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Structural Flexibility Enables Alternative Maturation, ARGONAUTE Sorting and Activities of miR168, a Global Gene Silencing Regulator in Plants

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Molecular Plant 2018年第8期11卷 1008-1023页

作者： taichiro iki Antoine Cléry Nicolas G. Bologna Alexis Sarazin Christopher A. Brosnan Nathan Pumplin Frédéric H.T. Allain Olivier Voinnet Department of Biology Swiss Federal Institute of Technology (ETH) Universit&tstrasse 2 ZUrich 8092 Switzerland Institute of Molecular Biology and Biophysics Department of Biology Swiss Federal Institute of Technology (ETH) Zürich Switzerland Biomolecular NMR spectroscopy Platform ETH Zürich Switzerland Present address: Laboratory of Germline Biology Graduate School of Frontier Biosciences Osaka University 1-3 Yamadaoka Suita Osaka Japan

In eukaryotes, the RNase-Ⅲ Dicer often produces length/sequence microRNA （miRNA） variants, called ＂isomiRs＂, owing to intrinsic structural/sequence determinants of the miRNA precursors （pre-miRNAs）. In this study, we combined biophysics, genetics and biochemistry approaches to study Arabidopsis miR168, the key feedback regulator of central plant silencing effector protein ARGONAUTE1 （AGO1）. We identified a motif conserved among plant premiR168 orthologs, which enables flexible internal basepairing underlying at least three metastable structural configurations. These configurations promote alternative, accurate Dicer cleavage events generating length and structural isomiR168 variants with distinctive AGO sorting properties and modes of action. Among these isomiR168s, a duplex with a 22-nt guide strand exhibits strikingly preferential affinity for AGO10, the closest AGO1 paralog. The 22-nt miR168-AGO10 complex antagonizes AGO1 accumulation in part via ＂transitive RNAi＂, a silencing-amplification process, to maintain appropriate AGO1 cellular homeostasis. Furthermore, we found that the tombusviral P19 silencing-suppressor protein displays markedly weaker affinity for the 22-nt form among its isomiR168 cargoes, thereby promoting AGO10-directed suppression of AGOl-mediated antiviral silencing. Taken together, these findings indicate that structural flexibility, a previously overlooked property of premiRNAs, considerably increases the versatility and regulatory potential of individual MIRNA genes, and that some pathogens might have evolved the capacity or mechanisms to usurp this property.

关键词： microRNA miR168 Dicer ARGONAUTE tombusvirus P19

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Novel SLC30A2 mutations in the pathogenesis of transient neonatal zinc deficiency

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Pediatric Investigation 2023年第1期7卷 6-12页

作者： taichiro Muto Yuriko Kawase Kaori Aiba Miyuki Okuma Naoya Itsumura Shuangyu Luo Namino Ogawa Tokuji Tsuji Taiho Kambe Department of Pediatrics Aichi Medical University HospitalNagakuteJapan Department of Dermatology Toshiba Central HospitalTokyoJapan Department of Pediatrics Toyohashi Municipal HospitalToyohashiJapan Department of Pediatrics Toshiba Central HospitalTokyoJapan Department of AppliedMolecular Biology Division of Integrated Life ScienceGraduate School of BiostudiesKyoto UniversityKyotoJapan

Importance:Transient neonatal zinc deficiency(TNZD)occurs in breastfed infants due to abnormally low breast milk zinc levels.Mutations in the solute carrier family 30 member 2(SLC30A2)gene,which encodes the zinc transporter ZNT2,cause low zinc concentration in breast milk.Objective:This study aimed to provide further insights into TNZD pathophysiology.Methods:SLC30A2 sequencing was performed in three unrelated Japanese mothers,whose infants developed TNZD due to low-zinc milk consumption.The effects of the identified mutations were examined using cell-based assays and luciferase reporter analysis.Results:Novel SLC30A2 mutations were identified in each mother.One harbored a heterozygous missense mutation in the ZNT2 zinc-binding site,which resulted in defective zinc transport.The other two mothers exhibited multiple heterozygous mutations in the SLC30A2 promoter,the first mutations in the SLC30A2 regulatory region reported to date.Interpretation:This report provides new genetic insights into TNZD pathogenesis in breastfed infants.

