: 671 - 83   2011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:Human Genetics  

    Autosomal dominant osteogenesis imperfecta (OI) is caused by mutations in COL1A1 or COL1A2. We identified a dominant missense mutation, c.3235G>A in COL1A1 exon 45 predicting p.G1079S, in a Japanese family with mild OI. As mutations in exon 45 exhibit mild to lethal phenotypes, we tested if disruption of an exonic splicing cis-element determines the clinical phenotype, but detected no such mutations. In the Japanese family, juvenile-onset hyperuricemia cosegregated with OI, but not in the previously reported Italian and Canadian families with c.3235G>A. After confirming lack of a founder haplotype in three families, we analyzed PRPSAP1 and PRPSAP2 as candidate genes for hyperuricemia on chr 17 where COL1A1 is located, but found no mutation. We next resequenced the whole exomes of two siblings in the Japanese family and identified variable numbers of previously reported hyperuricemia-associated SNPs in ABCG2 and SLC22A12. The same SNPs, however, were also detected in normouricemic individuals in three families. We then identified two missense SNVs in ZPBP2 and GPATCH8 on chromosome 17 that cosegregated with hyperuricemia in the Japanese family. ZPBP2 p.T69I was at the non-conserved region and was predicted to be benign by in silico analysis, whereas GPATCH8 p.A979P was at a highly conserved region and was predicted to be deleterious, which made p.A979P a conceivable candidate for juvenile-onset hyperuricemia. GPATCH8 is only 5.8 Mbp distant from COL1A1 and encodes a protein harboring an RNA-processing domain and a zinc finger domain, but the molecular functions have not been elucidated to date. © Springer-Verlag 2011.

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  62. Molecular hydrogen inhibits lipopolysaccharide/interferon gamma-induced nitric oxide production through modulation of signal transduction in macrophages 査読有り

    Itoh Tomohiro, Hamada Nanako, Terazawa Riyako, Ito Mikako, Ohno Kinji, Ichihara Masatoshi, Nozawa Yoshinori, Ito Masafumi

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   411 巻 ( 1 ) 頁: 143 - 149   2011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:Biochemical and Biophysical Research Communications  

    Molecular hydrogen has been reported to be effective for a variety of disorders and its effects have been ascribed to the reduction of oxidative stress. However, we have recently demonstrated that hydrogen inhibits type I allergy through modulating intracellular signal transduction. In the present study, we examined the hydrogen effects on lipopolysaccharide/interferon γ LPS/IFNγ-induced nitric oxide (NO) production in murine macrophage RAW264 cells. Treatment with hydrogen reduced LPS/IFNγ-induced NO release, which was associated with a diminished induction of inducible isoform of nitric oxide synthase (iNOS). Hydrogen treatment inhibited LPS/IFNγ-induced phosphorylation of apoptosis signal-regulating kinase 1 (ASK1) and its downstream signaling molecules, p38 MAP kinase and JNK, as well as IκBα, but did not affect activation of NADPH oxidase and production of reactive oxygen species (ROS). As ROS is an upstream activator of ASK1, inhibition of ASK1 by hydrogen without suppressing ROS implies that a potential target molecule of hydrogen should be located at the receptor or immediately downstream of it. These results suggested a role for molecular hydrogen as a signal modulator. Finally, oral intake of hydrogen-rich water alleviated anti-type II collagen antibody-induced arthritis in mice, a model for human rheumatoid arthritis. Taken together, our studies indicate that hydrogen inhibits LPS/IFNγ-induced NO production through modulation of signal transduction in macrophages and ameliorates inflammatory arthritis in mice, providing the molecular basis for hydrogen effects on inflammation and a functional interaction between two gaseous signaling molecules, NO and molecular hydrogen. © 2011 Elsevier Inc.

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  63. Molecular hydrogen suppresses Fc epsilon RI-mediated signal transduction and prevents degranulation of mast cells 査読有り

    Itoh Tomohiro, Fujita Yasunori, Ito Mikako, Masuda Akio, Ohno Kinji, Ichihara Masatoshi, Kojima Toshio, Nozawa Yoshinori, Ito Masafumi

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   389 巻 ( 4 ) 頁: 651 - 656   2009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:Biochemical and Biophysical Research Communications  

    Molecular hydrogen ameliorates oxidative stress-associated diseases in animal models. We found that oral intake of hydrogen-rich water abolishes an immediate-type allergic reaction in mice. Using rat RBL-2H3 mast cells, we demonstrated that hydrogen attenuates phosphorylation of the FcεRI-associated Lyn and its downstream signal transduction, which subsequently inhibits the NADPH oxidase activity and reduces the generation of hydrogen peroxide. We also found that inhibition of NADPH oxidase attenuates phosphorylation of Lyn in mast cells, indicating the presence of a feed-forward loop that potentiates the allergic responses. Hydrogen accordingly inhibits all tested signaling molecule(s) in the loop. Hydrogen effects have been solely ascribed to exclusive removal of hydroxyl radical. In the immediate-type allergic reaction, hydrogen exerts its beneficial effect not by its radical scavenging activity but by modulating a specific signaling pathway. Effects of hydrogen in other diseases are possibly mediated by modulation of yet unidentified signaling pathways. Our studies also suggest that hydrogen is a gaseous signaling molecule like nitric oxide. © 2009 Elsevier Inc. All rights reserved.

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  64. Alu-Mediated Acquisition of Unstable ATTCT Pentanucleotide Repeats in the Human ATXN10 Gene 査読有り

    Kurosaki Tatsuaki, Matsuura Tohru, Ohno Kinji, Ueda Shintaroh

    MOLECULAR BIOLOGY AND EVOLUTION   26 巻 ( 11 ) 頁: 2573 - 2579   2009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:Molecular Biology and Evolution  

    Spinocerebellar ataxia type 10 is caused by ATTCT repeat expansion in the ATXN10 gene in humans. We studied the evolutionary history of the human genome to determine the time and mechanism of the acquisition of unstable ATTCT repeats in the genome. We found that long interspersed element-1 (LINE-1) was inserted into ATXN10 intron 9; Alu was then inserted in the middle of LINE-1; and endogenous retrovilcus K was lastly retrotransposed in the middle of Alu. The ATTCT repeat was located on the boundary between the 3′-end of the Alu element and the direct repeat arising from LINE-1. We determined nucleotide sequences of the orthologous region of 50 individuals representing 33 primate species and compared them with the human sequence. The analysis revealed that the ATTCT repeat is present only in human and apes. Old World monkeys also possess pentanucleotide repeats, but their motifs are TGTCT and GGTCT. New World monkeys and prosimians are not informative because they lack the corresponding region in ATXN10 intron 9. Our studies dictate two parsimonious scenarios of evolution. First, a TTTCT motif arose from a TTTTT motif at the junction of Alu and LINE-1, which was followed by introduction of A to make an ATTCT motif in hominoids. Second, an ATTCT motif was directly generated from an ancestral ATTTT motif in the common ancestor of catarrhines. We also demonstrate that orangutan uniquely introduced G to make a GTTCT motif and later C to make a GTTCC motif, where newly introduced nucleotides are underlined. Our studies reveal that nucleotide substitutions in a poly(A) tail of the Alu element and the following amplification of pentanucleotides occurred in the lineages of Old World monkeys and hominoids and that unstable ATTCT pentanucleotide repeats originated in the common ancestor of hominoids. These findings also highlight a new aspect of the role of retrotransposons in human disease and evolution, which might be useful in investigating the mystery of human uniqueness.

    DOI: 10.1093/molbev/msp172

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  65. Myasthenic syndrome due to defects in rapsyn: Clinical and molecular findings in 39 patients. 査読有り

    Milone M, Shen XM, Selcen D, Ohno K, Brengman J, Iannaccone ST, Harper CM, Engel AG

    Neurology   73 巻 ( 3 ) 頁: 228 - 35   2009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:Neurology  

    Background: Pathogenic mutations in rapsyn result in endplate acetylcholine receptor (AChR) deficiency and are a common cause of postsynaptic congenital myasthenic syndromes. Methods: Clinical, electrophysiologic, pathologic, and molecular studies were done in 39 patients. Results: In all but one patient, the disease presented in the first 2 years of life. In 9 patients, the myasthenic symptoms included constant or episodic ophthalmoparesis, and 1 patient had a pure limb-girdle phenotype. More than one-half of the patients experienced intermittent exacerbations. Long-term follow-up was available in 25 patients after start of cholinergic therapy: 21 became stable or were improved and 2 of these became asymptomatic; 3 had a progressive course; and 1 died in infancy. In 7 patients who had endplate studies, the average counts of AChR per endplate and the synaptic response to ACh were less reduced than in patients harboring low AChR expressor mutations. Eight patients were homozygous and 23 heterozygous for the common p.N88K mutation. Six mutations, comprising 3 missense mutations, an in-frame deletion, a splice-site mutation, and a nonsense mutation, are novel. Homozygosity for p.N88K was associated with varying grades of severity. No genotype-phenotype correlations were observed except in 8 Near-Eastern patients homozygous for the promoter mutation (c.-38A>G), who had a mild course. Conclusions: All but 1 patient presented early in life and most responded to cholinergic agonists. With early diagnosis and therapy, rapsyn deficiency has a benign course in most patients. There was no consistent phenotype- genotype correlation except for an E-box mutation associated with jaw deformities. Copyright © by AAN Enterprises, Inc.

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  66. Molecular hydrogen is protective against 6-hydroxydopamine-induced nigrostriatal degeneration in a rat model of Parkinson's disease. 査読有り

    Fu Y, Ito M, Fujita Y, Ito M, Ichihara M, Masuda A, Suzuki Y, Maesawa S, Kajita Y, Hirayama M, Ohsawa I, Ohta S, Ohno K

    Neuroscience letters   453 巻 ( 2 ) 頁: 81 - 5   2009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:Neuroscience Letters  

    Molecular hydrogen serves as an antioxidant that reduces hydroxyl radicals, but not the other reactive oxygen and nitrogen species. In the past year, molecular hydrogen has been reported to prevent or ameliorate eight diseases in rodents and one in human associated with oxidative stress. In Parkinson's disease, mitochondrial dysfunction and the associated oxidative stress are major causes of dopaminergic cell loss in the substantia nigra. We examined effects of ∼50%-saturated molecular hydrogen in drinking water before or after the stereotactic surgery on 6-hydroxydopamine-induced nigrostrital degeneration in a rat model of Parkinson's disease. Methamphetamine-induced behavioral analysis showed that molecular hydrogen prevented both the development and progression of the nigrostrital degeneration. Tyrosine hydroxylase staining of the substantia nigra and striatum also demonstrated that pre- and post-treatment with hydrogen prevented the dopaminergic cell loss. Our studies suggest that hydrogen water is likely able to retard the development and progression of Parkinson's disease. © 2009 Elsevier Ireland Ltd. All rights reserved.

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  67. Ancestral Origin of the ATTCT Repeat Expansion in Spinocerebellar Ataxia Type 10 (SCA10) 査読有り

    Almeida Teresa, Alonso Isabel, Martins Sandra, Ramos Eliana Marisa, Azevedo Luisa, Ohno Kinji, Amorim Antonio, Saraiva-Pereira Maria Luiza, Jardim Laura Bannach, Matsuura Tohru, Sequeiros Jorge, Silveira Isabel

    PLOS ONE   4 巻 ( 2 ) 頁: e4553 - -   2009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:PLoS ONE  

    Spinocerebellar ataxia type 10 (SCA10) is an autosomal dominant neurodegenerative disease characterized by cerebellar ataxia and seizures. The disease is caused by a large ATTCT repeat expansion in the ATXN10 gene. The first families reported with SCA10 were of Mexican origin, but the disease was soon after described in Brazilian families of mixed Portuguese and Amerindian ancestry. The origin of the SCA10 expansion and a possible founder effect that would account for its geographical distribution have been the source of speculation over the last years. To unravel the mutational origin and spread of the SCA10 expansion, we performed an extensive haplotype study, using closely linked STR markers and intragenic SNPs, in families from Brazil and Mexico. Our results showed (1) a shared disease haplotype for all Brazilian and one of the Mexican families, and (2) closely-related haplotypes for the additional SCA10 Mexican families; (3) little or null genetic distance in small normal alleles of different repeat sizes, from the same SNP lineage, indicating that they are being originated by a single step mechanism; and (4) a shared haplotype for pure and interrupted expanded alleles, pointing to a gene conversion model for its generation. In conclusion, we show evidence for an ancestral common origin for SCA10 in Latin America, which might have arisen in an ancestral Amerindian population and later have been spread into the mixed populations of Mexico and Brazil. © 2009 Almeida et al.

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  68. Long-range PCR for the diagnosis of spinocerebellar ataxia type 10 査読有り

    Kurosaki Tatsuaki, Matsuura Tohru, Ohno Kinji, Ueda Shintaroh

    NEUROGENETICS   9 巻 ( 2 ) 頁: 151 - 152   2008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:Neurogenetics  

    DOI: 10.1007/s10048-007-0117-x

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  69. Myotonic dystrophy type 2 in Japan: ancestral origin distinct from Caucasian families 査読有り

    Saito Tsukasa, Amakusa Yoshinobu, Kimura Takashi, Yahara Osamu, Aizawa Hitoshi, Ikeda Yoshio, Day John W., Ranum Laura P. W., Ohno Kinji, Matsuura Tohru

    NEUROGENETICS   9 巻 ( 1 ) 頁: 61 - 63   2008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:Neurogenetics  

    Myotonic dystrophy type 2 (DM2) is caused by expansion of a tetranucleotide CCTG repeat in intron 1 of the ZNF9 gene on chromosome 3q21. All studied DM2 mutations have been reported in Caucasians and share an identical haplotype, suggesting a common founder. We identified a Japanese patient with DM2 and showed that the affected haplotype is distinct from the previously identified DM2 haplotype shared among Caucasians. These data strongly suggest that DM2 expansion mutations originate from separate founders in Europe and Japan and are more widely distributed than previously recognized. © 2007 Springer-Verlag.

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  70. Thermodynamic instability of siRNA duplex is a prerequisite for dependable prediction of siRNA activities 査読有り

    Ichihara Masatoshi, Murakumo Yoshiki, Masuda Akio, Matsuura Toru, Asai Naoya, Jijiwa Mayumi, Ishida Maki, Shinmi Jun, Yatsuya Hiroshi, Qiao Shanlou, Takahashi Masahide, Ohno Kinji

    NUCLEIC ACIDS RESEARCH   35 巻 ( 18 ) 頁: e123 - -   2007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:Nucleic Acids Research  

    We developed a simple algorithm, i-Score (inhibitory-Score), to predict active siRNAs by applying a linear regression model to 2431 siRNAs. Our algorithm is exclusively comprised of nucleotide (nt) preferences at each position, and no other parameters are taken into account. Using a validation dataset comprised of 419 siRNAs, we found that the prediction accuracy of i-Score is as good as those of s-Biopredsi, ThermoComposition21 and DSIR, which employ a neural network model or more parameters in a linear regression model. Reynolds and Katoh also predict active siRNAs efficiently, but the numbers of siRNAs predicted to be active are less than one-eighth of that of i-Score. We additionally found that exclusion of thermostable siRNAs, whose whole stacking energy (ΔG) is less than -34.6 kcal/mol, improves the prediction accuracy in i-Score, s-Biopredsi, ThermoComposition21 and DSIR. We also developed a universal target vector, pSELL, with which we can assay an siRNA activity of any sequence in either the sense or antisense direction. We assayed 86 siRNAs in HEK293 cells using pSELL, and validated applicability of i-Score and the whole ΔG value in designing siRNAs. © 2007 The Author(s).

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  71. Effects of preceding sialadenitis on the development of autoimmunity against salivary gland

    Ohno K., Hattori T., Kagami H., Ueda M.

    ORAL DISEASES   13 巻 ( 2 ) 頁: 158 - 162   2007年3月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Oral Diseases  

    Objective: The mechanism underlying the onset and development of autoimmune diseases such as Sjogren's syndrome is not well understood. Here, we examined the effects of preceding inflammation of the salivary gland at the onset of autoimmunity against the salivary gland. Materials and methods: One side of the submandibular gland duct was ligated in mice and the effect on the contralateral gland was investigated. After histological evaluation with hematoxylin and eosin staining, the presence of autoantibodies and immune compounds was examined. Results: In all five strains of mice that were used, the salivary gland of the ligated side showed severe inflammation and atrophic change. In two mouse strains (SJL/J and PL/J), mild sialadenitis was observed on the non-ligated side 8 weeks after ligation. Autoantibodies reacting to the salivary gland were detected in three mouse strains (C3H/He, SJL/J, and PL/J). Immune complex was also detected in the duct basement membrane. Conclusion: The results indicate that the autoimmune mechanism is activated by the transient inflammation in the salivary gland under a specific genetic background. © 2007 Blackwell Munksgaard.

