Takashi Fujii
Osaka University
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Publication
Featured researches published by Takashi Fujii.
American Journal of Medical Genetics | 2009
Noriko Fukumoto; Takashi Fujii; Onofre Combarros; M. Ilyas Kamboh; Shin-Jen Tsai; Sachio Matsushita; Benedetta Nacmias; David E. Comings; Humberto Arboleda; Martin Ingelsson; Bradley T. Hyman; Hiroyasu Akatsu; Andrew Grupe; Agnes L. Nishimura; Mayana Zatz; Kari Mattila; Juha O. Rinne; Yu-ichi Goto; Takashi Asada; Shun Nakamura; Hiroshi Kunugi
Conflicting results have been reported as to whether genetic variations (Val66Met and C270T) of the brain‐derived neurotrophic factor gene (BDNF) confer susceptibility to Alzheimers disease (AD). We genotyped these polymorphisms in a Japanese sample of 657 patients with AD and 525 controls, and obtained weak evidence of association for Val66Met (Pu2009=u20090.063), but not for C270T. After stratification by sex, we found a significant allelic association between Val66Met and AD in women (Pu2009=u20090.017), but not in men. To confirm these observations, we collected genotyping data for each sex from 16 research centers worldwide (4,711 patients and 4,537 controls in total). The meta‐analysis revealed that there was a clear sex difference in the allelic association; the Met66 allele confers susceptibility to AD in women (odds ratiou2009=u20091.14, 95% CI 1.05–1.24, Pu2009=u20090.002), but not in men. Our results provide evidence that the Met66 allele of BDNF has a sexually dimorphic effect on susceptibility to AD.
Science | 2012
P. Gayathri; Takashi Fujii; Jakob Møller-Jensen; F van den Ent; Keiichi Namba; Jan Löwe
Plasmid Partitioning Bacterial plasmids need to be able to partition faithfully into daughter cells. Combining structural data and advanced microscopy, Gayathri et al. (p. 1334, published online 25 October; see the cover) describe how actin-like ParM filaments form a bipolar spindle for the faithful segregation of low-copy-number plasmids to the two cell poles of Escherichia coli, despite being polar, with two distinct ends. ParM filaments are elongated by a small adaptor protein ParR that physically links the filament end(s) to a centromere-like region on the plasmid. Antiparallel filament bundling and sliding appear to produce a bipolar spindle made of filaments that elongate unidirectionally so that all the plasmids are segregated together in one large bundle. A bipolar spindle, formed by antiparallel actinlike filaments, pushes sister plasmids apart. To ensure their stable inheritance by daughter cells during cell division, bacterial low-copy-number plasmids make simple DNA segregating machines that use an elongating protein filament between sister plasmids. In the ParMRC system of the Escherichia coli R1 plasmid, ParM, an actinlike protein, forms the spindle between ParRC complexes on sister plasmids. By using a combination of structural work and total internal reflection fluorescence microscopy, we show that ParRC bound and could accelerate growth at only one end of polar ParM filaments, mechanistically resembling eukaryotic formins. The architecture of ParM filaments enabled two ParRC-bound filaments to associate in an antiparallel orientation, forming a bipolar spindle. The spindle elongated as a bundle of at least two antiparallel filaments, thereby pushing two plasmid clusters toward the poles.