关键词： Dermatology Breastfeeding Transient neonatal zinc deficiency(TNZD) Low-zinc breast milk SLC30A2/ZNT2 Promoter Zinc-binding motif

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Hepatic resection for hepatocellular carcinoma

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Hepatoma Research 2018年第8期4卷 97-106页

作者： Shun Yamaguchi taichiro Kosaka Susumu Eguchi Department of Surgery Nagasaki University Graduate School of Biomedical SciencesNagasaki 8528102Japan

Hepatic resection has become the standard treatment of primary liver cancer. Indications for hepatic resection in patients with hepatocellular carcinoma (HCC) vary greatly between Japan and other countries because the clinical practice guidelines for HCC defined by the Japan Society of Hepatology differ from the EASL-EORTC clinical practice guidelines. Hepatic resection is not recommended as a treatment for the patients at Barcelona Clinic Liver Cancer (BCLC) stage B. Otherwise, there are many surgeons/clinicians who believe that not all HCC patients at BCLC stage B should be excluded from an indication for hepatectomy because many reports showed good prognosis after hepatic resection for HCC patients over BCLC stage B. The survival rate is expected to increase with better outcomes of hepatectomy in the future. This paper has described indications for hepatectomy for patients with HCC through comparison of domestic guidelines with overseas guidelines, focusing on their differences.

关键词： Hepatic resection hepatocellular carcinoma guidelines

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Real-world efficacy of daclatasvir and asunaprevir with respect to resistance-associated substitutions

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World Journal of Hepatology 2017年第25期9卷 1064-1072页

作者： Hideki Fujii Atsushi Umemura taichiro Nishikawa Kanji Yamaguchi Michihisa Moriguchi Hideki Nakamura Kohichiroh Yasui Masahito Minami Saiyu Tanaka Hiroki Ishikawa Hiroyuki Kimura Shiro Takami Yasuyuki Nagao Toshihide Shima Yoshito Itoh Department of Molecular Gastroenterology and Hepatology Kyoto Prefectural University of Medicine Department of Gastroenterology Japanese Red Cross Kyoto Daiichi Hospital Department of Gastroenterology and Hepatology North Medical CenterKyoto Prefectural University of Medicine Department of Internal Medicine Aiseikai Yamashina Hospital Center for Digestive and Liver Diseases Nara City Hospital Department of Gastroenterology and Hepatology Omihachiman Community Medical Center Department of Gastroenterology Otsu Municipal Hospital Department of Gastroenterology Matsushita Memorial Hospital Center of Gastroenterology and Hepatology Saiseikai Suita Hospital

AIM To investigate daclatasvir(DCV) and asunaprevir(ASV) efficacy in hepatitis C(HCV) patients, with respect to resistance-associated substitutions(RASs).METHODS A total of 392 HCV-infected patients from multiple centers were included in this study. We evaluated their clinical courses and sustained virologic responses(SVR) according to pretreatment factors(gender, age, history of interferon-based regimens, platelet counts, level of viremia, pretreatment NA5A:L31, and Y93 substitutions). We also analyzed the pretreatment and post-treatment major RASs of NS3:D168, NS5A:L31 and Y93 substitutions using a direct-sequencing method in 17 patients who were unable to achieve SVR at 12 wk after treatment completion(SVR12).RESULTS The overall SVR12 rate was 88.3%. Thirty-one patients discontinued treatment before 24 wk because of adverse events, 23 of whom achieved SVR12. There were no significant differences in SVR12 rates with respect to gender, age, history of interferon-based regimens, and platelet counts. The SVR12 rate in patients with viral loads of ≥ 6.0 log IU/m L was significantly lower than those with viral loads of < 6.0 log IU/m L(P < 0.001). The SVR12 rate in patients with Y93 substitution-positive was significantly lower than those with Y93 substitution-negative(P < 0.001). The L31 substitution-positive group showed a lower SVR12 rate than the L31 substitution-negative group, but the difference was not statistically significant. Seventeen patients who did not achieve SVR12 and had available pretreatment and post-treatment sera had additional RASs in NS3:D168, NS5:L31, and Y93 substitution at treatment failure.CONCLUSION Combination of DCV and ASV is associated with a high SVR rate. Baseline RASs should be thoroughly assessed to avoid additional RASs after treatment failure.