    DOI: 10.1111/j.1601-0825.2005.01219.x

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  72. Spectrum of splicing errors caused by CHRNE mutations affecting introns and intron/exon boundaries. 査読有り

    Ohno K, Tsujino A, Shen XM, Milone M, Engel AG

    Journal of medical genetics   42 巻 ( 8 ) 頁: e53   2005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:Journal of medical genetics  

    DOI: 10.1136/jmg.2004.026682

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  73. Choline acetyltransferase structure reveals distribution of mutations that cause motor disorders 査読有り

    Cai YY, Cronin CN, Engel AG, Ohno K, Hersh LB, Rodgers DW

    EMBO JOURNAL   23 巻 ( 10 ) 頁: 2047 - 2058   2004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:EMBO Journal  

    DOI: 10.1038/sj.emboj.7600221

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  74. C-terminal and heparin-binding domains of collagenic tail subunit are both essential for anchoring acetylcholinesterase at the synapse 査読有り

    Kimbell LM, Ohno K, Engel AG, Rotundo RL

    JOURNAL OF BIOLOGICAL CHEMISTRY   279 巻 ( 12 ) 頁: 10997 - 11005   2004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:Journal of Biological Chemistry  

    DOI: 10.1074/jbc.M305462200

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  75. Lack of founder haplotype for the rapsyn N88K mutation: N88K is an ancient founder mutation or arises from multiple founders. 査読有り

    Ohno K, Engel AG

    Journal of medical genetics   41 巻 ( 1 ) 頁: e8   2004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: 10.1136/jmg.2003.012245

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  76. Fundamental gating mechanism of nicotinic receptor channel revealed by mutation causing a congenital myasthenic syndrome. 査読有り

    Wang HL, Ohno K, Milone M, Brengman JM, Evoli A, Batocchi AP, Middleton LT, Christodoulou K, Engel AG, Sine SM

    The Journal of general physiology   116 巻 ( 3 ) 頁: 449 - 62   2000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: 10.1085/jgp.116.3.449

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  77. The spectrum of mutations causing end-plate acetylcholinesterase deficiency 査読有り

    Ohno K, Engel AG, Brengman JM, Shen XM, Heidenreich F, Vincent A, Milone M, Tan E, Demirci M, Walsh P, Nakano S, Akiguchi I

    ANNALS OF NEUROLOGY   47 巻 ( 2 ) 頁: 162 - 170   2000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: 10.1002/1531-8249(200002)47:2<162::AID-ANA5>3.3.CO;2-H

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  78. Mutation causing congenital myasthenia reveals acetylcholine receptor beta/delta subunit interaction essential for assembly. 査読有り

    Quiram PA, Ohno K, Milone M, Patterson MC, Pruitt NJ, Brengman JM, Sine SM, Engel AG

    The Journal of clinical investigation   104 巻 ( 10 ) 頁: 1403 - 10   1999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: 10.1172/JCI8179

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  79. Congenital end-plate acetylcholinesterase deficiency caused by a nonsense mutation and an A-->G splice-donor-site mutation at position +3 of the collagenlike-tail-subunit gene (COLQ): how does G at position +3 result in aberrant splicing? 査読有り

    Ohno K, Brengman JM, Felice KJ, Cornblath DR, Engel AG

    American journal of human genetics   65 巻 ( 3 ) 頁: 635 - 44   1999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: 10.1086/302551

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  80. Congenital myasthenic syndrome caused by a mutation in the Ets-binding site of the promoter region of the acetylcholine receptor epsilon subunit gene. 査読有り

    Ohno K, Anlar B, Engel AG

    Neuromuscular disorders : NMD   9 巻 ( 3 ) 頁: 131 - 5   1999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: 10.1016/s0960-8966(99)00007-3

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  81. Congenital myasthenic syndromes: recent advances. 査読有り

    Engel AG, Ohno K, Sine SM

    Archives of neurology   56 巻 ( 2 ) 頁: 163 - 7   1999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: 10.1001/archneur.56.2.163

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  82. Myasthenic syndromes in Turkish kinships due to mutations in the acetylcholine receptor. 査読有り

    Ohno K, Anlar B, Ozdirim E, Brengman JM, DeBleecker JL, Engel AG

    Annals of neurology   44 巻 ( 2 ) 頁: 234 - 41   1998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)  

    DOI: 10.1002/ana.410440214

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  83. Quinidine normalizes the open duration of slow-channel mutants of the acetylcholine receptor. 査読有り

    Fukudome T, Ohno K, Brengman JM, Engel AG

    Neuroreport   9 巻 ( 8 ) 頁: 1907 - 11   1998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: 10.1097/00001756-199806010-00044

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  84. AChR channel blockade by quinidine sulfate reduces channel open duration in the slow-channel congenital myasthenic syndrome. 査読有り

    Fukudome T, Ohno K, Brengman JM, Engel AG

    Annals of the New York Academy of Sciences   841 巻   頁: 199 - 202   1998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/j.1749-6632.1998.tb10928.x

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  85. Frameshifting and splice-site mutations in the acetylcholine receptor epsilon subunit gene in three Turkish kinships with congenital myasthenic syndromes. 査読有り

    Ohno K, Anlar B, Ozdirim E, Brengman JM, Engel AG

    Annals of the New York Academy of Sciences   841 巻   頁: 189 - 94   1998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/j.1749-6632.1998.tb10926.x

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  86. Congenital myasthenic syndromes. New insights from molecular genetic and patch-clamp studies. 査読有り

    Engel AG, Ohno K, Milone M, Sine SM

    Annals of the New York Academy of Sciences   841 巻   頁: 140 - 56   1998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/j.1749-6632.1998.tb10921.x

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  87. Congenital myasthenic syndrome caused by novel loss-of-function mutations in the human AChR epsilon subunit gene. 査読有り

    Milone M, Ohno K, Fukudome T, Shen XM, Brengman J, Griggs RC, Engel AG

    Annals of the New York Academy of Sciences   841 巻   頁: 184 - 8   1998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/j.1749-6632.1998.tb10925.x

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  88. Congenital myasthenic syndromes: experiments of nature. 査読有り

    Engel AG, Ohno K, Sine SM

    Journal of physiology, Paris   92 巻 ( 2 ) 頁: 113 - 7   1998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)  

    DOI: 10.1016/S0928-4257(98)80147-2

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  89. Mode switching kinetics produced by a naturally occurring mutation in the cytoplasmic loop of the human acetylcholine receptor epsilon subunit. 査読有り

    Milone M, Wang HL, Ohno K, Prince R, Fukudome T, Shen XM, Brengman JM, Griggs RC, Sine SM, Engel AG

    Neuron   20 巻 ( 3 ) 頁: 575 - 88   1998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)  

    DOI: 10.1016/s0896-6273(00)80996-4

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  90. Slow-channel myasthenic syndrome caused by enhanced activation, desensitization, and agonist binding affinity attributable to mutation in the M2 domain of the acetylcholine receptor alpha subunit. 査読有り

    Milone M, Wang HL, Ohno K, Fukudome T, Pruitt JN, Bren N, Sine SM, Engel AG

    The Journal of neuroscience : the official journal of the Society for Neuroscience   17 巻 ( 15 ) 頁: 5651 - 65   1997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)  

    DOI: 10.1523/JNEUROSCI.17-15-05651.1997

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  91. Mutation in the M1 domain of the acetylcholine receptor alpha subunit decreases the rate of agonist dissociation. 査読有り

    Wang HL, Auerbach A, Bren N, Ohno K, Engel AG, Sine SM

    The Journal of general physiology   109 巻 ( 6 ) 頁: 757 - 66   1997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: 10.1085/jgp.109.6.757

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  92. Congenital myasthenic syndromes due to heteroallelic nonsense/missense mutations in the acetylcholine receptor epsilon subunit gene: identification and functional characterization of six new mutations. 査読有り

    Ohno K, Quiram PA, Milone M, Wang HL, Harper MC, Pruitt JN 2nd, Brengman JM, Pao L, Fischbeck KH, Crawford TO, Sine SM, Engel AG

    Human molecular genetics   6 巻 ( 5 ) 頁: 753 - 66   1997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: 10.1093/hmg/6.5.753

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  93. End-plate acetylcholine receptor deficiency due to nonsense mutations in the epsilon subunit. 査読有り

    Engel AG, Ohno K, Bouzat C, Sine SM, Griggs RC

    Annals of neurology   40 巻 ( 5 ) 頁: 810 - 7   1996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: 10.1002/ana.410400521

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  94. New mutations in acetylcholine receptor subunit genes reveal heterogeneity in the slow-channel congenital myasthenic syndrome. 査読有り

    Engel AG, Ohno K, Milone M, Wang HL, Nakano S, Bouzat C, Pruitt JN 2nd, Hutchinson DO, Brengman JM, Bren N, Sieb JP, Sine SM

    Human molecular genetics   5 巻 ( 9 ) 頁: 1217 - 27   1996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: 10.1093/hmg/5.9.1217

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  95. Congenital myasthenic syndrome caused by decreased agonist binding affinity due to a mutation in the acetylcholine receptor epsilon subunit. 査読有り

    Ohno K, Wang HL, Milone M, Bren N, Brengman JM, Nakano S, Quiram P, Pruitt JN, Sine SM, Engel AG

    Neuron   17 巻 ( 1 ) 頁: 157 - 70   1996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: 10.1016/s0896-6273(00)80289-5

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  96. MELAS- and Kearns-Sayre-type co-mutation [corrected] with myopathy and autoimmune polyendocrinopathy. 査読有り

    Ohno K, Yamamoto M, Engel AG, Harper CM, Roberts LR, Tan GH, Fatourechi V

    Annals of neurology   39 巻 ( 6 ) 頁: 761 - 6   1996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: 10.1002/ana.410390612

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  97. Mutation of the acetylcholine receptor alpha subunit causes a slow-channel myasthenic syndrome by enhancing agonist binding affinity. 査読有り

    Sine SM, Ohno K, Bouzat C, Auerbach A, Milone M, Pruitt JN, Engel AG

    Neuron   15 巻 ( 1 ) 頁: 229 - 39   1995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: 10.1016/0896-6273(95)90080-2

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  98. Congenital myasthenic syndrome caused by prolonged acetylcholine receptor channel openings due to a mutation in the M2 domain of the epsilon subunit. 査読有り

    Ohno K, Hutchinson DO, Milone M, Brengman JM, Bouzat C, Sine SM, Engel AG

    Proceedings of the National Academy of Sciences of the United States of America   92 巻 ( 3 ) 頁: 758 - 62   1995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: 10.1073/pnas.92.3.758

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  99. PATIENTS WITH IDIOPATHIC CARDIOMYOPATHY BELONG TO THE SAME MITOCHONDRIAL-DNA GENE FAMILY OF PARKINSONS-DISEASE AND MITOCHONDRIAL ENCEPHALOMYOPATHY 査読有り

    OZAWA T, TANAKA M, SUGIYAMA S, INO H, OHNO K, HATTORI K, OHBAYASHI T, ITO T, DEGUCHI H, KAWAMURA K, NAKANE Y, HASHIBA K

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   177 巻 ( 1 ) 頁: 518 - 525   1991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: 10.1016/0006-291X(91)92014-B

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  100. DISTINCT CLUSTERING OF POINT MUTATIONS IN MITOCHONDRIAL-DNA AMONG PATIENTS WITH MITOCHONDRIAL ENCEPHALOMYOPATHIES AND WITH PARKINSONS-DISEASE 査読有り

    OZAWA T, TANAKA M, INO H, OHNO K, SANO T, WADA Y, YONEDA M, TANNO Y, MIYATAKE T, TANAKA T, ITOYAMA S, IKEBE S, HATTORI N, MIZUNO Y

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   176 巻 ( 2 ) 頁: 938 - 946   1991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)  

    DOI: 10.1016/S0006-291X(05)80276-1

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  101. MULTIPLE MITOCHONDRIAL-DNA DELETIONS EXIST IN CARDIOMYOCYTES OF PATIENTS WITH HYPERTROPHIC OR DILATED CARDIOMYOPATHY 査読有り

    OZAWA T, TANAKA M, SUGIYAMA S, HATTORI K, ITO T, OHNO K, TAKAHASHI A, SATO W, TAKADA G, MAYUMI B, YAMAMOTO K, ADACHI K, KOGA Y, TOSHIMA H

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   170 巻 ( 2 ) 頁: 830 - 836   1990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: 10.1016/0006-291X(90)92166-W

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  102. DIFFERENTLY DELETED MITOCHONDRIAL GENOMES IN MATERNALLY INHERITED CHRONIC PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA 査読有り

    TANAKA M, YONEDA M, OHNO K, SATO W, YAMAMOTO M, NONAKA I, HORAI S, OZAWA T

    JOURNAL OF INHERITED METABOLIC DISEASE   12 巻 ( 3 ) 頁: 359 - 362   1989年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1007/BF01799242

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  103. MATERNAL INHERITANCE OF DELETED MITOCHONDRIAL-DNA IN A FAMILY WITH MITOCHONDRIAL MYOPATHY 査読有り

    OZAWA T, YONEDA M, TANAKA M, OHNO K, SATO W, SUZUKI H, NISHIKIMI M, YAMAMOTO M, NONAKA I, HORAI S

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   154 巻 ( 3 ) 頁: 1240 - 1247   1988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)  

    DOI: 10.1016/0006-291X(88)90272-0

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  104. Examination of Abnormal Alpha-synuclein Aggregates in the Enteric Neural Plexus in Patients with Ulcerative Colitis. 査読有り 国際誌

    Gibo N, Hamaguchi T, Miki Y, Yamamura T, Nakaguro M, Ito M, Nakamuara M, Kawashima H, Hirayama M, Hirooka Y, Wakabayashi K, Ohno K

    Journal of gastrointestinal and liver diseases : JGLD   31 巻 ( 3 ) 頁: 290 - 300   2022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: 10.15403/jgld-4313

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  105. Efficacy of auranofin as an inhibitor of desmoid progression. 査読有り 国際誌

    Ito K, Nishida Y, Hamada S, Shimizu K, Sakai T, Ohkawara B, Alman BA, Enomoto A, Ikuta K, Koike H, Zhang J, Ohno K, Imagama S

    Scientific reports   12 巻 ( 1 ) 頁: 11918 - 11918   2022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/s41598-022-15756-9

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  106. Extremely low-frequency pulses of faint magnetic field induce mitophagy to rejuvenate mitochondria. 査読有り 国際誌

    Toda T, Ito M, Takeda JI, Masuda A, Mino H, Hattori N, Mohri K, Ohno K

    Communications biology   5 巻 ( 1 ) 頁: 453 - 453   2022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: 10.1038/s42003-022-03389-7

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  107. Possible Repositioning of an Oral Anti-Osteoporotic Drug, Ipriflavone, for Treatment of Inflammatory Arthritis via Inhibitory Activity of KIAA1199, a Novel Potent Hyaluronidase. 査読有り 国際誌

    Koike H, Nishida Y, Shinomura T, Ohkawara B, Ohno K, Zhuo L, Kimata K, Ushida T, Imagama S

    International journal of molecular sciences   23 巻 ( 8 )   2022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:International Journal of Molecular Sciences  

    KIAA1199 has a strong hyaluronidase activity in inflammatory arthritis. This study aimed to identify a drug that could reduce KIAA1199 activity and clarify its effects on inflammatory arthritis. Rat chondrosarcoma (RCS) cells were strongly stained with Alcian blue (AB). Its stainability was reduced in RCS cells, which were over-expressed with the KIAA1199 gene (RCS-KIAA). We screened the drugs that restore the AB stainability in RCS-KIAA. The effects of the drug were evaluated by particle exclusion assay, HA ELISA, RT-PCR, and Western blotting. We further evaluated the HA accumulation and the MMP1 and three expressions in fibroblast-like synoviocytes (FLS). In vivo, the effects of the drug on symptoms and serum concentration of HA in a collagen-induced arthritis mouse were evaluated. Ipriflavone was identified to restore AB stainability at 23%. Extracellular matrix formation was significantly increased in a dose-dependent manner (p = 0.006). Ipriflavone increased the HA accumulation and suppressed the MMP1 and MMP3 expression on TNF-α stimulated FLS. In vivo, Ipriflavone significantly improved the symptoms and reduced the serum concentrations of HA. Conclusions: We identified Ipriflavone, which has inhibitory effects on KIAA1199 activity. Ipriflavone may be a therapeutic candidate based on its reduction of KIAA1199 activity in inflammatory arthritis.

    DOI: 10.3390/ijms23084089

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  108. Promethazine Downregulates Wnt/β-Catenin Signaling and Increases the Biomechanical Forces of the Injured Achilles Tendon in the Early Stage of Healing. 査読有り 国際誌

    Sakaguchi T, Ohkawara B, Kishimoto Y, Miyamoto K, Ishizuka S, Hiraiwa H, Ishiguro N, Imagama S, Ohno K

    The American journal of sports medicine   50 巻 ( 5 ) 頁: 1317 - 1327   2022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:American Journal of Sports Medicine  

    Background: Wnt/β-catenin signaling suppresses the differentiation of cultured tenocytes, but its roles in tendon repair remain mostly elusive. No chemical compounds are currently available to treat tendon injury. Hypothesis: We hypothesized that the inhibition of Wnt/β-catenin signaling would accelerate tendon healing. Study Design: Controlled laboratory study. Methods: Tendon-derived cells (TDCs) were isolated from rat Achilles tendons. The right Achilles tendon was injured via a dermal punch, while the left tendon was sham operated. A Wnt/β-catenin inhibitor, IWR-1, and an antihistamine agent, promethazine (PH), were locally and intramuscularly injected, respectively, for 2 weeks after surgery. The healing tendons were histologically and biomechanically evaluated. Results: The amount of β-catenin protein was increased in the injured tendons from postoperative weeks 0.5 to 2. Inhibition of Wnt/β-catenin signaling by IWR-1 in healing tendons improved the histological abnormalities and decreased β-catenin, but it compromised the biomechanical properties. As we previously reported that antihistamine agents suppressed Wnt/β-catenin signaling in human chondrosarcoma cells, we examined the effects of antihistamines on TDCs. We found that a first-generation antihistamine agent, PH, increased the expression of the tendon marker genes Mkx and Tnmd in TDCs. Intramuscular injection of PH did not improve histological abnormalities, but it decreased β-catenin in healing tendons and increased the peak force and stiffness of the healing tendons on postoperative week 2. On postoperative week 8, however, the biomechanical properties of vehicle-treated tendons became similar to those of PH-treated tendons. Conclusion: IWR-1 and PH suppressed Wnt/β-catenin signaling and improved the histological abnormalities of healing tendons. IWR-1, however, compromised the biomechanical properties of healing tendons, whereas PH improved them. Clinical Relevance: PH is a candidate repositioned drug that potentially accelerates tendon repair.

