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Articles by Y Nakamura
Total Records ( 7 ) for Y Nakamura
  M Inoue , D Jinbo , Y Nakamura , M Taniguchi and K. Urakami
 

Aim. To evaluate the capability of a computerized test battery for Alzheimer's disease screening which has been newly developed to provide a standardized and efficient method for widespread use in routine clinical and community-based settings.

Methods. Participants were 72 individuals diagnosed with Alzheimer's disease and 102 healthy elderly individuals. Both groups were tested by the battery. Receiver operating characteristic analysis was used to examine the ability of the battery to differentiate between those with Alzheimer's disease and cognitively healthy elderly individuals.

Results. On a group level, the Alzheimer's disease group performed worse than the control group on each of the 4 computerized test tasks. Receiver operating characteristic analysis yielded maximum sensitivity and specificity values of 96% and 86% for total scores, respectively.

Conclusion. We believe the battery is very useful for routine clinical and community-based settings.

  I Nozaki , T Hamaguchi , N Sanjo , M Noguchi Shinohara , K Sakai , Y Nakamura , T Sato , T Kitamoto , H Mizusawa , F Moriwaka , Y Shiga , Y Kuroiwa , M Nishizawa , S Kuzuhara , T Inuzuka , M Takeda , S Kuroda , K Abe , H Murai , S Murayama , J Tateishi , I Takumi , S Shirabe , M Harada , A Sadakane and M. Yamada
 

We analysed the epidemiological data and clinical features of patients with prion diseases that had been registered by the Creutzfeldt-Jakob Disease Surveillance Committee, Japan, over the past 10 years, since 1999. We obtained information on 1685 Japanese patients suspected as having prion diseases and judged that 1222 patients had prion diseases, consisting of definite (n = 180, 14.7%) and probable (n = 1029, 84.2%) cases, except for dura mater graft-associated Creutzfeldt–Jakob disease which also included possible cases (n = 13, 1.1%). They were classified into 922 (75.5%) with sporadic Creutzfeldt–Jakob disease, 216 (17.7%) with genetic prion diseases, 81 (6.6%) with acquired prion diseases, including 80 cases of dura mater graft-associated Creutzfeldt–Jakob disease and one case of variant Creutzfeldt–Jakob disease, and three cases of unclassified Creutzfeldt–Jakob disease (0.2%). The annual incidence rate of prion disease ranged from 0.65 in 1999 to 1.10 in 2006, with an average of 0.85, similar to European countries. Although methionine homozygosity at codon 129 polymorphism of the prion protein gene was reported to be very common (93%) in the general Japanese population, sporadic Creutzfeldt–Jakob disease in Japan was significantly associated with codon 129 homozygosity (97.5%), as reported in western countries. In sporadic Creutzfeldt–Jakob disease, MM1 type (Parchi’s classification) is the most common, as in western countries. Among atypical sporadic Creutzfeldt–Jakob disease cases, the MM2 type appeared most common, probably related to the very high proportion of methionine allele in the Japanese population. As for iatrogenic Creutzfeldt–Jakob disease, only dura mater graft-associated Creutzfeldt–Jakob disease cases were reported in Japan and, combined with the data from previous surveillance systems, the total number of dura mater graft-associated Creutzfeldt–Jakob disease was 138, comprising the majority of worldwide dura mater graft-associated Creutzfeldt–Jakob disease patients. Regarding genetic prion diseases, the most common mutation of prion protein gene was V180I (41.2%), followed by P102L (18.1%), E200K (17.1%) and M232R (15.3%), and this distribution was quite different from that in Europe. In particular, V180I and M232R were quite rare mutations worldwide. Patients with V180I or M232R mutations rarely had a family history of prion diseases, indicating that a genetic test for sporadic cases is necessary to distinguish these from sporadic Creutzfeldt–Jakob disease. In conclusion, our prospective 10-year surveillance revealed a frequent occurrence of dura mater graft-associated Creutzfeldt–Jakob disease, and unique phenotypes of sporadic Creutzfeldt–Jakob disease and genetic prion diseases related to the characteristic distribution of prion protein gene mutations and polymorphisms in Japan, compared with those in western countries.

  T Kubo , Y Kuroda , H Shimizu , A Kokubu , N Okada , F Hosoda , Y Arai , Y Nakamura , H Taniguchi , K Yanagihara , I Imoto , J Inazawa , S Hirohashi and T. Shibata
 

The tyrosine kinase (TK) family is an important regulator of signaling pathways that control a variety of physiological and pathological conditions, and a substantial proportion of TK genes are genetically altered in cancer. To clarify the somatic mutation profile of TK genes and discover potential targets for gastric cancer (GC) therapy, we undertook a systematic screening of mutations in the kinase domains of all human TK genes (636 exons of 90 genes) in 17 GC cell lines and 52 microdissected primary GCs with poorly differentiated histology. We identified 26 non-synonymous alterations (22 genes in total) that included 11 sequence alterations in cell lines and 15 somatic mutations in primary tumors. Recurrent mutations were found in four genes including a known oncogene (NTRK3), the Src kinase family (LTK and CSK) and a potential Wnt signal activator (ROR2). In addition, we analyzed copy number alterations of all the TK gene loci in the same cohort samples by array-based comparative genomic hybridization analysis and identified 24 high-level amplifications and two homozygous deletions. Both sequence alteration and frequent copy number aberration were detected in two TK genes (HCK and ERBB2), strongly suggesting that they encode potential oncogenes in GC. Our focused and integrated analyses of systemic resequencing and gene copy number have revealed the novel onco-kinome profile of GC and pave the way to a comprehensive understanding of the GC genome.