关键词： Hepatitis C Asunaprevir Combination therapy Resistance-associated substitutions Daclatasvir

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Relationship changes in lifestyle, cardiovascular risk factors, and mental health in Japanese workers: A four-year follow up with high-risk and population strategies of the occupational health promotion (HIPOP-OHP) study

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Health 2012年第11期4卷 1053-1061页

作者： Junko Minai taichiro Tanaka Tomonori Okamura Shunichi Fukuhara Yoshimi Suzukamo Hirotsugu Ueshima Zentaro Yamagata Department of Health Science Shiga University of Medical Science Otsu Japan Department of Health Sciences School of Medicine University of Yamanashi Chuo Japan Department of Healthcare Epidemiology Kyoto University Graduate School of Medicine and Public Health Kyoto Japan Department of Physical Medicine and Rehabilitation Tohoku University Graduate School of Medicine Sendai Japan Department of Preventive Medicine and Public Health Keio University Tokyo Japan School of Nursing and Rehabilitation Science Odawara International University of Health and Welfare Odawara Japan

Background: Cardiovascular diseases (CVD) are major causes of death in Japan, and controlling the risk factors for CVD is an important public health task. Lifestyle factors, for example, diet and stress, have impacts on risk factors such as hypertension and hyperlipidemia. Deterioration of mental health is related to CVD pathogenesis. Aim: We investigated the relationships between levels of mental health, 4-year changes in lifestyle, and CVD risk factors among Japanese workers, using the SF-36 (Japanese version), which is a comprehensive scale measuring health-related quality of life. We hypothesized that workers’ mental health levels would influence 4-year changes in their lifestyles and CVD risk factors. Methods: Data from the High-Risk and Population Strategy for Occupational Health Promotion (HIPOP-OHP) study, which were collected by examination and administration of the SF-36, were used. The relationships between mental health levels at baseline, lifestyle chan- ges, and cardiovascular risk factors were longitudinally analyzed. Subjects with total SF-36 scores ≥65 were classified as the “Good Mental Health Group,” and those with total scores <65 were classified as the “Poor Mental Health Group.” Results: Multiple logistic regression analyses showed that, as compared to people who had poor mental health, those who had good mental health at baseline had a significantly higher probability of good maintenance of improvements in body mass index, (OR = 1.20, 95% CI: 1.03 - 1.39), blood pressure (OR = 1.20, 95% CI: 1.01 - 1.43), total cholesterol (OR = 1.07, 95% CI: 0.86 - 1.33) and HDL cholesterol (OR = 1.26, 95% CI: 1.07 - 1.47). Conclusion: Japanese workers with good mental health tend to improve or maintain good lifestyle conditions and minimize CVD risk factors, while those with poor mental health generally have difficulty improving their lifestyles and lowering their CVD risk.

关键词： Lifestyle Cardiovascular Risk Factors Mental Health Japanese Workers HIPOP-OHP

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Comparison of peg-interferon, ribavirin plus telaprevir vs simeprevir by propensity score matching

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World Journal of Hepatology 2015年第28期7卷 2841-2848页

作者： Hideki Fujii Takeshi Nishimura Atsushi Umemura taichiro Nishikawa Kanji Yamaguchi Michihisa Moriguchi Yoshio Sumida Hironori Mitsuyoshi Chihiro Yokomizo Saiyu Tanaka Hiroki Ishikawa Kenichi Nishioji Hiroyuki Kimura Shiro Takami Yasuyuki Nagao Takayuki Takeuchi Toshihide Shima Yoshihiko Sawa Masahito Minami Kohichiroh Yasui Yoshito Itoh Department of Molecular Gastroenterology and Hepatology Kyoto Prefectural University of Medicine Department of Gastroenterology Japanese Red Cross Kyoto Daiichi Hospital Department of Gastroenterology and Hepatology North Medical Center Kyoto Prefectural University of Medicine Department of Gastroenterology Osaka General Hospital of West Japan Railway Company Center for Digestive and Liver Diseases Nara City Hospital Department of Gastroenterology and Hepatology Omihachiman Community Medical Center Health Care Division Kyoto Second Red Cross Hospital Department of Gastroenterology Otsu Municipal Hospital Department of Gastroenterology Matsushita Memorial Hospital Higashiomicity Notogawa Hospital Center of Gastroenterology and Hepatology Saiseikai Suita Hospital Department of Internal Medicine Aiseikai Yamashina Hospital