    DOI: 10.1177/03635465221077116

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  109. Molecular Hydrogen Enhances Proliferation of Cancer Cells That Exhibit Potent Mitochondrial Unfolded Protein Response. 査読有り 国際誌

    Hasegawa T, Ito M, Hasegawa S, Teranishi M, Takeda K, Negishi S, Nishiwaki H, Takeda JI, LeBaron TW, Ohno K

    International journal of molecular sciences   23 巻 ( 5 )   2022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:International Journal of Molecular Sciences  

    Molecular hydrogen ameliorates pathological states in a variety of human diseases, animal models, and cell models, but the effects of hydrogen on cancer have been rarely reported. In addition, the molecular mechanisms underlying the effects of hydrogen remain mostly unelucidated. We found that hydrogen enhances proliferation of four out of seven human cancer cell lines (the responders). The proliferation-promoting effects were not correlated with basal levels of cellular reactive oxygen species. Expression profiling of the seven cells showed that the responders have higher gene expression of mitochondrial electron transport chain (ETC) molecules than the non-responders. In addition, the responders have higher mitochondrial mass, higher mitochondrial superoxide, higher mitochondrial membrane potential, and higher mitochondrial spare respiratory capacity than the non-responders. In the responders, hydrogen provoked mitochondrial unfolded protein response (mtUPR). Suppression of cell proliferation by rotenone, an inhibitor of mitochondrial ETC complex I, was rescued by hydrogen in the responders. Hydrogen triggers mtUPR and induces cell proliferation in cancer cells that have high basal and spare mitochondrial ETC activities.

    DOI: 10.3390/ijms23052888

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  110. Meclozine ameliorates skeletal muscle pathology and increases muscle forces in mdx mice. 査読有り 国際誌

    Kawamura Y, Hida T, Ohkawara B, Matsushita M, Kobayashi T, Ishizuka S, Hiraiwa H, Tanaka S, Tsushima M, Nakashima H, Ito K, Imagama S, Ito M, Masuda A, Ishiguro N, Ohno K

    Biochemical and biophysical research communications   592 巻   頁: 87 - 92   2022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:Biochemical and Biophysical Research Communications  

    We screened pre-approved drugs for the survival of the Hu5/KD3 human myogenic progenitors. We found that meclozine, an anti-histamine drug that has long been used for motion sickness, promoted the proliferation and survival of Hu5/KD3 cells. Meclozine increased expression of MyoD, but reduced expression of myosin heavy chain and suppressed myotube formation. Withdrawal of meclozine, however, resumed the ability of Hu5/KD3 cells to differentiate into myotubes. We examined the effects of meclozine on mdx mouse carrying a nonsense mutation in the dystrophin gene and modeling for Duchenne muscular dystrophy. Intragastric administration of meclozine in mdx mouse increased the body weight, the muscle mass in the lower limbs, the cross-sectional area of the paravertebral muscle, and improved exercise performances. Previous reports show that inhibition of phosphorylation of ERK1/2 improves muscle functions in mouse models for Emery-Dreifuss muscular dystrophy and cancer cachexia, as well as in mdx mice. We and others previously showed that meclozine blocks the phosphorylation of ERK1/2 in cultured cells. We currently showed that meclozine decreased phosphorylation of ERK1/2 in muscles in mdx mice but not in wild-type mice. This was likely to be one of the underlying mechanisms of the effects of meclozine on mdx mice.

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  111. Altered gut microbiota in Parkinson's disease patients with motor complications. 査読有り 国際誌

    Takahashi K, Nishiwaki H, Ito M, Iwaoka K, Takahashi K, Suzuki Y, Taguchi K, Yamahara K, Tsuboi Y, Kashihara K, Hirayama M, Ohno K, Maeda T

    Parkinsonism & related disorders   95 巻   頁: 11 - 17   2022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:Parkinsonism and Related Disorders  

    Introduction: Parkinson's disease (PD) is associated with gut dysbiosis. However, whether gut dysbiosis can cause motor complications is unclear. Methods: Subjects were enrolled from four independent movement disorder centers in Japan. We performed 16S ribosomal RNA gene sequence analysis of gut microbiota. Relative abundance of gut microbiota and relationships between them and clinical characteristics were statistically analyzed. Analysis of co-variance (ANCOVA) was used to assess altered gut microbiota associated with wearing-off or dyskinesia. Results: We enrolled 223 patients with PD. Wearing-off was noted in 47.5% of patients and dyskinesia in 21.9%. We detected 98 genera of bacteria. Some changes in the gut microbiota were observed in patients with PD and motor complications. After Bonferroni correction, patients with wearing-off showed decreased relative abundance of Lachnospiraceae Blautia (p < 0.0001) and increased relative abundance of Lactobacillaceae Lactobacillus (p < 0.0001), but patients with dyskinesia no longer showed significant changes in the gut microbiota. Adjustment with two models of confounding factors followed by ANCOVA revealed that age (p < 0.0001), disease duration (p = 0.01), and wearing-off (p = 0.0004) were independent risks for the decreased relative abundance of Lachnospiraceae Blautia, and wearing-off (p = 0.009) was the only independent risk factor for the increased relative abundance of Lachnospiraceae Lactobacillus. Conclusion: Relative abundance of Lachnospiraceae Blautia and Lactobacillaceae Lactobacillus was significantly decreased and increased, respectively, in the gut microbiota of PD patients with motor complications. This indicates that an altered gut microbiota is associated with the development of motor complications in patients with advanced PD.

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  112. Regulated splicing of large exons is linked to phase-separation of vertebrate transcription factors. 査読有り 国際誌

    Kawachi T, Masuda A, Yamashita Y, Takeda JI, Ohkawara B, Ito M, Ohno K

    The EMBO journal   40 巻 ( 22 ) 頁: e107485   2021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:EMBO Journal  

    Although large exons cannot be readily recognized by the spliceosome, many are evolutionarily conserved and constitutively spliced for inclusion in the processed transcript. Furthermore, whether large exons may be enriched in a certain subset of proteins, or mediate specific functions, has remained unclear. Here, we identify a set of nearly 3,000 SRSF3-dependent large constitutive exons (S3-LCEs) in human and mouse cells. These exons are enriched for cytidine-rich sequence motifs, which bind and recruit the splicing factors hnRNP K and SRSF3. We find that hnRNP K suppresses S3-LCE splicing, an effect that is mitigated by SRSF3 to thus achieve constitutive splicing of S3-LCEs. S3-LCEs are enriched in genes for components of transcription machineries, including mediator and BAF complexes, and frequently contain intrinsically disordered regions (IDRs). In a subset of analyzed S3-LCE-containing transcription factors, SRSF3 depletion leads to deletion of the IDRs due to S3-LCE exon skipping, thereby disrupting phase-separated assemblies of these factors. Cytidine enrichment in large exons introduces proline/serine codon bias in intrinsically disordered regions and appears to have been evolutionarily acquired in vertebrates. We propose that layered splicing regulation by hnRNP K and SRSF3 ensures proper phase-separation of these S3-LCE-containing transcription factors in vertebrates.

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  113. Zonisamide upregulates neuregulin-1 expression and enhances acetylcholine receptor clustering at the in vitro neuromuscular junction. 査読有り 国際誌

    Inoue T, Ohkawara B, Bushra S, Kanbara S, Nakashima H, Koshimizu H, Tomita H, Ito M, Masuda A, Ishiguro N, Imagama S, Ohno K

    Neuropharmacology   195 巻   頁: 108637 - 108637   2021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:Neuropharmacology  

    Decreased acetylcholine receptor (AChR) clustering compromises signal transmission at the neuromuscular junction (NMJ) in myasthenia gravis, congenital myasthenic syndromes, and motor neuron diseases. Although the enhancement of AChR clustering at the NMJ is a promising therapeutic strategy for these maladies, no drug is currently available for this enhancement. We previously reported that zonisamide (ZNS), an anti-epileptic and anti-Parkinson's disease drug, enhances neurite elongation of the primary spinal motor neurons (SMNs). As nerve sprouting occurs to compensate for the loss of AChR clusters in human diseases, we examined the effects of ZNS on AChR clustering at the NMJ. To this end, we established a simple and quick co-culture system to reproducibly make in vitro NMJs using C2C12 myotubes and NSC34 motor neurons. ZNS at 1–20 μM enhanced the formation of AChR clusters dose-dependently in co-cultured C2C12 myotubes but not in agrin-treated single cultured C2C12 myotubes. We observed that molecules that conferred responsiveness to ZNS were not secreted into the co-culture medium. We found that 10 μM ZNS upregulated the expression of neuregulin-1 (Nrg1) in co-cultured cells but not in single cultured C2C12 myotubes or single cultured NSC34 motor neurons. In accordance with this observation, inhibition of the Nrg1/ErbB signaling pathways nullified the effect of 10 μM ZNS on the enhancement of AChR clustering in in vitro NMJs. Although agrin was not induced by 10 μM ZNS in co-cultured cells, anti-agrin antibody attenuated ZNS-mediated enhancement of AChR clustering. We conclude that ZNS enhances agrin-dependent AChR-clustering by upregulating the Nrg1/ErbB signaling pathways in the presence of NMJs.

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  114. Desloratadine inhibits heterotopic ossification by suppression of BMP2-Smad1/5/8 signaling. 査読有り 国際誌

    Kusano T, Nakatani M, Ishiguro N, Ohno K, Yamamoto N, Morita M, Yamada H, Uezumi A, Tsuchida K

    Journal of orthopaedic research : official publication of the Orthopaedic Research Society   39 巻 ( 6 ) 頁: 1297 - 1304   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)   出版者・発行元:Journal of Orthopaedic Research  

    Heterotopic ossification (HO) is a pathological condition in which ectopic bone forms within soft tissues such as skeletal muscle. Human platelet-derived growth factor receptor α positive (PDGFRα+) cells, which were proved to be the original cells of HO were incubated in osteogenic differentiation medium with Food and Drug Administration-approved compounds. Alkaline phosphatase activity was measured as a screening to inhibit osteogenic differentiation. For the compounds which inhibited osteogenic differentiation of PDGFRα+ cells, we examined dose dependency of its effect using alizarin red S staining and its cell toxicity using WST-8. In addition, regulation of bone morphogenetic proteins (BMP)-Smad signaling which is the major signal of osteogenic differentiation was investigated by Western blotting to elucidate the mechanism of osteogenesis inhibitory effect by the compound. In vivo experiment, complete transverse incision of Achilles tendons in mice was made and mice were fed the compound by mixing with drinking water after operation. Ten weeks after operation, we assessed and quantified HO by micro-computed tomography scan. Intriguingly, we discovered desloratadine inhibited osteogenic differentiation of PDGFRα+ cells using the drug repositioning method. Desloratadine inhibited osteogenic differentiation of the cells dose dependently without cell toxicity. Desloratadine suppressed phosphorylation of Smad1/5/8 induced by BMP2 in PDGFRα+ cells. In Achilles tenotomy mice model, desloratadine treatment significantly inhibited ectopic bone formation compared with control. In conclusion, we discovered desloratadine inhibited osteogenic differentiation using human PDGFRα+ cells and proved its efficacy using Achilles tenotomy ectopic bone formation model in vivo. Our study paved the way to inhibit HO in early clinical use because of its guaranteed safety.

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  115. Intestinal Collinsella may mitigate infection and exacerbation of COVID-19 by producing ursodeoxycholate. 査読有り 国際誌

    Hirayama M, Nishiwaki H, Hamaguchi T, Ito M, Ueyama J, Maeda T, Kashihara K, Tsuboi Y, Ohno K

    PloS one   16 巻 ( 11 ) 頁: e0260451   2021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:PLoS ONE  

    The mortality rates of COVID-19 vary widely across countries, but the underlying mechanisms remain unelucidated. We aimed at the elucidation of relationship between gut microbiota and the mortality rates of COVID-19 across countries. Raw sequencing data of 16S rRNA V3-V5 regions of gut microbiota in 953 healthy subjects in ten countries were obtained from the public database. We made a generalized linear model (GLM) to predict the COVID- 19 mortality rates using gut microbiota. GLM revealed that low genus Collinsella predicted high COVID-19 mortality rates with a markedly low p-value. Unsupervised clustering of gut microbiota in 953 subjects yielded five enterotypes. The mortality rates were increased from enterotypes 1 to 5, whereas the abundances of Collinsella were decreased from enterotypes 1 to 5 except for enterotype 2. Collinsella produces ursodeoxycholate. Ursodeoxycholate was previously reported to inhibit binding of SARS-CoV-2 to angiotensin-converting enzyme 2; suppress pro-inflammatory cytokines like TNF-α, IL-1β, IL-2, IL-4, and IL-6; have antioxidant and anti-apoptotic effects; and increase alveolar fluid clearance in acute respiratory distress syndrome. Ursodeoxycholate produced by Collinsella may prevent COVID-19 infection and ameliorate acute respiratory distress syndrome in COVID-19 by suppressing cytokine storm syndrome.

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  116. Meclozine Attenuates the MARK Pathway in Mammalian Chondrocytes and Ameliorates FGF2-Induced Bone Hyperossification in Larval Zebrafish. 査読有り 国際誌

    Takemoto G, Matsushita M, Okamoto T, Ito T, Matsuura Y, Takashima C, Chen-Yoshikawa TF, Ebi H, Imagama S, Kitoh H, Ohno K, Hosono Y

    Frontiers in cell and developmental biology   9 巻   頁: 694018 - 694018   2021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:Frontiers in Cell and Developmental Biology  

    Meclozine has been developed as an inhibitor of fibroblast growth factor receptor 3 (FGFR3) to treat achondroplasia (ACH). Extracellular signal regulated kinase (ERK) phosphorylation was attenuated by meclozine in FGF2-treated chondrocyte cell line, but the site of its action has not been elucidated. Although orally administered meclozine promoted longitudinal bone growth in a mouse model of ACH, its effect on craniofacial bone development during the early stage remains unknown. Herein, RNA-sequencing analysis was performed using murine chondrocytes from FGF2-treated cultured tibiae, which was significantly elongated by meclozine treatment. Gene set enrichment analysis demonstrated that FGF2 significantly increased the enrichment score of mitogen-activated protein kinase (MAPK) family signaling cascades in chondrocytes; however, meclozine reduced this enrichment. Next, we administered meclozine to FGF2-treated larval zebrafish from 8 h post-fertilization (hpf). We observed that FGF2 significantly increased the number of ossified vertebrae in larval zebrafish at 7 days post-fertilization (dpf), while meclozine delayed vertebral ossification in FGF2-induced zebrafish. Meclozine also reversed the FGF2-induced upregulation of ossified craniofacial bone area, including ceratohyal, hyomandibular, and quadrate. The current study provided additional evidence regarding the inhibitory effect of meclozine on the FGF2-induced upregulation of MAPK signaling in chondrocytes and FGF2-induced development of craniofacial and vertebral bones.

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  117. Zonisamide ameliorates neuropathic pain partly by suppressing microglial activation in the spinal cord in a mouse model. 査読有り 国際誌

    Koshimizu H, Ohkawara B, Nakashima H, Ota K, Kanbara S, Inoue T, Tomita H, Sayo A, Kiryu-Seo S, Konishi H, Ito M, Masuda A, Ishiguro N, Imagama S, Kiyama H, Ohno K

    Life sciences   263 巻   頁: 118577 - 118577   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)   出版者・発行元:Life Sciences  

    Neuropathic pain is caused by a lesion or a functional impairment of the sensory nervous system and allodynia is one of the frequently observed symptoms in neuropathic pain. Allodynia represents abnormal pain due to a non-noxious stimulus that does not normally provoke pain. Cellular mechanisms underlying neuropathic pain remain mostly elusive, and partial pain relief can be achieved in a limited number of patients by antidepressants, anticonvulsants topical anesthetics, and others. Zonisamide (ZNS) is widely used as an anti-epileptic and anti-Parkinson's disease drug. A recent report shows that ZNS suppresses neuropathic pain associated with diabetes mellitus in a mouse model. We made a mouse model of neuropathic pain in the hindlimb by cutting the nerve at the intervertebral canal at lumbar level 4 (L4). At 28 days after nerve injury, ZNS ameliorated allodynic pain, and reduced the expression of inflammatory cytokines and the nerve injury-induced increase of Iba1-positive microglia in the spinal dorsal horn at L4. In BV2 microglial cells, ZNS reduced the number of lipopolysaccharide-induced amoeboid-shaped cells, representing activated microglia. These results suggest that ZNS is a potential therapeutic agent for neuropathic pain partly by suppressing microglia-mediated neuroinflammation.

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  118. Meta-Analysis of Gut Dysbiosis in Parkinson's Disease. 査読有り 国際誌

    Nishiwaki H, Ito M, Ishida T, Hamaguchi T, Maeda T, Kashihara K, Tsuboi Y, Ueyama J, Shimamura T, Mori H, Kurokawa K, Katsuno M, Hirayama M, Ohno K

    Movement disorders : official journal of the Movement Disorder Society   35 巻 ( 9 ) 頁: 1626 - 1635   2020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:Movement Disorders  

    Background: PD may begin with the intestinal accumulation of α-synuclein fibrils, which can be causally associated with gut dysbiosis. The variability of gut microbiota across countries prevented us from identifying shared gut dysbiosis in PD. Objectives: To identify gut dysbiosis in PD across countries. Methods: We performed 16S ribosomal RNA gene sequencing analysis of gut microbiota in 223 patients with PD and 137 controls, and meta-analyzed gut dysbiosis by combining our dataset with four previously reported data sets from the United States, Finland, Russia, and Germany. We excluded uncommon taxa from our analyses. For pathway analysis, we developed the Kyoto Encyclopedia of Genes and Genomes orthology set enrichment analysis method. Results: After adjusting for confounding factors (body mass index, constipation, sex, age, and catechol-O-methyl transferase inhibitor), genera Akkermansia and Catabacter, as well as families Akkermansiaceae, were increased, whereas genera Roseburia, Faecalibacterium, and Lachnospiraceae ND3007 group were decreased in PD. Catechol-O-methyl transferase inhibitor intake markedly increased family Lactobacillaceae. Inspection of these bacteria in 12 datasets that were not included in the meta-analysis revealed that increased genus Akkermansia and decreased genera Roseburia and Faecalibacterium were frequently observed across countries. Kyoto Encyclopedia of Genes and Genomes orthology set enrichment analysis revealed changes in short-chain fatty acid metabolisms in our dataset. Conclusions: We report that intestinal mucin layer-degrading Akkermansia is increased and that short-chain fatty acid–producing Roseburia and Faecalibacterium are decreased in PD across countries. © 2020 International Parkinson and Movement Disorder Society.