  N Hosono , M Kato , K Kiyotani , T Mushiroda , S Takata , H Sato , H Amitani , Y Tsuchiya , K Yamazaki , T Tsunoda , H Zembutsu , Y Nakamura and M. Kubo
 

Background: Cytochrome P450 2D6 (CYP2D6), one of the most important drug-metabolizing enzymes, has been reported to possess variation in the encoding CYP2D6 gene (cytochrome P450, family 2, subfamily D, polypeptide 6) that affects enzymatic activity. For the pharmacogenetic study of CYP2D6, accurate measurement of the dosage of the functional gene is essential; however, current genotyping techniques are insufficient because of their inability to provide the exact copy number of functional CYP2D6 genes.

Methods: We developed 3 quantitative real-time PCR (qPCR) assays for estimating the total copy number of the CYP2D6 gene, as well as 24-multiplex PCR-based real-time Invader assays (mPCR-RETINAs) for estimating the allele ratio at each variation locus. After determining the allele copy number at each locus, we estimated the frequencies of CYP2D6 alleles in a population and the diplotype in each individual by a CNVphaser (copy number variation phaser). The qPCR assays and RETINAs used for HapMap Japanese and Chinese samples were applied to 455 Japanese individuals.

Results: Forty-two individuals (9.2%) had one CYP2D6 gene copy, 207 (45.5%) had 2 copies, 161 (35.4%) had 3 copies, 40 (8.8%) had 4 copies, and 5 (1.1%) had 5 copies of the CYP2D6 gene. We found 16 different CYP2D6 alleles, with frequencies similar to those described in previous reports. In the diplotype analysis, we observed that CYP2D6*1/*1 and *1/*10-*36 were the most common diplotypes (approximately 20%) in our population.

Conclusions: Our method is the first to determine the exact number of functional CYP2D6 gene copies. We believe our method will facilitate and accelerate the detailed pharmacogenetic analysis of CYP2D6.

  Y Nakamura , P. J Hornsby , P Casson , R Morimoto , F Satoh , Y Xing , M. R Kennedy , H Sasano and W. E. Rainey
 

Context: The human adrenal gland produces small amounts of testosterone that are increased under pathological conditions. However, the mechanisms through which the adrenal gland produces testosterone are poorly defined.

Objective: Our objective was to define the role of type 5 17β-hydroxysteroid dehydrogenase (AKR1C3) in human adrenal production of testosterone.

Design and Methods: Adrenal vein sampling was used to confirm ACTH stimulation of adrenal testosterone production. Adrenal expression of AKR1C3 was studied using microarray, quantitative real-time RT-PCR, and immunohistochemical analyses. AKR1C3 knockdown was accomplished in cultured adrenal cells (H295R) using small interfering RNA, followed by measurement of testosterone production.

Results: Acute ACTH administration significantly increased adrenal vein testosterone levels. Examination of the enzymes required for the conversion of androstenedione to testosterone using microarray analysis, quantitative real-time RT-PCR, and immunohistochemistry demonstrated that AKR1C3 was present in the adrenal gland and predominantly expressed in the zona reticularis. Decreasing adrenal cell expression of AKR1C3 mRNA and protein inhibited testosterone production in the H295R adrenal cell line.

Conclusions: The human adrenal gland directly secretes small, but significant, amounts of testosterone that increases in diseases of androgen excess. AKR1C3 is expressed in the human adrenal gland, with higher levels in the zona reticularis than in the zona fasciculata. AKR1C3, through its ability to convert androstenedione to testosterone, is likely responsible for adrenal testosterone production.

  M. M Islam , C Tani , M Watanabe Sugimoto , M Uraji , Md. S Jahan , C Masuda , Y Nakamura , I. C Mori and Y. Murata
 

Thioglucoside glucohydrolase (myrosinase), TGG1, is a strikingly abundant protein in Arabidopsis guard cells. We investigated responses of tgg1-3, tgg2-1 and tgg1-3 tgg2-1 mutants to abscisic acid (ABA) and methyl jasmonate (MeJA) to clarify whether two myrosinases, TGG1 and TGG2, function during stomatal closure. ABA, MeJA and H2O2 induced stomatal closure in wild type, tgg1-3 and tgg2-1, but failed to induce stomatal closure in tgg1-3 tgg2-1. All mutants and wild type showed Ca2+-induced stomatal closure and ABA-induced reactive oxygen species (ROS)production. A model is discussed in which two myrosinases redundantly function downstream of ROS production and upstream of cytosolic Ca2+ elevation in ABA and MeJA signaling in guard cells.

  T Takahashi , T Ida , T Sato , Y Nakashima , Y Nakamura , A Tsuji and M. Kojima
 

Ghrelin was originally isolated from rat stomach as an endogenous ligand for the GH secretagogue receptor. The major active form of ghrelin is a 28-amino acid peptide modified by an n-octanoic acid on the serine 3 residue, and this lipid modification is essential for the biological activity of ghrelin. However, it is not clear whether prohormone convertase (PC) and ghrelin O-acyltransferase (GOAT) are the minimal requirements for synthesis of acyl-modified ghrelin in cultured cells. By using three cultured cell lines, TT, AtT20 and COS-7, in which the expression levels of processing proteases and GOAT vary, we examined the processing patterns of ghrelin precursor. We found that not only PC1/3 but also both PC2 and furin could process proghrelin to the 28-amino acid ghrelin. Moreover, the presence of PC and GOAT in the cells, as well as n-octanoic acid in the culture medium, was necessary to produce n-octanoyl ghrelin.

 
 
 
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