AIM: To compare efficacy of telaprevir(TVR) and simeprevir(SMV) combined with pegylated interferon(PEG-IFN) and ribavirin(RBV) while treating chronic hepatitis C(CHC). METHODS: In all, 306 CHC patients were included in this study. There were 159 patients in the TVR combination therapy group and 147 patients in the SMV combination therapy group. To evaluate pretreatment factors contributing to sustained virological response at 12 wk(SVR12), univariate and multivariate analyses were performed in TVR and SMV groups. To adjust for patient background between TVR and SMV groups, propensity score matching was performed. Virological response during treatment and SVR12 were evaluated.RESULTS: Overall rates of SVR12 [undetectable serum hepatitis C virus(HCV) RNA levels] were 79.2% and 69.4% in TVR and SMV groups, respectively. Patients in the SMV group were older, had higher serum HCV RNA levels, lower hemoglobin, higher prevalence of unfavorable interleukin-28B(IL28B) genotype(rs8099917), and poorer response to previous PEG-IFN and RBV treatment. Propensity score matching was performed to adjust for backgrounds(n = 104) and demonstrated SVR12 rates of 74.0% and 73.1% in the TVR and SMV groups, respectively. In the TVR group, discontinuation rates were higher because of adverse events; however, breakthrough and nonresponse was more frequent in the in SMV group. Multivariate analysis revealed IL28 B genotype(rs8099917) as the only independent predictive factor of SVR12 in both groups.CONCLUSION: SVR12 rates were almost identical following propensity score matching.

关键词： Chronic hepatitis C Combination therapy Pegylated interferon Simeprevir Telaprevir Propensityscore matching Protease inhibitor

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美学修复中关于牙龈生物型的评估方法：目测法与直接测量法

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中国口腔医学继续教育杂志 2011年第6期14卷 372-376页

作者： Joseph Y.K.Kan taichiro Morimoto Kitichai Rungcharassaeng Phillip Roe Dennis H.Smith 李宜芬（译）姜婷（审）不详北京大学口腔医学院修复科北京市中关村南大街22号 100081

本研究旨在通过比较目测法与直接测量法．评估目测法（直接目测及利用牙周探针目测）在诊断上颌前牙唇侧牙龈生物型的可靠程度。48例患者（男性20例，女性28例）均有一个无法保留的上颌前牙。利用三种方法评估患牙牙龈生物型：直接目测... 详细信息

本研究旨在通过比较目测法与直接测量法．评估目测法（直接目测及利用牙周探针目测）在诊断上颌前牙唇侧牙龈生物型的可靠程度。48例患者（男性20例，女性28例）均有一个无法保留的上颌前牙。利用三种方法评估患牙牙龈生物型：直接目测法．牙周探查法，直接测量法。拔除患牙之前．先用直接目测法及牙周探查法评估牙龈生物型．拔除患牙后．利用无张力卡尺对其龈厚度进行直接测量．精确至01mm如果龈厚度≤1．0mm诊断为薄型，如〉1．0mm诊断为厚型。用McNemar法进行统计检验（a=0．05）．直接测量法所测牙龈厚度均数为1．06±027mm。厚薄型牙龈频数分布相等．各占50％。直接目测法与牙周探查法（P=0．0117），直接测量法（P=0．0001）比较有差异显著性。然而．牙周探查法与直接测量法结果无差异显著性（P=0.146）。这表明，牙周探查法相对直接测量法虽有一定主观性．但用于评估牙龈生物型仍具有足够的可靠性和客观性。

关键词：直接测量法评估方法目测法生物型牙龈美学修复差异显著性上颌前牙

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