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  119. CTGF/CCN2 facilitates LRP4-mediated formation of the embryonic neuromuscular junction. 査読有り 国際誌

    Ohkawara B, Kobayakawa A, Kanbara S, Hattori T, Kubota S, Ito M, Masuda A, Takigawa M, Lyons KM, Ishiguro N, Ohno K

    EMBO reports   21 巻 ( 8 ) 頁: e48462 - e48462   2020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:EMBO Reports  

    At the neuromuscular junction (NMJ), lipoprotein-related receptor 4 (LRP4) mediates agrin-induced MuSK phosphorylation that leads to clustering of acetylcholine receptors (AChRs) in the postsynaptic region of the skeletal muscle. Additionally, the ectodomain of LRP4 is necessary for differentiation of the presynaptic nerve terminal. However, the molecules regulating LRP4 have not been fully elucidated yet. Here, we show that the CT domain of connective tissue growth factor (CTGF/CCN2) directly binds to the third beta-propeller domain of LRP4. CTGF/CCN2 enhances the binding of LRP4 to MuSK and facilitates the localization of LRP4 on the plasma membrane. CTGF/CCN2 enhances agrin-induced MuSK phosphorylation and AChR clustering in cultured myotubes. Ctgf-deficient mouse embryos (Ctgf−/−) have small AChR clusters and abnormal dispersion of synaptic vesicles along the motor axon. Ultrastructurally, the presynaptic nerve terminals have reduced numbers of active zones and mitochondria. Functionally, Ctgf−/− embryos exhibit impaired NMJ signal transmission. These results indicate that CTGF/CCN2 interacts with LRP4 to facilitate clustering of AChRs at the motor endplate and the maturation of the nerve terminal.

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  120. InMeRF: prediction of pathogenicity of missense variants by individual modeling for each amino acid substitution. 査読有り 国際誌

    Takeda JI, Nanatsue K, Yamagishi R, Ito M, Haga N, Hirata H, Ogi T, Ohno K

    NAR genomics and bioinformatics   2 巻 ( 2 ) 頁: lqaa038   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)   出版者・発行元:NAR Genomics and Bioinformatics  

    In predicting the pathogenicity of a nonsynonymous single-nucleotide variant (nsSNV), a radical change in amino acid properties is prone to be classified as being pathogenic. However, not all such nsSNVs are associated with human diseases. We generated random forest (RF) models individually for each amino acid substitution to differentiate pathogenic nsSNVs in the Human Gene Mutation Database and common nsSNVs in dbSNP. We named a set of our models ‘Individual Meta RF’ (InMeRF). Ten-fold cross-validation of InMeRF showed that the areas under the curves (AUCs) of receiver operating characteristic (ROC) and precision–recall curves were on average 0.941 and 0.957, respectively. To compare InMeRF with seven other tools, the eight tools were generated using the same training dataset, and were compared using the same three testing datasets. ROC-AUCs of InMeRF were ranked first in the eight tools. We applied InMeRF to 155 pathogenic and 125 common nsSNVs in seven major genes causing congenital myasthenic syndromes, as well as in VANGL1 causing spina bifida, and found that the sensitivity and specificity of InMeRF were 0.942 and 0.848, respectively. We made the InMeRF web service, and also made genome-wide InMeRF scores available online (https://www.med.nagoya-u.ac.jp/neurogenetics/InMeRF/).

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  121. Ubiquitination of DNA Damage-Stalled RNAPII Promotes Transcription-Coupled Repair. 査読有り 国際誌

    Nakazawa Y, Hara Y, Oka Y, Komine O, van den Heuvel D, Guo C, Daigaku Y, Isono M, He Y, Shimada M, Kato K, Jia N, Hashimoto S, Kotani Y, Miyoshi Y, Tanaka M, Sobue A, Mitsutake N, Suganami T, Masuda A, Ohno K, Nakada S, Mashimo T, Yamanaka K, Luijsterburg MS, Ogi T

    Cell   180 巻 ( 6 ) 頁: 1228 - 1244.e24   2020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:Cell  

    Transcription-coupled nucleotide excision repair (TC-NER) is initiated by the stalling of elongating RNA polymerase II (RNAPIIo) at DNA lesions. The ubiquitination of RNAPIIo in response to DNA damage is an evolutionarily conserved event, but its function in mammals is unknown. Here, we identified a single DNA damage-induced ubiquitination site in RNAPII at RPB1-K1268, which regulates transcription recovery and DNA damage resistance. Mechanistically, RPB1-K1268 ubiquitination stimulates the association of the core-TFIIH complex with stalled RNAPIIo through a transfer mechanism that also involves UVSSA-K414 ubiquitination. We developed a strand-specific ChIP-seq method, which revealed RPB1-K1268 ubiquitination is important for repair and the resolution of transcriptional bottlenecks at DNA lesions. Finally, RPB1-K1268R knockin mice displayed a short life-span, premature aging, and neurodegeneration. Our results reveal RNAPII ubiquitination provides a two-tier protection mechanism by activating TC-NER and, in parallel, the processing of DNA damage-stalled RNAPIIo, which together prevent prolonged transcription arrest and protect against neurodegeneration.

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  122. Inhibition of cyclooxygenase-1 by nonsteroidal anti-inflammatory drugs demethylates MeR2 enhancer and promotes Mbnl1 transcription in myogenic cells. 査読有り 国際誌

    Huang K, Masuda A, Chen G, Bushra S, Kamon M, Araki T, Kinoshita M, Ohkawara B, Ito M, Ohno K

    Scientific reports   10 巻 ( 1 ) 頁: 2558 - 2558   2020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:Scientific Reports  

    Muscleblind-like 1 (MBNL1) is a ubiquitously expressed RNA-binding protein, which is highly expressed in skeletal muscle. Abnormally expanded CUG-repeats in the DMPK gene cause myotonic dystrophy type 1 (DM1) by sequestration of MBNL1 to nuclear RNA foci and by upregulation of another RNA-binding protein, CUG-binding protein 1 (CUGBP1). We previously reported that a nonsteroidal anti-inflammatory drug (NSAID), phenylbutazone, upregulates MBNL1 expression in DM1 mouse model by demethylation of MeR2, an enhancer element in Mbnl1 intron 1. NSAIDs inhibit cyclooxygenase (COX), which is comprised of COX-1 and COX-2 isoforms. In this study, we screened 29 NSAIDs in C2C12 myoblasts, and found that 13 NSAIDs enhanced Mbnl1 expression, where COX-1-selective NSAIDs upregulated Mbnl1 more than COX-2-selective NSAIDs. Consistently, knockdown of COX-1, but not of COX-2, upregulated MBNL1 expression in C2C12 myoblasts and myotubes, as well as in myotubes differentiated from DM1 patient-derived induced pluripotent stem cells (iPSCs). Luciferase assay showed that COX-1-knockdown augmented the MeR2 enhancer activity. Furthermore, bisulfite sequencing analysis demonstrated that COX-1-knockdown suppressed methylation of MeR2. These results suggest that COX-1 inhibition upregulates Mbnl1 transcription through demethylation of the MeR2 enhancer. Taken together, our study provides new insights into the transcriptional regulation of Mbnl1 by the COX-1-mediated pathway.

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  123. Freeze-drying enables homogeneous and stable sample preparation for determination of fecal short-chain fatty acids. 査読有り 国際誌

    Ueyama J, Oda M, Hirayama M, Sugitate K, Sakui N, Hamada R, Ito M, Saito I, Ohno K

    Analytical biochemistry   589 巻   頁: 113508 - 113508   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)   出版者・発行元:Analytical Biochemistry  

    Background: The analysis methods for fecal short-chain fatty acids (SCFAs) have evolved considerably. Recently, the role of SCFAs in gastrointestinal physiology and their association with intestinal microbiota and disease were reported. However, the intra-fecal variability and storage stability of SCFAs have not been extensively investigated. The aim of this study was to understand the limitations of the measurement of SCFAs in crude feces and develop a useful pre-examination procedure using the freeze-drying technique. Methods: SCFAs in crude feces, obtained from healthy volunteers, and freeze-dried feces were determined by derivatization with isobutyl chloroformate, followed by liquid–liquid extraction with hexane, and separation and analysis using gas chromatography–mass spectrometry. Results: Among the SCFAS, the maximum intra-fecal variability was observed for iso-butyrate (coefficient of variation of 37.7%), but the freeze-drying procedure reduced this variability (coefficient of variation of 7.9%). Similar improvements were also observed for other SCFAs. Furthermore, significant decreases in the SCFA amounts were observed with storage at 4 °C for 24 h. Conclusions: The freeze-drying procedure affords fecal SCFA stability, even with storage at room temperature for 3 d. The freeze-drying procedure allows reliable SCFA measurements without labour-intensive processes. Therefore, the freeze-drying procedure can be applied in basic, clinical, and epidemiological studies.

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  124. Competitive regulation of alternative splicing and alternative polyadenylation by hnRNP H and CstF64 determines acetylcholinesterase isoforms. 査読有り

    Nazim M, Masuda A, Rahman MA, Nasrin F, Takeda JI, Ohe K, Ohkawara B, Ito M, Ohno K

    Nucleic acids research   45 巻 ( 3 ) 頁: 1455-1468   2017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: 10.1093/nar/gkw823

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  125. [Studies on therapeutic strategies for congenital myasthenic syndromes.] 査読有り

    Ohno K

    Clinical calcium   27 巻 ( 3 ) 頁: 421-428   2017年

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

    DOI: CliCa1703421428

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  126. Competitive regulation of alternative splicing and alternative polyadenylation by hnRNP H and CstF64 determines acetylcholinesterase isoforms. 査読有り

    Nazim M, Masuda A, Rahman MA, Nasrin F, Takeda JI, Ohe K, Ohkawara B, Ito M, Ohno K

    Nucleic acids research     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)  

    DOI: 10.1093/nar/gkw823

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  127. Hydrogen-rich water ameliorates bronchopulmonary dysplasia (BPD) in newborn rats. 査読有り

    Muramatsu Y, Ito M, Oshima T, Kojima S, Ohno K

    Pediatric pulmonology   51 巻 ( 9 ) 頁: 928-35   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)  

    DOI: 10.1002/ppul.23386

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  128. Impaired Synaptic Development, Maintenance, and Neuromuscular Transmission in LRP4-Related Myasthenia. 査読有り

    Selcen D, Ohkawara B, Shen XM, McEvoy K, Ohno K, Engel AG

    JAMA neurology   72 巻 ( 8 ) 頁: 889-96   2015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)  

    PubMed

  129. Congenital myasthenic syndrome in Japan: ethnically unique mutations in muscle nicotinic acetylcholine receptor subunits. 査読有り

    Azuma Y, Nakata T, Tanaka M, Shen XM, Ito M, Iwata S, Okuno T, Nomura Y, Ando N, Ishigaki K, Ohkawara B, Masuda A, Natsume J, Kojima S, Sokabe M, Ohno K

    Neuromuscular disorders : NMD   25 巻 ( 1 ) 頁: 60-9   2015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: 10.1016/j.nmd.2014.09.002

    PubMed

  130. HnRNP C, YB-1 and hnRNP L coordinately enhance skipping of human MUSK exon 10 to generate a Wnt-insensitive MuSK isoform. 査読有り

    Nasrin F, Rahman MA, Masuda A, Ohe K, Takeda J, Ohno K

    Scientific reports   4 巻   頁: 6841   2014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: 10.1038/srep06841

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  131. SIL1, a causative cochaperone gene of Marinesco-Söjgren syndrome, plays an essential role in establishing the architecture of the developing cerebral cortex. 査読有り

    Inaguma Y, Hamada N, Tabata H, Iwamoto I, Mizuno M, Nishimura YV, Ito H, Morishita R, Suzuki M, Ohno K, Kumagai T, Nagata K

    EMBO molecular medicine   6 巻 ( 3 ) 頁: 414 - 29   2014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:EMBO Molecular Medicine  

    Marinesco-Sjögren syndrome (MSS) is a rare autosomal recessively inherited disorder with mental retardation (MR). Recently, mutations in the SIL1 gene, encoding a co-chaperone which regulates the chaperone HSPA5, were identified as a major cause of MSS. We here examined the pathophysiological significance of SIL1 mutations in abnormal corticogenesis of MSS. SIL1-silencing caused neuronal migration delay during corticogenesis ex vivo. While RNAi-resistant SIL1 rescued the defects, three MSS-causing SIL1 mutants tested did not. These mutants had lower affinities to HSPA5 in vitro, and SIL1-HSPA5 interaction as well as HSPA5 function was found to be crucial for neuronal migration ex vivo. Furthermore time-lapse imaging revealed morphological disorganization associated with abnormal migration of SIL1-deficient neurons. These results suggest that the mutations prevent SIL1 from interacting with and regulating HSPA5, leading to abnormal neuronal morphology and migration. Consistent with this, when SIL1 was silenced in cortical neurons in one hemisphere, axonal growth in the contralateral hemisphere was delayed. Taken together, abnormal neuronal migration and interhemispheric axon development may contribute to MR in MSS. © 2014 The Authors.

    DOI: 10.1002/emmm.201303069

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  132. HnRNP L and hnRNP LL antagonistically modulate PTB-mediated splicing suppression of CHRNA1 pre-mRNA. 査読有り

    Rahman MA, Masuda A, Ohe K, Ito M, Hutchinson DO, Mayeda A, Engel AG, Ohno K

    Scientific reports   3 巻   頁: 2931   2013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: 10.1038/srep02931

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  133. GFPT1-myasthenia: clinical, structural, and electrophysiologic heterogeneity. 査読有り

    Selcen D, Shen XM, Milone M, Brengman J, Ohno K, Deymeer F, Finkel R, Rowin J, Engel AG

    Neurology   81 巻 ( 4 ) 頁: 370-8   2013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: 10.1212/WNL.0b013e31829c5e9c

    PubMed

  134. Genetic defects and disorders at the neuromuscular junction

    Ohno K.

    Brain and Nerve   63 巻 ( 7 ) 頁: 669 - 678   2011年7月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Brain and Nerve  

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  135. The 2011 Medical Molecular Hydrogen Symposium: An inaugural symposium of the journal Medical Gas Research. 査読有り

    Ohta S, Nakao A, Ohno K

    Medical gas research   1 巻 ( 1 ) 頁: 10 - -   2011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:Medical Gas Research  

    This report summarizes a brief description/history of the Hydrogen Research Meetings as well as key presentations/oral abstracts delivered in the most recent symposium. Additionally, we introduced 38 diseases and physiological states for which hydrogen exhibits beneficial effects. © 2011 Ohta et al; licensee BioMed Central Ltd.

    DOI: 10.1186/2045-9912-1-10

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  136. hnRNP H enhances skipping of a nonfunctional exon P3A in CHRNA1 and a mutation disrupting its binding causes congenital myasthenic syndrome. 査読有り

    Masuda A, Shen XM, Ito M, Matsuura T, Engel AG, Ohno K

    Human molecular genetics   17 巻 ( 24 ) 頁: 4022-35   2008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: 10.1093/hmg/ddn305

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  137. Congenital myasthenia-related AChR delta subunit mutation interferes with intersubunit communication essential for channel gating. 査読有り

    Shen XM, Fukuda T, Ohno K, Sine SM, Engel AG

    The Journal of clinical investigation   118 巻 ( 5 ) 頁: 1867-76   2008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: 10.1172/JCI34527

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  138. Human branch point consensus sequence is yUnAy. 査読有り

    Gao K, Masuda A, Matsuura T, Ohno K

    Nucleic acids research   36 巻 ( 7 ) 頁: 2257-67   2008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)  

    DOI: 10.1093/nar/gkn073

    PubMed

  139. Essential role of GATA transcriptional factors in the activation of mast cells. 査読有り

    Masuda A, Hashimoto K, Yokoi T, Doi T, Kodama T, Kume H, Ohno K, Matsuguchi T

    Journal of immunology (Baltimore, Md. : 1950)   178 巻 ( 1 ) 頁: 360 - 8   2007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:Journal of Immunology  

    Mast cells are pivotal effector cells in IgE-mediated allergic reactions. GATA transcriptional factors such as GATA-1 and GATA-2 are expressed in mast cells, and recent studies have revealed that both GATA-1 and GATA-2 are required for mast cell development. However, the role of GATA transcriptional factors in differentiated mast cells has remained largely unknown. In this study, we repressed the activity of GATA-1 and GATA-2 by using three different approaches (inducible overexpression of a dominant-negative form of GATA, pharmacological inactivation, or small interfering RNA technology), and analyzed the molecular mechanisms of GATA transcriptional factors in the activation of mast cells. Surprisingly, the repression of GATA activity in differentiated mast cells led to the impairment of cell survival, IgE-induced degranulation, and cytokine production. Signal transduction and histone modification in the chromatin related to protein kinase Cβ were defective in these cells. These results identify that GATA has a critical role in the activation of mast cell. Copyright © 2006 by The American Association of Immunologists, Inc.

    DOI: 10.4049/jimmunol.178.1.360

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  140. In vitro and in silico analysis reveals an efficient algorithm to predict the splicing consequences of mutations at the 5' splice sites. 査読有り

    Sahashi K, Masuda A, Matsuura T, Shinmi J, Zhang Z, Takeshima Y, Matsuo M, Sobue G, Ohno K

    Nucleic acids research   35 巻 ( 18 ) 頁: 5995 - 6003   2007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:Nucleic Acids Research  

    We have found that two previously reported exonic mutations in the PINK1 and PARK7 genes affect pre-mRNA splicing. To develop an algorithm to predict underestimated splicing consequences of exonic mutations at the 5′ splice site, we constructed and analyzed 31 minigenes carrying exonic splicing mutations and their derivatives. We also examined 189 249 U2-dependent 5′ splice sites of the entire human genome and found that a new variable, the SD-Score, which represents a common logarithm of the frequency of a specific 5′ splice site, efficiently predicts the splicing consequences of these minigenes. We also employed the information contents (Ri) to improve the prediction accuracy. We validated our algorithm by analyzing 32 additional minigenes as well as 179 previously reported splicing mutations. The SD-Score algorithm predicted aberrant splicings in 198 of 204 sites (sensitivity =97.1%) and normal splicings in 36 of 38 sites (specificity = 94.7%). Simulation of all possible exonic mutations at positions -3, -2 and -1 of the 189 249 sites predicts that 37.8, 88.8 and 96.8% of these mutations would affect pre-mRNA splicing, respectively. We propose that the SD-Score algorithm is a practical tool to predict splicing consequences of mutations affecting the 5′ splice site. © 2007 The Author(s).

    DOI: 10.1093/nar/gkm647

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  141. Splicing abnormalities in congenital myasthenic syndromes

    Ohno K.

    Acta Myologica   24 巻 ( 2 ) 頁: 50 - 54   2005年10月

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

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  142. Gene symbol: CHRNE. Disease: Endplate acetylcholine receptor deficiency.

    Ohno K.

    Human genetics   117 巻 ( 2-3 )   2005年7月

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

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  143. Gene symbol: CHRNE. Disease: Endplate acetylcholine receptor deficiency.

    Ohno K.

    Human genetics   117 巻 ( 2-3 )   2005年7月

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

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  144. Gene symbol: CHRNE. Disease: Endplate acetylcholine receptor deficiency.

    Ohno K.

    Human genetics   117 巻 ( 2-3 )   2005年7月

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

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  145. Subunit-specific contribution to agonist binding and channel gating revealed by inherited mutation in muscle acetylcholine receptor M3-M4 linker. 査読有り

    Shen XM, Ohno K, Sine SM, Engel AG

    Brain : a journal of neurology   128 巻 ( Pt 2 ) 頁: 345 - 55   2005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:Brain  

    We trace the cause of congenital myasthenic syndromes in two patients to mutations in the ε subunit of the muscle acetylcholine receptor (AChR). Both patients harbour deletion of an asparagine residue in the ε subunit (sN436del) at the C-terminus of the cytoplasmic loop linking the third (M3) and fourth (M4) transmembrane domains. The presence of a null mutation in the second allele of the ε subunit shows that εN346del determines the phenotype. Endplate studies show markedly reduced expression of the εN346del-AChR and compensatory accumulation of fetal γ-AChR. Expression studies in HEK cells reveal decreased expression of γN436del-AChR and abnormally brief channel openings. Thus, neuromuscular transmission is compromised by AChR deficiency, fast channel kinetics of the εN346del-AChR and incomplete phenotypic rescue by γ-AChR. Single-channel kinetic analysis shows that the εN436del shortens channel openings by reducing stability of the diliganded receptor: rates of channel closing and of ACh dissociation are increased and the rate of channel opening is decreased. In addition to shortening the M3-M4 loop, εN436del shifts a negatively charged aspartic acid residue adjacent to M4; the effects of εN436del are shown to result from shortening of the M3-M4 loop and not from juxtaposition of a negative charge to M4. To determine whether the consequences of εN346del are subunit-specific, we deleted residues that align with εN436 in β, δ and α subunits. Each deletion mutant reduces AChR expression, but whereas the β and δ mutants curtail channel open duration, the α mutant strikingly prolongs open duration. Kinetic analysis reveals that the α mutant increases the stability of the diliganded receptor: rates of channel closing and of ACh dissociation are decreased and the rate of channel opening is increased. The overall studies reveal subunit asymmetry in the contributions of the M3-M4 loops in optimizing AChR activation through allosteric links to the channel and the agonist binding site.

    DOI: 10.1093/brain/awh364

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  146. Molecular insights into acetylcholine receptor structure and function revealed by mutations causing congenital myasthenic syndromes

    Sine S.

    Advances in Molecular and Cell Biology   32 巻   頁: 95 - 119   2004年12月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Advances in Molecular and Cell Biology  

    DOI: 10.1016/S1569-2558(03)32005-3

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  147. Novel truncating RAPSN mutations causing congenital myasthenic syndrome responsive to 3,4-diaminopyridine. 査読有り

    Banwell BL, Ohno K, Sieb JP, Engel AG

    Neuromuscular disorders : NMD   14 巻 ( 3 ) 頁: 202-7   2004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)  

    DOI: 10.1016/j.nmd.2003.11.004

    PubMed

  148. Myofibrillar myopathy: clinical, morphological and genetic studies in 63 patients. 査読有り

    Selcen D, Ohno K, Engel AG

    Brain : a journal of neurology   127 巻 ( Pt 2 ) 頁: 439-51   2004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: 10.1093/brain/awh052

    PubMed

  149. A frameshifting mutation in CHRNE unmasks skipping of the preceding exon. 査読有り

    Ohno K, Milone M, Shen XM, Engel AG

    Human molecular genetics   12 巻 ( 23 ) 頁: 3055 - 66   2003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: 10.1093/hmg/ddg334

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  150. Congenital myasthenic syndromes: multiple molecular targets at the neuromuscular junction. 査読有り

    Engel AG, Ohno K, Shen XM, Sine SM

    Annals of the New York Academy of Sciences   998 巻   頁: 138-60   2003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)  

    PubMed

  151. Mechanistic diversity underlying fast channel congenital myasthenic syndromes. 査読有り

    Sine SM, Wang HL, Ohno K, Shen XM, Lee WY, Engel AG

    Annals of the New York Academy of Sciences   998 巻   頁: 128-37   2003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)  

    PubMed

  152. Myasthenic syndrome caused by mutation of the SCN4A sodium channel. 査読有り

    Tsujino A, Maertens C, Ohno K, Shen XM, Fukuda T, Harper CM, Cannon SC, Engel AG

    Proceedings of the National Academy of Sciences of the United States of America   100 巻 ( 12 ) 頁: 7377 - 82   2003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: 10.1073/pnas.1230273100

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  153. Sleuthing molecular targets for neurological diseases at the neuromuscular junction. 査読有り

    Engel AG, Ohno K, Sine SM

    Nature reviews. Neuroscience   4 巻 ( 5 ) 頁: 339 - 52   2003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: 10.1038/nrn1101

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  154. E-box mutations in the RAPSN promoter region in eight cases with congenital myasthenic syndrome. 査読有り

    Ohno K, Sadeh M, Blatt I, Brengman JM, Engel AG

    Human molecular genetics   12 巻 ( 7 ) 頁: 739-48   2003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)  

    PubMed

  155. Mutation causing severe myasthenia reveals functional asymmetry of AChR signature cystine loops in agonist binding and gating.

    Shen XM, Ohno K, Tsujino A, Brengman JM, Gingold M, Sine SM, Engel AG

    The Journal of clinical investigation   111 巻 ( 4 ) 頁: 497 - 505   2003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: 10.1172/JCI16997

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  156. Congenital myasthenic syndromes: progress over the past decade. 査読有り

    Engel AG, Ohno K, Sine SM

    Muscle & nerve   27 巻 ( 1 ) 頁: 4-25   2003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: 10.1002/mus.10269

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  157. Congenital myasthenic syndromes: A diverse array of molecular targets

    Engel AG, Ohno K, Sine SM

    JOURNAL OF NEUROCYTOLOGY   32 巻 ( 5-8 ) 頁: 1017-1037   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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  158. Naturally occurring mutations at the acetylcholine receptor binding site independently alter ACh binding and channel gating. 査読有り

    Sine SM, Shen XM, Wang HL, Ohno K, Lee WY, Tsujino A, Brengmann J, Bren N, Vajsar J, Engel AG

    The Journal of general physiology   120 巻 ( 4 ) 頁: 483-96   2002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)  

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  159. Congenital myasthenic syndrome associated with episodic apnea and sudden infant death

    Byring RF, Pihko H, Tsujino A, Shen XM, Gustafsson B, Hackman P, Ohno K, Engel AG, Udd B

    NEUROMUSCULAR DISORDERS   12 巻 ( 6 ) 頁: 548-553   2002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)  

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  160. Rapsyn mutations in humans cause endplate acetylcholine-receptor deficiency and myasthenic syndrome

    Ohno K, Engel AG, Shen XM, Selcen D, Brengman J, Harper CM, Tsujino A, Milone M

    AMERICAN JOURNAL OF HUMAN GENETICS   70 巻 ( 4 ) 頁: 875-885   2002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)  

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  161. The spectrum of congenital myasthenic syndromes

    Engel AG, Ohno K, Sine SM

    MOLECULAR NEUROBIOLOGY   26 巻 ( 2-3 ) 頁: 347-367   2002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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  162. A modified alignment of human and rodent 5 ' untranslated sequences of the acetylcholine receptor epsilon subunit gene reveals additional regions of high homology - Reply

    Ohno K, Anlar B, Engel AG

    NEUROMUSCULAR DISORDERS   10 巻 ( 3 ) 頁: 214-214   2000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)  

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  163. Molecular basis of congenital myasthenic syndromes: Mutations in the acetylcholine receptor

    Engel AG, Ohno K, Wang HL, Milone M, Sine SM

    NEUROSCIENTIST   4 巻 ( 3 ) 頁: 185-194   1998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)  

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  164. Genetic profiles of three inbred strains derived from wild rats (Rattus norvegicus) trapped in Japan

    Kondo Y, Ohno K, Oda S, Serikawa T

    EXPERIMENTAL ANIMALS   45 巻 ( 4 ) 頁: 405 - 409   1996年10月

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  165. Mapping of the dilute-opisthotonus (dop) gene on chromosome 8 of the rat

    Ohno K, Kanou Y, Oda S, Wakasugi N, Inouye M, Yamamura H

    EXPERIMENTAL ANIMALS   45 巻 ( 1 ) 頁: 71 - 75   1996年1月

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  166. MITOCHONDRIAL-DNA DELETIONS IN INHERITED RECURRENT MYOGLOBINURIA

    OHNO K, TANAKA M, SAHASHI K, IBI T, SATO W, YAMAMOTO T, TAKAHASHI A, OZAWA T

    ANNALS OF NEUROLOGY   29 巻 ( 4 ) 頁: 364 - 369   1991年4月

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    掲載種別:研究論文(学術雑誌)  

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  167. MITOCHONDRIAL-DNA MUTATIONS IN MITOCHONDRIAL MYOPATHY, ENCEPHALOPATHY, LACTIC-ACIDOSIS, AND STROKE-LIKE EPISODES (MELAS)

    TANAKA M, INO H, OHNO K, OHBAYASHI T, IKEBE S, SANO T, ICHIKI T, KOBAYASHI M, WADA Y, OZAWA T

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   174 巻 ( 2 ) 頁: 861 - 868   1991年1月

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  168. QUANTITATIVE-DETERMINATION OF DELETED MITOCHONDRIAL-DNA RELATIVE TO NORMAL DNA IN PARKINSONIAN STRIATUM BY A KINETIC PCR ANALYSIS

    OZAWA T, TANAKA M, IKEBE S, OHNO K, KONDO T, MIZUNO Y

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   172 巻 ( 2 ) 頁: 483 - 489   1990年10月

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  169. INCREASE OF DELETED MITOCHONDRIAL-DNA IN THE STRIATUM IN PARKINSONS-DISEASE AND SENESCENCE

    IKEBE S, TANAKA M, OHNO K, SATO W, HATTORI K, KONDO T, MIZUNO Y, OZAWA T

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   170 巻 ( 3 ) 頁: 1044 - 1048   1990年8月

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    掲載種別:研究論文(学術雑誌)  

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  170. DIRECT SEQUENCING OF DELETED MITOCHONDRIAL-DNA IN MYOPATHIC PATIENTS

    TANAKA M, SATO W, OHNO K, YAMAMOTO T, OZAWA T

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   164 巻 ( 1 ) 頁: 156 - 163   1989年10月

     詳細を見る

    掲載種別:研究論文(学術雑誌)  

    Web of Science

  171. MULTIPLE POPULATIONS OF DELETED MITOCHONDRIAL-DNA DETECTED BY A NOVEL GENE AMPLIFICATION METHOD

    SATO W, TANAKA M, OHNO K, YAMAMOTO T, TAKADA G, OZAWA T

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   162 巻 ( 2 ) 頁: 664 - 672   1989年7月

     詳細を見る

    掲載種別:研究論文(学術雑誌)  

    Web of Science

  172. CRYOPRESERVATION OF STRAINS AND MUTANT-GENES IN MICE

    YOSHIKI A, OHNO K, WAKASUGI N

    EXPERIMENTAL ANIMALS   36 巻 ( 4 ) 頁: 379 - 386   1987年10月

     詳細を見る

    掲載種別:研究論文(学術雑誌)  

    Web of Science

▼全件表示

書籍等出版物 47

  1. Decoding abnormal splicing code in human diseases

    Rahman MA, Nasrin F, Masuda A, Ohno K. ( 担当: 共著)

    J Invest Genomics   2015年 

     詳細を見る

    記述言語:英語

  2. Intestinal dysbiosis and lowered serum lipopolysaccharide-binding protein in Parkinson's disease

    Hasegawa S, Goto S, Tsuji H, Okuno T, Asahara T, Nomoto K, Shibata A, Fujisawa Y, Okamoto A, Ohno K, Hirayama M. ( 担当: 共著)

    PLoS One  2015年 

     詳細を見る

    記述言語:英語

  3. Beneficial biological effects and the underlying mechanisms of molecular hydrogen - Comprehensive review of 321 original articles -

    Ichihara M, Sobue S, Ito M, Ito M, Hirayama M, Ohno K. ( 担当: 共著)

    Med Gas Res   2015年 

     詳細を見る

    記述言語:英語

  4. Collagen Q is a key player for developing rational therapy for congenital myasthenia andfor dissecting the mechanisms of anti-MuSK myasthenia gravis

    Ohno, K. and Ito, M. and Kawakami, Y.( 担当: 共著)

    J Mol Neurosci  2014年 

     詳細を見る

    記述言語:英語

  5. Molecular Genetics of Congenital Myasthenic Syndromes

    Ohno K, Ohkawara B, Ito M, Engel AG. ( 担当: 共著)

    John Wiley & Sons, Inc.  2014年 

     詳細を見る

    記述言語:英語

  6. Mutation analysis of a large cohort of GNE myopathy reveals a diverse array of GNE mutations affecting sialic acid biosynthesis

    Ohno, K.( 担当: 単著)

    J Neurol Neurosurg Psychiatry   2014年 

     詳細を見る

    記述言語:英語

  7. Multiple effects of molecular hydrogen and its distinct mechanism

    Noda M, Fujita K, Ohsawa I, Ito M, Ohno K.( 担当: 共著)

    J Neurol Disord  2014年 

     詳細を見る

    記述言語:英語

  8. Beneficial effects of hydrogen in the CNS and a new brain-stomach interaction

    Noda M, Ito M, Ohsawa I, Ohno K.( 担当: 共著)

    Eur J Neurodeg Dis   2014年 

     詳細を見る

    記述言語:英語

  9. Specific binding of collagen Q to the neuromuscular junction is exploited to cure congenital myasthenia and to explore bases of myasthenia gravis

    Ohno, K. and Ito, M. and Kawakami, Y. and Krejci, E. and Engel, A. G.( 担当: 共著)

    Chem Biol Interact  2013年 

     詳細を見る

    記述言語:英語

  10. Intronic and exonic nucleotide variations that affect RNA splicing in humans

    Ohe, K. and Masuda, A. and Ohno, K.( 担当: 共著)

    iConcept Press  2013年 

     詳細を見る

    記述言語:英語

  11. Glycosylation defects as an emerging novel cause leading to a limb-girdle type of congenital myasthenic syndromes

    Ohno, K.( 担当: 単著)

    J Neurol Neurosurg Psychiatry   2013年 

     詳細を見る

    記述言語:英語

  12. Molecular Hydrogen as an Emerging Therapeutic Medical Gas for Neurodegenerative and Other Diseases

    Ohno, K. and Ito, M. and Ichihara, M. and Ito, M.( 担当: 共著)

    Hindawi Publishing Corp.  2012年 

     詳細を見る

    記述言語:英語

  13. Congenital myasthenic syndromes

    Engel, A. G. and Shen, X-M. and Ohno, K. and Sine, S. M.( 担当: 共著)

    Oxford University Press  2012年 

     詳細を見る

    記述言語:英語

  14. Congenital Myasthenic Syndromes -Molecular Bases of Congenital Defects of Proteins at the Neuromuscular Junction-

    Ohno, K. and Ito, M. and Engel, A. G.( 担当: 共著)

    InTech  2012年 

     詳細を見る

    記述言語:英語

  15. The 2011 Medical Molecular Hydrogen Symposium: An inaugural symposium of the journal Medical Gas Research

    Ohta, S. and Nakao, A. and Ohno, K.( 担当: 共著)

    Med Gas Res  2011年 

     詳細を見る

    記述言語:英語

  16. Molecular defects of acetylcholine receptor subunits in congenital myasthenic syndromes

    Ohno, K. and Engel, A. G. ( 担当: 共著)

    Research Signpost  2011年 

     詳細を見る

    記述言語:英語

  17. RNA pathologies in neurological disorders

    Ohno, K. and Masuda, A.( 担当: 共著)

    Springer  2011年 

     詳細を見る

    記述言語:英語

  18. Splicing abnormalities in congenital myasthenic syndromes

    Ohno, K. and Engel, A. G.( 担当: 共著)

    Acta Myol  2005年 

     詳細を見る

    記述言語:英語

  19. Molecular Insights into Acetylcholine Receptor Structure and Function Revealed by Mutations Causing Congenital Myasthenic Syndromes

    Sine, S. M. and Engel, A. G. and Wang, H-L. and Ohno, K.( 担当: 共著)

    Elsevier Science  2004年 

     詳細を見る

    記述言語:英語

  20. Congenital myasthenic syndromes (Chapter 66)

    Engel, A. G. and Ohno, K. and Sine, S. M.( 担当: 共著)

    McGraw Hill  2004年 

     詳細を見る

    記述言語:英語

  21. Mechanistic diversity underlying fast channel congenital myasthenic syndromes

    Sine, S. M. and Wang, H. L. and Ohno, K. and Shen, X. M. and Lee, W. Y. and Engel, A. G.( 担当: 共著)

    Ann N Y Acad Sci  2003年 

     詳細を見る

    記述言語:英語

  22. Congenital myasthenic syndromes

    Engel, A. G. and Ohno, K. and Harper, C. M.( 担当: 共著)

    Butterworth and Heinemann  2003年 

     詳細を見る

    記述言語:英語

  23. Congenital myasthenic syndromes: Multiple molecular targets at the neuromuscular junction

    Engel, A. G. and Ohno, K. and Shen, X. M. and Sine, S. M.( 担当: 共著)

    Myasthenia Gravis and Related Disorders  2003年 

     詳細を見る

    記述言語:英語

  24. Congenital myasthenic syndromes: A diverse array of molecular targets

    Engel, A. G. and Ohno, K. and Sine, S. M.( 担当: 共著)

    J Neurocytol  2003年 

     詳細を見る

    記述言語:英語

  25. Congenital myasthenic syndromes: progress over the past decade

    Engel, A. G. and Ohno, K. and Sine, S. M.( 担当: 共著)

    Muscle Nerve  2003年 

     詳細を見る

    記述言語:英語

  26. Sleuthing molecular targets for neurological diseases at the neuromuscular junction

    Engel, A. G. and Ohno, K. and Sine, S. M.( 担当: 共著)

    Nat Rev Neurosci  2003年 

     詳細を見る

    記述言語:英語

  27. Congenital myasthenic syndromes: genetic defects of the neuromuscular junction

    Ohno, K. and Engel, A. G.( 担当: 共著)

    Curr Neurol Neurosci Rep  2002年 

     詳細を見る

    記述言語:英語

  28. Congenital myasthenic syndromes (Chapter 13)

    Engel, A. G. and Ohno, K.( 担当: 共著)

    Lippincott Williams & Wilkins  2002年 

     詳細を見る

    記述言語:英語

  29. Congenital Myasthenic Syndromes

    Engel, A. G. and Ohno, K. and Selcen, D.( 担当: 共著)

    International Society of Neuropathology/World Federation of Neurology. ISN Neuropath Press  2002年 

     詳細を見る

    記述言語:英語

  30. The spectrum of congenital myasthenic syndromes

    Engel, A. G. and Ohno, K. and Sine, S. M.( 担当: 共著)

    Mol Neurobiol  2002年 

     詳細を見る

    記述言語:英語

  31. Acetylcholine receptor channelopathies and other congenital myasthenic syndromes (Chapter 12)

    Engel, A. G. and Ohno, K. and Sine, S. M.( 担当: 共著)

    Butterworth and Heinemann  2001年 

     詳細を見る

    記述言語:英語

  32. Congenital myasthenic syndromes

    Engel, A. G. and Ohno, K. and Stans, A. A.( 担当: 共著)

    Karger  2000年 

     詳細を見る

    記述言語:英語

  33. Congenital myasthenic syndromes in the molecular era

    Engel, A. G. and Ohno, K. and Shen, X. M. and Milone, M. and Tsujino, A.( 担当: 共著)

    Acta Myologica  2000年 

     詳細を見る

    記述言語:英語

  34. Congenital myasthenic syndromes: recent advances

    Engel, A. G. and Ohno, K. and Sine, S. M.( 担当: 共著)

    Arch Neurol  1999年 

     詳細を見る

    記述言語:英語

  35. Congenital myasthenic syndromes (Chapter 11)

    Engel, A. G. and Ohno, K. and Sine, S. M.( 担当: 共著)

    Oxford University Press  1999年 

     詳細を見る

    記述言語:英語

  36. Molecular basis of congenital myasthenic syndromes: Mutations in the acetylcholine receptor

    Engel, A. G. and Ohno, K. and Wang, H. L. and Milone, M. and Sine, S. M.( 担当: 共著)

    Neuroscientist  1998年 

     詳細を見る

    記述言語:英語

  37. Congenital myasthenic syndromes. New insights from molecular genetic and patch-clamp studies

    Engel, A. G. and Ohno, K. and Milone, M. and Sine, S. M.( 担当: 共著)

    Ann N Y Acad Sci  1998年 

     詳細を見る

    記述言語:英語

  38. Congenital myasthenic syndromes: experiments of nature

    Engel, A. G. and Ohno, K. and Sine, S. M.( 担当: 共著)

    J Physiol Paris  1998年 

     詳細を見る

    記述言語:英語

  39. Congenital myasthenic syndromes from mutations in acetylcholine receptor genes

    Engel, A. G. and Ohno, K. and Milone, M. and Sine, S. M.( 担当: 共著)

    Neurology  1997年 

     詳細を見る

    記述言語:英語

  40. Mitochondrial DNA mutations in idiopathic cardiomyopathy and in presbycardia

    Tanaka, M. and Hattori, K. and Ito, H. and Ohbayashi, T. and Ohno, K. and Sato, W. and Sugiyama, S. and Ozawa, T.( 担当: 共著)

    Raven Press  1991年 

     詳細を見る

    記述言語:英語

  41. Mitochondrial DNA disease: phylogeny and expression

    Ozawa, T. and Tanaka, M. and Hayakawa, M. and Sugiyama, S. and Ino, H. and Sato, W. and Ohno, K. and Ikebe, S. and Yoneda, M.( 担当: 共著)

    Academic Press  1991年 

     詳細を見る

    記述言語:英語

  42. Mitochondrial DNA mutations: types, mechanism and expression

    Ozawa, T. and Tanaka, M. and Hayakawa, M. and Sugiyama, S. and Sato, W. and Ohno, K. and Ikebe, S. and Yoneda, M.( 担当: 共著)

    Raven Press  1991年 

     詳細を見る

    記述言語:英語

  43. Diseases caused by mitochondrial DNA mutations: types and mechanism

    Ozawa, T. and Tanaka, M. and Sato, W. and Ohno, K. and Yoneda, M.( 担当: 共著)

    Jpn. Soc. Neuropathol.  1991年 

     詳細を見る

    記述言語:英語

  44. Types and mechanism of mitochondrial DNA mutations in mitochondrial myopathy and related diseases

    Ozawa, T. and Tanaka, M. and Sato, W. and Ohno, K. and Yoneda, M. and Yamamoto, T.( 担当: 共著)

    Chapman and Hall  1991年 

     詳細を見る

    記述言語:英語

  45. Visceral myopathy with external ophthalmoplegia and multiple mitochondrial DNA deletions

    Sahashi, K. and Ibi, T. and Ohno, K. and Tanaka, M. and Tashiro, M. and Tsuchiya, I. and Nakao, M. and Yuasa, K. and Mitsuma, T. and Takahashi, A. and Ozawa, T.( 担当: 共著)

    Elsevier Science Publishers  1991年 

     詳細を見る

    記述言語:英語

  46. S1 nuclease analysis and direct sequencing of deleted mitochondrial DNA in myopathic patients: Role of directly repeated sequences in deletion

    Tanaka, M, . and Sato, W. and Ohno, K. and Yamamoto, T. and Ozawa, T.( 担当: 共著)

    Plenum  1990年 

     詳細を見る

    記述言語:英語

  47. Mitochondrial DNA mutations as an etiology of human degenerative diseases

    Ozawa, T. and Tanaka, M. and Sato, W. and Ohno, K. and Sugiyama, S. and Yoneda, M. and Yamamoto, T. and Hattori, K. and Ikebe, S. and Tashiro, M. and Sahashi, K.( 担当: 共著)

    Plenum  1990年 

     詳細を見る

    記述言語:英語

▼全件表示

講演・口頭発表等 97

  1. Anti-MuSK antibodies in myasthenia gravis block binding of collagen Q to MuSK expressed at the neuromuscular junction 国際会議

    Kawakami Y, Ito M, Hirayama M, Sahashi K, Ohkawara B, Masuda A, Hishida H, Mabuchi N, Engel AG, Ohno K

    41st Annual Meeting, Society for Neuroscience 

     詳細を見る

    開催年月日: 2011年11月

    記述言語:英語   会議種別:口頭発表(一般)  

  2. Glut1 deficiency syndrome with a SLC2A1 splice site mutation and normal erythrocyte glucose uptake 国際会議

    Ishihara N, Azuma Y, Yanagihara K, Yokoi S, Nakata T, Aso K, Ohno K, Natsume J

    12th International congress of human genetics 

     詳細を見る

    開催年月日: 2011年10月

    記述言語:英語   会議種別:口頭発表(一般)  

  3. Genome-wide analysis of RNA-binding sites of HuR 国際会議

    Masuda A, Ito M, Fujita Y, Ohno K

    16th Annual Meeting of the RNA Society 

     詳細を見る

    開催年月日: 2011年6月

    記述言語:英語   会議種別:口頭発表(一般)  

  4. Protein-anchoring therapy for delivering acetylcholinesterase to the neuromuscular junction 国際会議

    Ito M, Suzuki Y, Okada T, Fukudome T, Yoshimura T, Masuda A, Takeda S, Krejci E, Ohno K

    4th International Congress of Myology 

     詳細を見る

    開催年月日: 2011年5月

    記述言語:英語   会議種別:口頭発表(招待・特別)  

  5. The role of Rspo3 in head cartilage morphogenesis 国際会議

    Ohkawara B, Ohno K, Niehrs C

    16th International Conference of the International Society of Differentiation 

     詳細を見る

    開催年月日: 2010年11月

    記述言語:英語   会議種別:口頭発表(一般)  

  6. Mutations at the C-terminal domain (CTD)of collagen Q (ColQ) causing acetylcholinesterase (AChE) deficiency prevent anchoring of ColQ to the neuromuscular junction (NMJ) 国際会議

    Sugiyama A, Ito M, Nakata T, Azuma Y, Masuda A, Okumura A, Komaki H, Ohno K

    40th Annual Meeting, Society for Neuroscience 

     詳細を見る

    開催年月日: 2010年11月

    記述言語:英語   会議種別:口頭発表(一般)  

  7. rAAV8-Mediated Protein-Anchoring Therapy for Targeting Collagen Q-Tailed Acetylcholinesterase to the Neuromuscular Junction 国際会議

    Ito M, Suzuki Y, Okada T, Fukudome T, Yoshimura T, Masuda A, Takeda S, Krejci E, Ohno K

    American Society of Gene & Cell Therapy 13th Annual Meeting 

     詳細を見る

    開催年月日: 2010年5月

    記述言語:英語   会議種別:口頭発表(一般)  

  8. A mutation on a nonfunctional exon P3A in CHRNA1 identified in a patient with congenital myasthenic syndrome loses binding affinity for a splicing-suppressing hnRNP L and gains binding affinity for a splicing-enhancing hnRNP LL

    Rahman MA, Masuda A, Ito M, Ohno K

    2nd GCOE International Symposium 

     詳細を見る

    開催年月日: 2009年11月

    記述言語:英語   会議種別:口頭発表(一般)  

  9. Degeneracy of splicing cis-elements and tolerance to disease-causing mutations

    Ohno K

    2nd GCOE International Symposium 

     詳細を見る

    開催年月日: 2009年11月

    記述言語:英語   会議種別:口頭発表(招待・特別)  

  10. Aberrantly spliced genes in human diseases - a deep sequencing approach

    Andersen HS, Docter TK, Serup J, Sundahl L, Masuda A, Ohno K,resen BS

    2nd GCOE International Symposium 

     詳細を見る

    開催年月日: 2009年11月

    記述言語:英語   会議種別:口頭発表(一般)  

  11. AG-independence of the 3' splice site determines tolerance to aberrant splicing due to a mutation at the first nucleotide of an exon

    Fu Y, Masuda A, Ito M, Ohno K

    2nd GCOE International Symposium 

     詳細を見る

    開催年月日: 2009年11月

    記述言語:英語   会議種別:口頭発表(一般)  

  12. Exploratory analyses of gene expression profile and aberrant splicing in schizophrenia using exon array 国際会議

    Ito Y, Yamada S, Aleksic B, Kushima I, Nakamura Y, Yoshimi A, Nagai T, Noda Y, Ohno K, Ozaki N

    XVII World Congress of Psychiatric Genetics 

     詳細を見る

    開催年月日: 2009年11月

    記述言語:英語   会議種別:口頭発表(招待・特別)  

  13. Misregulation of diacylglycerol kinase eta (DGKη) splicing as a potential cause of neuropsychiatric symptoms in myotonic dystrophy type 1 国際会議

    Matsuura T, Amakusa Y, Yamashita Y, Shinmi J, Kurosaki T, Kinoshita M, Aizawa H, Kimura T, Yahara O, Abe K, Ohno K

    7th International Myotonic Dystrophy Consortium Meeting 

     詳細を見る

    開催年月日: 2009年9月

    記述言語:英語   会議種別:口頭発表(一般)  

  14. Molecular mechanisms and regulations of congenital neuromuscular transmission defects 国際会議

    Ohno K

    Université Paris Descartes Séminaire 

     詳細を見る

    開催年月日: 2009年7月

    記述言語:英語   会議種別:口頭発表(招待・特別)  

  15. Protein anchoring therapy for endplate acetylcholinesterase deficiency 国際会議

    Ohno K, Ito M, Suzuki Y, Okada T, Fukudome T, Yoshimura T, Takeda S, Krejci E.

    Eighth French-Japanese Workshop on Muscular Dystrophies 

     詳細を見る

    開催年月日: 2009年7月

    記述言語:英語   会議種別:口頭発表(招待・特別)  

  16. 分子状水素は6-OHDA誘発性パーキンソン病モデルのドパミン神経細胞死を抑制する

    付源、伊藤美佳子、藤田泰典、伊藤雅史、市原正智、増田章男、鈴木優美、前澤聡、梶田泰一、平山正昭、大澤郁朗、太田成男、大野欽司

     詳細を見る

    開催年月日: 2009年5月

    記述言語:日本語  

  17. Molecular Hydrogen as an Antioxidant - Review and our experience -

    Ohno K

    University of Fukui Biomedical Imaging Research Center Research seminar 

     詳細を見る

    開催年月日: 2009年2月

    記述言語:英語   会議種別:口頭発表(招待・特別)  

  18. Degeneracy of Splicing Cis-Elements and Tolerance to Disease-Causing Mutations in Human

    Ohno K

    "The expanding world of post-transcriptional regulation of gene expression" 

     詳細を見る

    開催年月日: 2008年12月

    記述言語:英語   会議種別:口頭発表(招待・特別)  

  19. rAAV8-mediated protein anchoring therapy for congenital defect of collagen Q

    14th annual meeting of the Japan Society of Gene Therapy, Sapporo, Hokkaido, Japan June 12-14, 2008 

     詳細を見る

    開催年月日: 2008年6月

    記述言語:日本語  

  20. 先天性筋無力症候群および他の神経筋疾患におけるRNAスプライシング異常症

    大野欽司

    順天堂大学細胞生物学セミナー 東京 

     詳細を見る

    開催年月日: 2007年9月

    記述言語:日本語   会議種別:口頭発表(招待・特別)  

    国名:日本国  

  21. 教育講演「神経・筋疾患におけるRNA病態」

    第48回日本神経学会総会 名古屋市 

     詳細を見る

    開催年月日: 2007年5月

    記述言語:日本語   会議種別:口頭発表(招待・特別)  

    国名:日本国  

  22. 招待講演「先天性筋無力症候群の分子病態」

    大野欽司

    長崎MG講演会 長崎市 

     詳細を見る

    開催年月日: 2007年2月

    記述言語:日本語   会議種別:口頭発表(招待・特別)  

    国名:日本国  

  23. Exploring the consensus sequence of the intronic branch point in humans

    MBSJ 2006 Forum: Molecular Biology - The Next Decade -Conference&Scientific Exhibition-, Nagoya, Aichi, Japan 

     詳細を見る

    開催年月日: 2006年12月

    記述言語:日本語  

    国名:日本国  

  24. Pathomechanisms of congenital defects of neuromuscular signal transduction -Progress of therapies against intractable muscular diseases-

    Ohno K

    Fujita Health University COE International Workshop 

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    開催年月日: 2006年12月

    記述言語:英語   会議種別:口頭発表(招待・特別)  

  25. 招待講演「予期せぬpre-mRNA異常症 -自験例の解析とsplicing異常予測アルゴリズムの構築―」

    大野欽司

    第2回神戸スプライシングカンファレンス 神戸市 

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    開催年月日: 2006年11月

    記述言語:日本語   会議種別:口頭発表(招待・特別)  

    国名:日本国  

  26. 教育講演「先天性神経筋伝達分子欠損症のRNA・タンパク病態」

    大野欽司

    第49回日本神経化学会大会 名古屋市 

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    開催年月日: 2006年9月

    記述言語:日本語   会議種別:口頭発表(招待・特別)  

    国名:日本国  

  27. 56. 大野欽司.特別講演「神経筋接合部欠損の臨床と分子病態 ー重症筋無力症と先天性筋無力症候群ー」

    大野欽司

    第25回日本小児神経学会東海地方会 名古屋市 

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    開催年月日: 2006年7月

    記述言語:日本語   会議種別:口頭発表(招待・特別)  

    国名:日本国  

  28. イントロン5’末端の+4、+5、+6位塩基がU1 snRNAに相補ではない時、エキソン3’末端領域の点変異はスプライシング変異になる

    佐橋健太郎、新見淳、祖父江元、大野欽司

    第8回RNAミーティング 淡路市、日本 

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    開催年月日: 2006年7月

    記述言語:日本語  

    国名:日本国  

  29. 55. 大野欽司.シンポジウム「RNA発現調節異常の一因としてのpre-mRNA splicing異常症」

    大野欽司

    第95回日本病理学会総会 東京 

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    開催年月日: 2006年5月

    記述言語:日本語   会議種別:口頭発表(招待・特別)  

    国名:日本国  

  30. モーニングレクチャー「神経筋接合部分子欠損症の分子病態」

    大野欽司

    第18回日本神経免疫学会学術集会 名古屋市 

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    開催年月日: 2006年3月

    記述言語:日本語   会議種別:口頭発表(招待・特別)  

    国名:日本国  

  31. Underestimated aberrant splicings in neuromuscular disorders.

    MEXT Grant-in-Aid for Scientific Research on Priority Areas“Spaciotemporal Network of RNA Information Flow" International Symposium 2005 

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    開催年月日: 2005年8月

    記述言語:英語  

    国名:日本国  

    Hirosaki, Japan

  32. Underestimated aberrant splicings in neuromuscular disorders

    Ohno K

    MEXT Grant-in-Aid for Scientific Research on Priority Areas "Spaciotemporal Network of RNA Information Flow" International Symposium 2005 

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    開催年月日: 2005年8月

    記述言語:英語   会議種別:口頭発表(招待・特別)  

  33. Splicing abnormalities in congenital myasthenic syndromes 国際会議

    Sixth French-Japanese Workshop on Muscular Dystrophies “Further progress toward therapy for muscular dystrophies" 

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    開催年月日: 2005年7月

    記述言語:英語  

  34. Splicing abnormalities in congenital myasthenic syndromes 国際会議

    Ohno K, Engel AG

    Sixth French-Japanese Workshop on Muscular Dystrophies "Further progress toward therapy for muscular dystrophies" 

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    開催年月日: 2005年7月

    記述言語:英語   会議種別:口頭発表(招待・特別)  

  35. Unusual splicing abnormalities in congenital myasthenic syndromes

    1st Kobe Conference on Splicing 

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    開催年月日: 2005年6月

    記述言語:英語  

    国名:日本国  

    Kobe, Japan

  36. 先天性筋無力症候群の診断・治療・分子病態

    大野欽司.

    第12回メイヨーニューロサイエンスフォーラム 

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    開催年月日: 2005年5月

    記述言語:日本語  

    国名:日本国  

    鹿児島、日本

  37. 教育講演「ポリモルフィズムのmRNA代謝とタンパク機能に与える影響の解析」

    大野欽司.

    第6回日本がん分子疫学研究会学術総会 

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    開催年月日: 2005年5月

    記述言語:日本語  

    国名:日本国  

  38. 神経筋接合部分子欠損症のタンパク病態とRNA病態

    大野欽司.

    第14回東海ニューロサイエンス研究会 

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    開催年月日: 2005年4月

    記述言語:日本語  

    国名:日本国  

  39. Congenital myasthenic syndromes: Multiple molecular targets at the neuromuscular junction 国際会議

    Engel AG, Ohno K, Sine SM

    XIth International Symposium on Cholinergic Mechanisms 

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    開催年月日: 2002年5月

    記述言語:英語   会議種別:口頭発表(招待・特別)  

  40. How does an A-to-G splice donor site mutation at position +3 result in aberrant splicing? A lesson learned from a mutation in the COLQ gene 国際会議

    Ohno K, Brengman JM, Engel AG

    49th Annual Meeting of the American Society of Human Genetics 

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    開催年月日: 1999年10月

    記述言語:英語   会議種別:口頭発表(一般)  

  41. Congenital endplate acetylcholinesterase deficiency caused by nonsense, splice-site, missense mutations in the collagenic tail subunit of asymmetric AChE 国際会議

    Ohno K, Brengman, JM, Nakano S, Walsh P, Heidenrich F, Vincent A, Nagwany S, Engel AG

    51st Annual Meeting of the American Academy of Neurology 

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    開催年月日: 1999年4月

    記述言語:英語   会議種別:口頭発表(一般)  

  42. Acetylcholine receptor β-subunit mutations causing endplate AChR deficiency and reduced assembly with the δ subunit 国際会議

    Quiram PA, Ohno K, Milone M, Patterson MC, Pruitt NJ, Brengman JM, Sine SM, Engel AG

    51st Annual Meeting of the American Academy of Neurology 

     詳細を見る

    開催年月日: 1999年4月

    記述言語:英語   会議種別:口頭発表(一般)  

  43. Unusual congenital myasthenic syndrome with endplate AChR deficiency caused by α subunit mutations and a remitting-relapsing clinical course 国際会議

    Milone M, Shen X-M, Ohno K, Harper CM, Fukudome T, Stilling G, Brengman JM, Engel AG

    51st Annual Meeting of the American Academy of Neurology 

     詳細を見る

    開催年月日: 1999年4月

    記述言語:英語   会議種別:口頭発表(一般)  

  44. Congenital endplate acetylcholinesterase deficiency: Novel missense and null mutations in the collagen-like tail subunit of the asymmetric enzyme 国際会議

    Ohno K, Brengman JM, Milone M, Shen X-M, Tsujino A, Anlar B, Engel AG

    48th Annual Meeting of the American Society of Human Genetics 

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    開催年月日: 1998年10月

    記述言語:英語   会議種別:口頭発表(一般)  

  45. A mutation in the promoter region of acetylcholine receptor ε subunit gene causes congenital myasthenic syndrome 国際会議

    Brengman JM, Ohno K, Anlar B, Engel AG

    48th Annual Meeting of the American Society of Human Genetics 

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    開催年月日: 1998年10月

    記述言語:英語   会議種別:口頭発表(一般)  

  46. Congenital endplate acetylcholinesterase deficiency: Novel missense, null, splice-site mutations in the collagen-like tail subunit of the asymmetric enzyme 国際会議

    Ohno K, Brengman JM, Milone M, Anlar B, Felice KJ, Engel AG

    123rd Annual Meeting of the American Neurological Association (Works in Progress) 

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    開催年月日: 1998年10月

    記述言語:英語   会議種別:口頭発表(一般)  

  47. Congenital endplate acetylcholinesterase deficiency 国際会議

    Ohno K, Brengman JM, Tsujino A, Engel AG

    IXth International Congress on Neuromuscular Diseases (Surprise box) 

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    開催年月日: 1998年8月 - 1998年9月

    記述言語:英語   会議種別:口頭発表(招待・特別)  

  48. Congenital myasthenic syndrome due to a splice site and a novel one codon deletion mutation in the acetylcholine receptor ε subunit gene 国際会議

    Shen X-M, Ohno K, Fukudome T, Brengman JM, Engel AG

    IXth International Congress on Neuromuscular Diseases 

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    開催年月日: 1998年8月 - 1998年9月

    記述言語:英語   会議種別:口頭発表(一般)  

  49. Acetylcholine receptor channel blockade for treatment of the slow-channel congenital myasthenic syndrome 国際会議

    Fukudome T, Ohno K, Brengman JM, Engel AG

    IXth International Congress on Neuromuscular Diseases 

     詳細を見る

    開催年月日: 1998年8月 - 1998年9月

    記述言語:英語   会議種別:口頭発表(一般)  

  50. Low-affinity fast channel congenital myasthenic syndrome caused by new missense mutations in the acetylcholine receptor α subunit 国際会議

    Milone M, Ohno K, Brengman JM, Batocchi AP, Tonali PA, Engel AG

    IXth International Congress on Neuromuscular Diseases 

     詳細を見る

    開催年月日: 1998年8月 - 1998年9月

    記述言語:英語   会議種別:口頭発表(一般)  

  51. Congenital myasthenic syndrome due to two novel mutations in the acetylcholine receptor ε subunit gene 国際会議

    Brengman JM, Ohno K, Shen X-M, Engel AG

    IXth International Congress on Neuromuscular Diseases 

     詳細を見る

    開催年月日: 1998年8月 - 1998年9月

    記述言語:英語   会議種別:口頭発表(一般)  

  52. Insights into congenital myasthenic syndromes from patch-clamp studies 国際会議

    Milone M, Ohno K, Sine SM, Wang H-L, Engel AG

    IXth International Congress on Neuromuscular Diseases (Work Shop) 

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    開催年月日: 1998年8月 - 1998年9月

    記述言語:英語   会議種別:口頭発表(招待・特別)  

  53. Congenital endplate acetylcholinesterase deficiency: mutations in the collagen-like tail subunit (ColQ) of the asymmetric enzyme 国際会議

    Ohno K, Brengman JM, Tsujino A, Engel AG

    IXth International Congress on Neuromuscular Diseases (Work Shop) 

     詳細を見る

    開催年月日: 1998年8月 - 1998年9月

    記述言語:英語   会議種別:口頭発表(招待・特別)  

  54. Slow-channel congenital myasthenic syndrome caused by a novel mutation in the acetylcholine receptor ε subunit 国際会議

    Ohno K, Milone M, Brengman JM, LoMonaco M, Evoli A, Tonali PA, Engel AG

    50th Annual Meeting of the American Academy of Neurology 

     詳細を見る

    開催年月日: 1998年4月 - 1998年5月

    記述言語:英語   会議種別:口頭発表(一般)  

  55. Congenital myasthenic syndromes linked to chromosome 17p are caused by defects in acetylcholine receptor ε subunit gene 国際会議

    Middleton LT, Ohno K, Christodoulou K, Brengman JM, Engel AG

    50th Annual Meeting of the American Academy of Neurology 

     詳細を見る

    開催年月日: 1998年4月 - 1998年5月

    記述言語:英語   会議種別:口頭発表(一般)  

  56. Congenital myasthenic syndromes due to null mutations in acetylcholine receptor ε subunit gene in Turkish kinships 国際会議

    Anlar B, Ohno K, Özdirim E, Brengman JM, DeBleecker JL, Engel AG

    50th Annual Meeting of the American Academy of Neurology 

     詳細を見る

    開催年月日: 1998年4月 - 1998年5月

    記述言語:英語   会議種別:口頭発表(一般)  

  57. Low-affinity fast-channel congenital myasthenic syndrome caused by new missense mutations in the acetylcholine receptor α subunit 国際会議

    Milone M, Ohno K, Brengman JM, Batocchi AP, Tonali PA, Engel AG

    50th Annual Meeting of the American Academy of Neurology 

     詳細を見る

    開催年月日: 1998年4月 - 1998年5月

    記述言語:英語   会議種別:口頭発表(一般)  

  58. Frameshift and splice-site mutations in acetylcholine receptor ε subunit gene in five Turkish kinships with congenital myasthenic syndromes 国際会議

    Ohno K, Anlar B, Özdirim E, Brengman JM, DeBleecker JL, Engel AG

    47th Annual Meeting of the American Society of Human Genetics 

     詳細を見る

    開催年月日: 1997年10月 - 1997年11月

    記述言語:英語   会議種別:口頭発表(一般)  

  59. Congenital myasthenic syndrome due to a null mutation and an inframe duplication of the acetylcholine receptor ε subunit gene 国際会議

    Milone M, Ohno K, Fukudome T, Shen X-M, Brengman JM, Griggs RC, Engel AG

    47th Annual Meeting of the American Society of Human Genetics 

     詳細を見る

    開催年月日: 1997年10月 - 1997年11月

    記述言語:英語   会議種別:口頭発表(一般)  

  60. Congenital myasthenic syndromes: New insights from molecular genetic and patch-clamp studies. 国際会議

    Engel AG, Ohno K, Milone M, Sine SM

    IXth International Conference on Myasthenia Gravis and Related Disorders 

     詳細を見る

    開催年月日: 1997年5月

    記述言語:英語   会議種別:口頭発表(一般)  

  61. AChR channel blockade by quinidine sulfate reduces channel open duration in the slow-channel congenital myasthenic syndrome 国際会議

    Fukudome T, Ohno K, Brengman JM, Engel AG

    IXth International Conference on Myasthenia Gravis and Related Disorders 

     詳細を見る

    開催年月日: 1997年5月

    記述言語:英語   会議種別:口頭発表(一般)  

  62. Frame-shifting and splice-site mutations in acetylcholine receptor ε subunit gene in 3 Turkish kinships with congenital myasthenic syndrome 国際会議

    Ohno K, Brengman JM, Anlar B, Engel AG

    IXth International Conference on Myasthenia Gravis and Related Disorders 

     詳細を見る

    開催年月日: 1997年5月

    記述言語:英語   会議種別:口頭発表(一般)  

  63. A missense null mutation and an inframe duplication in acetylcholine receptor εsubunit gene in a congenital myasthenic syndrome 国際会議

    Milone M, Ohno K, Fukudome T, Shen X-M, Brengman, JM, Engel AG

    IXth International Conference on Myasthenia Gravis and Related Disorders 

     詳細を見る

    開催年月日: 1997年5月

    記述言語:英語   会議種別:口頭発表(一般)  

  64. Congenital myasthenic syndromes due to heteroallelic nonsense/missense mutations in the acetylcholine receptor ε subunit gene: Report of 5 new mutations 国際会議

    Ohno K, Quiram PA, Milone M, Wang H-L, Harper CM, Pruitt JN, Brengman JM, Pao L, Fischbeck KH, Crawford TO, Sine SM, Engel AG

    49th Annual Meeting of the American Academy of Neurology 

     詳細を見る

    開催年月日: 1997年4月

    記述言語:英語   会議種別:口頭発表(一般)  

  65. Quinidine sulfate normalizes the open duration of slow channel congenital myasthenic syndrome acetylcholine receptor channels expressed in human embryonic kidney cells 国際会議

    Fukudome T, Ohno K, Brengman JM, Engel AG

    49th Annual Meeting of the American Academy of Neurology 

     詳細を見る

    開催年月日: 1997年4月

    記述言語:英語   会議種別:口頭発表(一般)  

  66. Point mutations of mitochondrial DNA in familial hemiplegic migraine 国際会議

    Ohno K, Tanaka M, Takano A, Teramoto J

    3rd Internet World Congress on Biomedical Science 

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    開催年月日: 1996年12月

    記述言語:英語   会議種別:口頭発表(一般)  

  67. Mutational analysis in a congenital myasthenic syndrome reveals a novel acetylcholine receptor ε subunit mutation 国際会議

    Ohno K, Fukudome T, Nakano S, Milone M, Feasby TE, Tyce GM, Engel AG

    26th Annual Meeting, Society for Neuroscience 

     詳細を見る

    開催年月日: 1996年11月

    記述言語:英語   会議種別:口頭発表(一般)  

  68. Congenital myasthenic syndrome due to frameshifting acetylcholine receptor ε subunit mutation 国際会議

    Milone M, Ohno K, Pruitt JN, Brengman JM, Sine SM, Engel AG

    26th Annual Meeting, Society for Neuroscience 

     詳細を見る

    開催年月日: 1996年11月

    記述言語:英語   会議種別:口頭発表(一般)  

  69. Novel slow-channel syndrome due to mutation in the acetylcholine receptor α subunit with increased conductance, nanomolar affinity for acetylcholine, prolonged open durations of the AChR channel 国際会議

    Milone M, Ohno K, Wang H-L, Fukudome T, Pruitt JN, Sine SM, Engel AG

    121st Annual Meeting of the American Neurological Association (Works in Progress) 

     詳細を見る

    開催年月日: 1996年10月

    記述言語:英語   会議種別:口頭発表(一般)  

  70. Identification of neuromuscular junction acetylcholine receptor mutations in the slow-channel congenital myasthenic syndrome 国際会議

    Ohno K, Milone M, Wang H-L, Nakano S, Hutchinson D, Pruitt JN, Brengman JM, Bren N, Sieb J, Sine SM, Engel AG

    48th Annual Meeting of the American Academy of Neurology 

     詳細を見る

    開催年月日: 1996年3月

    記述言語:英語   会議種別:口頭発表(一般)  

  71. Congenital myasthenic syndrome caused by decreased agonist affinity due to mutation in a ligand binding domain of the acetylcholine receptor εsubunit 国際会議

    Ohno K, Wang H-L, Milone M, Nakano S, Bren N, Pruitt JN, Engel AG, Sine SM

    40th Annual Meeting of Biophysical Society 

     詳細を見る

    開催年月日: 1996年2月

    記述言語:英語   会議種別:口頭発表(一般)  

  72. Congenital myasthenic syndrome caused by prolonged acetylcholine receptor channel openings due to a mutation in the M2 domain of the ε subunit 国際会議

    Ohno K, Hutchinson DO, Milone M, Brengman JM, Engel AG, Bouzat C, Sine SM

    2nd Internet World Congress on Biomedical Science 

     詳細を見る

    開催年月日: 1995年12月

    記述言語:英語   会議種別:口頭発表(一般)  

  73. Autoimmune polyglandular syndromes type II and Kearns-Sayre syndrome 国際会議

    Roberts LR, Tan GH, Ohno K, Yamamoto M, Engel AG, Fatourechi V

    77th Annual Meeting, the Endocrine Society 

     詳細を見る

    開催年月日: 1995年6月

    記述言語:英語   会議種別:口頭発表(一般)  

  74. A congenital myasthenic syndrome with severe acetylcholine receptor deficiency caused by heteroallelic frameshifting mutations in the ε subunit 国際会議

    Ohno K, Engel AG, Milone M, Brengman JM, Sieb J, Iannaccone S

    47th Annual Meeting of the American Academy of Neurology 

     詳細を見る

    開催年月日: 1995年5月

    記述言語:英語   会議種別:口頭発表(一般)  

  75. Large-scale deletion and an A3243G mutation of mitochondrial DNA in the same patient 国際会議

    Yamamoto M, Ohno K, Engel AG, Roberts LR, Tan GH, Fatourechi V

    47th Annual Meeting of the American Academy of Neurology 

     詳細を見る

    開催年月日: 1995年5月

    記述言語:英語   会議種別:口頭発表(一般)  

  76. Molecular genetic basis of a slow channel syndrome 国際会議

    Ohno K, Hutchinson DO, Milone M, Nakano S, Sieb J, Brengman JM, Engel AG

    VIIIth International Congress on Neuromuscular Diseases (Surprise Box) 

     詳細を見る

    開催年月日: 1994年7月

    記述言語:英語   会議種別:口頭発表(招待・特別)  

  77. Two types of newly recognized familial mitochondrial myopathies 国際会議

    Sahashi K, Ibi T, Ohno K, Tanaka M, Tashiro M, Marui K, Nakao N, Ozawa T

    VIIIth International Congress on Neuromuscular Diseases 

     詳細を見る

    開催年月日: 1994年7月

    記述言語:英語   会議種別:口頭発表(一般)  

  78. A congenital myasthenic syndrome with two distinct nonsense mutations in the ε subunit of the acetylcholine receptor 国際会議

    Ohno K, Brengman JM, Hutchinson DO, Griggs RC, Engel AG

    VIIIth International Congress on Neuromuscular Diseases 

     詳細を見る

    開催年月日: 1994年7月

    記述言語:英語   会議種別:口頭発表(一般)  

  79. A congenital myasthenic syndrome with a nonsense mutation in the ε subunit of the acetylcholine receptor 国際会議

    Ohno K, Engel AG, Brengman JM, Hutchinson DO, Griggs RC

    46th Annual Meeting of American Academy of Neurology 

     詳細を見る

    開催年月日: 1994年5月

    記述言語:英語   会議種別:口頭発表(一般)  

  80. Identification of a novel control element, Mt5, in the major noncoding region of human mitochondrial DNA 国際会議

    Ohno K, Tanaka M, Suzuki H, Kumar S, Ozawa T

    Mitochondrial Biogenesis: Mechanism and Pathology 

     詳細を見る

    開催年月日: 1992年12月

    記述言語:英語   会議種別:口頭発表(一般)  

  81. Mitochondrial DNA mutations in patients with cerebellar ataxia 国際会議

    Miyata E, Ohno K, Tanaka M, Yamamoto H, Ozawa T

    Mitochondrial Biogenesis: Mechanism and Pathology 

     詳細を見る

    開催年月日: 1992年12月

    記述言語:英語   会議種別:口頭発表(一般)  

  82. Identification of a novel control element, Mt5, in the major noncoding region of human mitochondrial DNA 国際会議

    Ohno K, Tanaka M, Suzuki H, Kumar S, Ozawa T

    1st IUBMB Conference 

     詳細を見る

    開催年月日: 1992年6月

    記述言語:英語   会議種別:口頭発表(一般)  

  83. Alteration of initiator codon into ACA for threonine in the mitochondrial ND5 gene in Pearson's syndrome 国際会議

    Tanaka M, Sano T, Ohno K, Wada Y, Ozawa T

    1st IUBMB Conference 

     詳細を見る

    開催年月日: 1992年6月

    記述言語:英語   会議種別:口頭発表(一般)  

  84. Aging of skeletal muscle fiber on respiratory function 国際会議

    Sahashi K, Ibi T, Tashiro M, Suoh H, Mitsuma T, Ohno K, Tanaka M, Takahashi A, Ozawa T

    8th Asian and Oceanian Congress of Neurology 

     詳細を見る

    開催年月日: 1991年9月

    記述言語:英語   会議種別:口頭発表(一般)  

  85. Mitochondria DNA disease: Types and mechanism 国際会議

    Ozawa T, Tanaka M, Sato W, Ohno K, Sugiyama S, Yoneda M, Yamamoto T, Hattori K, Ikebe S, Tashiro M, Sahashi K

    XIth International Congress of Neuropathology 

     詳細を見る

    開催年月日: 1990年10月

    記述言語:英語   会議種別:口頭発表(一般)  

  86. ミトコンドリアDNA 変異と表現型

    田中雅嗣、小澤高将、佐藤 弥、大野欽司

    第63回日本生化学会、大阪 

     詳細を見る

    開催年月日: 1990年10月

    記述言語:日本語   会議種別:口頭発表(招待・特別)  

    国名:日本国  

  87. Mitochondrial DNA Deletions in Inherited Recurrent Myoglobinuria 国際会議

    Ohno K, Tanaka M, Sahashi K, Ibi T, Takahashi A, Ozawa T

    VII International Congress on Neuromuscular Diseases 

     詳細を見る

    開催年月日: 1990年9月

    記述言語:英語   会議種別:口頭発表(一般)  

  88. The mitochondrial metabolism in neuromuscular disorders 国際会議

    Tashiro M, Sahashi K, Ibi T, Ohno K, Tanaka M, Ozawa T

    VII International Congress on Neuromuscular Diseases 

     詳細を見る

    開催年月日: 1990年9月

    記述言語:英語   会議種別:口頭発表(一般)  

  89. Clinical and molecular genetic analyses of chronic external ophthalmoplegia 国際会議

    Sahashi K, Ibi T, Tashiro M, Ohno K, Tanaka M, Yamamoto T, Ozawa T

    VII International Congress on Neuromuscular Diseases 

     詳細を見る

    開催年月日: 1990年9月

    記述言語:英語   会議種別:口頭発表(一般)  

  90. Cytoplasmic body and mitochondrial DNA deletion 国際会議

    Ibi T, Sahashi K, Tashiro M, Ohno K, Tanaka M, Yamamoto T, Ozawa T

    VII International Congress on Neuromuscular Diseases 

     詳細を見る

    開催年月日: 1990年9月

    記述言語:英語   会議種別:口頭発表(一般)  

  91. Visceral myopathy with external ophthalmoplegia and multiple mitochondrial DNA deletions 国際会議

    Sahashi K, Ibi T, Ohno K, Tanaka M, Tashiro M, Tsuchiya I, Mitsuma T, Takahashi A, Ozawa T

    XXth International Congress of Neurovegetative Research 

     詳細を見る

    開催年月日: 1990年9月

    記述言語:英語   会議種別:口頭発表(一般)  

  92. ミトコンドリア遺伝子病の分子生物学的解析の最近の進歩

    田中雅嗣、大野欽司、米田 誠、佐藤 弥、池辺紳一郎、小澤高将

     詳細を見る

    開催年月日: 1990年

    記述言語:日本語   会議種別:口頭発表(招待・特別)  

    国名:日本国  

  93. Maternally inherited mitochondrial DNA mutation causes molecular defects in the respiratory chain and myopathy 国際会議

    Tanaka M, Sato W, Ohno K, Yoneda M, Yamamoto T, Ikebe S, Sahashi K, Ozawa T

    Mitochondrial Biogenesis: Mechanism and Pathology 

     詳細を見る

    開催年月日: 1989年12月

    記述言語:英語   会議種別:口頭発表(一般)  

  94. ミトコンドリア カルヂオ ミオパチー

    小澤高将、田中雅嗣、杉山 理、高橋 昭、大野欽司、米田 誠、宮武 正、佐藤 弥、高田五郎

     詳細を見る

    開催年月日: 1989年2月

    記述言語:日本語   会議種別:口頭発表(招待・特別)  

    国名:日本国  

  95. ミトコンドリアDNA異常と病態

    小澤高将、田中雅嗣、杉山 理、佐藤 弥、大野欽司、山本智子、服部和樹、太田由枝

     詳細を見る

    開催年月日: 1989年

    記述言語:日本語   会議種別:口頭発表(招待・特別)  

    国名:日本国  

  96. A novel etiology of cardiomyopathy with angiopathy: defect in a mitochondrial enzyme, Complex I 国際会議

    Tanaka M, Sato W, Yoneda M, Ohno K, Nemoto D, Mimura Y, Takada G, Sugiyama S, Ozawa T

    14th Annual Lorne conference on protein structure and function 

     詳細を見る

    開催年月日: 1989年

    記述言語:英語   会議種別:口頭発表(一般)  

  97. Mitochondrial gene abnormality as a novel cause of cardiac conduction block 国際会議

    Ozawa T, Tanaka M, Ohno K, Yoneda M, Sato W, Sugiyama S, Ibi T, Sahashi K, Kamiya T, Uno M

    14th Annual Lorne conference on protein structure and function 

     詳細を見る

    開催年月日: 1989年

    記述言語:英語   会議種別:口頭発表(一般)  

▼全件表示

共同研究・競争的資金等の研究課題 21

  1. 先天性筋無力症候群の診断・病態・治療法開発研究(「難治性疾患克服研究事業」課題番号:H23-難治-一般-073)

    2011年4月 - 2013年3月

    科学技術振興調整費 

      詳細を見る

    資金種別:競争的資金

  2. 筋ジストロフィーおよび関連疾患の診断・治療開発を目指した基盤研究(主任研究者:西野一三)

    2011年4月 - 2012年3月

    精神・神経疾患研究委託費(西野班) 

      詳細を見る

    資金種別:競争的資金

  3. ミオトニア症候群の病態解明・制御研究

    2011年4月 - 2012年3月

    H23傾斜的研究費(部局競争的研究費) 

      詳細を見る

    資金種別:競争的資金

  4. Schwartz-Jampel症候群のわが国における診断システム確立とモデルマウスによる病態解明と治療研究(「難治性疾患克服研究事業」主任研究者:平澤 恵理)(課題番号:H23-難治-一般-055)

    2011年4月 - 2012年3月

    科学技術振興調整費 

      詳細を見る

    資金種別:競争的資金

  5. 網羅的スプライシング暗号解析に基づくRNA病の解明と治療技術の探索(研究代表者: 萩原正敏)

    2010年4月 - 2013年3月

    革新的細胞解析研究プログラム(セルイノベーション) 

      詳細を見る

    資金種別:競争的資金

  6. 筋チャネル病および関連疾患の診断・治療指針作成および新規治療法開発に向けた基盤整備のための研究(筋強直性ジストロフィーのスプライシング異常の網羅的な解析とその制御研究)(「難治性疾患克服研究事業」主任研究者:高橋正紀)(課題番号:H22-難治-一般-118)

    2010年4月 - 2012年3月

    科学技術振興調整費 

      詳細を見る

    資金種別:競争的資金

  7. 筋強直性ジストロフィー治療薬の開発

    2010年4月 - 2012年3月

    科学技術コモンズ試験費・技術移転調査費 

      詳細を見る

    資金種別:競争的資金

  8. 筋強直性ジストロフィーのスプライシング異常を補正する既認可薬オフラベル薬効の患者培養細胞・動物実験における検証(企業責任者:鍵山直人/研究責任者:大野欽司)(課題番号:26-J-Je44)

    2010年4月 - 2011年3月

    研究成果最適展開支援事業A-STEPフィージビリティスタディ(シーズ顕在化) 

      詳細を見る

    資金種別:競争的資金

  9. 先天性筋無力症候群の診断・病態・治療法開発研究(「難治性疾患克服研究事業」課題番号:H22-難治-一般-028、H22YP028-00)

    2010年4月 - 2011年3月

    科学技術振興調整費 

      詳細を見る

    資金種別:競争的資金

  10. 筋強直性ジストロフィー1型の無気力・無関心はビ・シフィールRの投与で改善できる(研究代表者:木下正信)

    2010年4月 - 2011年3月

    平成22年度 傾斜的研究費(部局分・部局競争的経費) 

      詳細を見る

    資金種別:競争的資金

  11. 神経筋疾患におけるスプライシング異常(Aberrant splicing in neuromuscular diseases)(課題番号:26-J-Je28)

    2009年4月 - 2013年3月

    戦略的国際科学技術協力推進事業 日本(JST)-デンマーク(DASTI)研究交流 

      詳細を見る

    資金種別:競争的資金

  12. 分子状水素の抗酸化作用分子機構の解明と新規生理活性分子の同定による神経変性疾患発症予防法の開発(課題番号:26-J-Je20)

    2009年4月 - 2010年3月

    地域イノベーション創出総合支援事業 重点地域研究開発推進プログラム 平成21年度「シーズ発掘試験」 A(発掘型) 

      詳細を見る

    資金種別:競争的資金

  13. 先天性筋無力症候群の分子病態解明と治療法開発研究(筋ジストロフィーおよびその関連疾患の分子病態解明、診断法確立と薬物治療の開発に関する研究(主任研究者:砂田芳秀)(課題番号:20委-13)

    2008年4月 - 2011年3月

    精神・神経疾患研究委託費(砂田班) 

      詳細を見る

    資金種別:競争的資金

  14. 筋強直性ジストロフィーの病態に関与するスプライシング異常遺伝子の新規同定と既認可薬による制御研究(研究代表者:木下正信)

    2008年4月 - 2010年3月

    平成20年度 傾斜的研究費(部局分・部局競争的経費) 

      詳細を見る

    資金種別:競争的資金

  15. 神経筋接合部分子欠損症の分子病態とその制御(拠点リーダー:祖父江元)

    2008年4月 - 2010年3月

    グローバルCOE 共同研究推進費 

      詳細を見る

    資金種別:競争的資金

  16. (財)内藤記念科学振興財団 第37回(2005年度)内藤記念科学奨励金「神経筋疾患におけるpre-mRNAスプライシング異常症の病態研究と制御」(200万円)

    2006年4月 - 2007年9月

    (財)内藤記念科学振興財団 第37回(2005年度)内藤記念科学奨励金 

      詳細を見る

    資金種別:競争的資金

  17. 神経筋疾患におけるpre-mRNAスプライシング異常症の病態研究と制御

    2006年4月 - 2007年9月

    (財)内藤記念科学振興財団 第37回(2005年度)内藤記念科学奨励金 

      詳細を見る

    資金種別:競争的資金

  18. 神経筋疾患のRNA病態・治療研究

    2005年6月 - 2007年3月

    (財)武田科学振興財団 2005年度一般研究奨励 

      詳細を見る

    資金種別:競争的資金

  19. (財)武田科学振興財団 2005年度一般研究奨励「神経筋疾患のRNA病態・治療研究」(200万円)

    2005年6月

    (財)武田科学振興財団 2005年度一般研究奨励 

      詳細を見る

    資金種別:競争的資金

  20. 終板アセチルコリンエステラーゼ欠損症、及び、他の細胞外マトリックス分子欠損症におけるタンパク標的療法の開発研究(「こころの健康科学研究事業」課題番号:H17:H17-こころ-023/H18~19:H17-こころ-一般-023)

    2005年4月 - 2008年3月

    科学技術振興調整費 

      詳細を見る

    資金種別:競争的資金

  21. 神経筋接合部分子欠損症のRNA分子病態と治療法開発研究(筋ジストロフィーおよびその関連する疾患の病態生理の解明と治療薬物の開発に関する研究)(主任研究者:清水輝夫)(課題番号:17指-10)

    2005年4月 - 2008年3月

    精神・神経疾患研究委託費(清水班) 

      詳細を見る

    資金種別:競争的資金

▼全件表示

科研費 15

  1. 神経筋接合部の正常分子構築解明と先天性筋無力症候群の分子病態研究(課題番号:15H04840)

    2015年4月 - 2018年3月

    科学研究費補助金  基盤研究(B)

    大野 欽司

      詳細を見る

    担当区分:研究代表者 

  2. 神経変性疾患関連RNA結合タンパクFUSによる転写抑制機構解明(課題番号:25118508)

    2013年4月 - 2015年3月

    科学研究費補助金  新学術研究(研究領域提案型)(公募研究)

    大野 欽司

      詳細を見る

    担当区分:研究代表者 

  3. 神経筋接合部分子LRP4の分子構築解明(課題番号:25670164)

    2013年4月 - 2014年3月

    科学研究費補助金  萌芽研究

    大野 欽司

      詳細を見る

    担当区分:研究代表者 

  4. 神経筋接合部の正常構築と分子病態研究(課題番号:24390221)

    2012年4月 - 2015年3月

    科学研究費補助金  基盤研究(B)

    大野 欽司

      詳細を見る

    担当区分:研究代表者 

  5. ES細胞由来運動神経細胞に対する神経筋接合部形成促進薬の網羅的探索法に関する研究(平田仁)

    2012年4月 - 2015年3月

    科学研究費補助金  萌芽研究

    平田 仁

      詳細を見る

    担当区分:研究分担者 

  6. 分子状水素による健康増進・疾患抑制の新規分子機構の解明(伊藤雅史)(課題番号:22300244)

    2010年4月 - 2011年3月

    科学研究費補助金  基盤研究(B)

    伊藤 雅史

      詳細を見る

    担当区分:研究分担者 

  7. 神経筋接合分子欠損症におけるmRNA病態研究と治療法開発研究(課題番号:21390266)

    2009年4月 - 2012年3月

    科学研究費補助金  基盤研究(B)

    大野 欽司

      詳細を見る

    担当区分:研究代表者 

  8. スプライシング暗号の解読による神経発生過程の解明(萩原正敏)(課題番号:21249013 )

    2009年4月 - 2012年3月

    科学研究費補助金  基盤研究(A)

    萩原 正敏

      詳細を見る

    担当区分:研究分担者 

  9. In silico解析とin vitro解析によるRNAスプライシング機構の研究(課題番号:20016011)

    2008年4月 - 2009年3月

    科学研究費補助金  特定領域研究

    大野 欽司

      詳細を見る

    担当区分:研究代表者 

  10. 神経筋接合分子欠損症および他の筋疾患におけるmRNA病態研究と治療法開発研究(課題番号:19390237)

    2007年4月 - 2009年3月

    科学研究費補助金  基盤研究(B)

    大野 欽司

      詳細を見る

    担当区分:研究代表者 

  11. 優性遺伝性非翻訳リピート病の異常スプライシング病態研究(松浦徹)(課題番号:19590988)

    2007年4月 - 2009年3月

    科学研究費補助金  基盤研究(C)

    松浦徹

      詳細を見る

    担当区分:研究分担者 

  12. ヒトゲノム配列解析によるRNAスプライシングとRNA代謝機構の研究(課題番号:18016011)

    2006年4月 - 2008年3月

    科学研究費補助金  特定領域研究

    大野欽司

      詳細を見る

    担当区分:研究代表者 

  13. mRNAの1次塩基配列と2次構造予測に基づくsiRNA設計アルゴリズムの開発研究(課題番号:18651098)

    2006年4月 - 2007年3月

    科学研究費補助金 

    大野欽司

      詳細を見る

    担当区分:研究代表者 

  14. 先天性筋無力症候群に関与する神経筋接合部分子の分子病態研究(課題番号:17390252)

    2005年4月 - 2007年3月

    科学研究費補助金  基盤研究(B)

    大野欽司

      詳細を見る

    担当区分:研究代表者 

  15. 神経筋疾患の原因となるpre-mRNAスプライシング異常症の分子病態研究(課題番号:17026016)

    2005年4月 - 2007年3月

    科学研究費補助金  特定領域研究

    大野欽司

      詳細を見る

    担当区分:研究代表者 

▼全件表示

産業財産権 3

  1. 骨系統疾患治療薬及びその用途

    大野欽司、石黒直樹、鬼頭浩史、松下雅樹

     詳細を見る

    出願人:国立大学法人名古屋大学

    出願番号:特願2013-047426号  出願日:2013年3月

    出願国:国内  

  2. 骨形成促進剤及びその用途

    大野欽司、石黒直樹、鬼頭浩史、三島健一

     詳細を見る

    出願人:国立大学法人名古屋大学

    出願番号:特願2011-185306号  出願日:2011年8月

    出願国:国内  

  3. 筋強直性ジストロフィー治療薬

    大野欽司、松浦徹

     詳細を見る

    出願人:国立大学法人名古屋大学

    出願番号:特願2009-167809号  出願日:2009年7月

    公開番号:WO2011/007866 

    出願国:国内  

 

担当経験のある科目 (本学) 1

  1. 基礎セミナーA

    2011