The Journal of Clinical Psychiatry | 2014
Shintaro Ogawa; Takashi Fujii; Norie Koga; Hiroaki Hori; Toshiya Teraishi; Kotaro Hattori; Takamasa Noda; Teruhiko Higuchi; Nobutaka Motohashi; Hiroshi Kunugi
OBJECTIVEnTryptophan, an essential amino acid, is the precursor to serotonin and is metabolized mainly by the kynurenine pathway. Both serotonin and kynurenine have been implicated in the pathophysiology of major depressive disorder (MDD). However, plasma tryptophan concentration in patients with MDD has not unequivocally been reported to be decreased, which prompted us to perform a meta-analysis on previous studies and our own data.nnnDATA SOURCESnWe searched the PubMed database for case-control studies published until August 31, 2013, using the search terms plasma AND tryptophan AND synonyms for MDD. An additional search was performed for the term amino acid instead of tryptophan. We obtained our own data in 66 patients with MDD (DSM-IV) and 82 controls who were recruited from March 2011 to July 2012. The majority of the patients were medicated (N = 53). Total plasma tryptophan concentrations were measured by the liquid chromatography/mass spectrometry method.nnnSTUDY SELECTIONnWe scrutinized 160 studies for eligibility. Original articles that were written in English and documented plasma tryptophan values in patients and controls were selected.nnnDATA EXTRACTIONnWe included 24 studies from the literature and our own data in the meta-analysis, which involved a total of 744 patients and 793 controls. Data on unmedicated patients (N = 156) and their comparison subjects (N = 203) were also extracted. To see the possible correlation between tryptophan concentrations and depression severity, meta-regression analysis was performed for 10 studies with the Hamilton Depression Rating Scale 17-item version score.nnnRESULTSnIn our case-control study, mean (SD) plasma tryptophan level was significantly decreased in the MDD patients versus the controls (53.9 [10.9] vs 57.2 [11.3] μmol/L; P = .03). The meta-analysis after adjusting for publication bias showed a significant decrease in patients with MDD with a modest effect size (Hedges g, -0.45). However, analysis on unmedicated subjects yielded a large effect (Hedges g, -0.84; P = .00015). We found a weak association with depression severity in the meta-regression analysis (P = .049).nnnCONCLUSIONSnThis meta-analysis provides convincing evidence for reduced plasma tryptophan levels in patients with MDD, particularly in unmedicated patients.
Journal of Psychiatric Research | 2012
Takashi Fujii; Miho Ota; Hiroaki Hori; Daimei Sasayama; Kotaro Hattori; Toshiya Teraishi; Noriko Yamamoto; Miyako Hashikura; Masahiko Tatsumi; Teruhiko Higuchi; Hiroshi Kunugi
Human P-glycoprotein (P-gp), which is encoded by ABCB1 (ATP-binding cassette, sub-family B member 1), is expressed in the blood brain barrier and protects the brain from many kinds of drugs and toxins including glucocorticoids by acting as an efflux pump. We examined whether functional polymorphisms of ABCB1 give susceptibility to major depressive disorder (MDD). The five functional single nucleotide polymorphisms (SNPs), A-41G (rs2188524), T-129C (rs3213619), C1236T (Gly412Gly: rs1128503), G2677A/T (Ala893Ser/Thr: rs2032582), and C3435T (Ile1145Ile: rs1045642) were genotyped in 631 MDD patients and 1100 controls in the Japanese population. A tri-allelic SNP, G2677A/T, was genotyped by pyrosequencing and the remaining SNPs were genotyped by the TaqMan 5-exonuclease allelic discrimination assay. The minor T3435 allele was significantly increased in MDD patients than in the controls (χ(2)xa0=xa04.5, dfxa0=xa01, pxa0=xa00.034, odds ratio [OR] 1.16, 95% confidential interval [CI] 1.01-1.34). Homozygotes for the T3435 allele was significantly more common in patients than in the controls (χ(2)xa0=xa07.5, dfxa0=xa01, pxa0=xa00.0062, OR 1.43, 95%CI 1.11-1.85). With respect to the other 4 SNPs, there was no significant difference in genotype or allele distribution. In the haplotype-based analysis, the proportion of individuals with the TT1236-TT3435 haploid genotype was significantly increased in patients than in controls (χ(2)xa0=xa08.5, dfxa0=xa01, p = 0.0037, OR 1.50, 95%CI 1.14-1.98). Our results suggest that the T3435 allele or carrying two copies of this allele confers susceptibility to MDD in the Japanese population.
Scientific Reports | 2012
Hiroaki Hori; Noriko Yamamoto; Takashi Fujii; Toshiya Teraishi; Daimei Sasayama; Junko Matsuo; Yumiko Kawamoto; Yukiko Kinoshita; Miho Ota; Kotaro Hattori; Masahiko Tatsumi; Kunimasa Arima; Hiroshi Kunugi
Recent genetic association studies have identified the A-allele of rs1006737 within CACNA1C as a risk factor for schizophrenia as well as mood disorders. Some evidence suggests that this polymorphism plays a role in cognitive function both in schizophrenia patients and healthy individuals; however, the precise nature of this association remains unclear. Here we investigated the possible association of this polymorphism with a wide range of neurocognitive functions in schizophrenia patients and in healthy subjects. Schizophrenia patients exhibited significantly poorer performance on all the cognitive domains as compared to healthy controls. In patients, A-allele carriers demonstrated significantly worse logical memory performance than the G-allele homozygotes. In controls, no significant association was observed between the genotype and any of the cognitive domains examined. These results add to the literature suggesting that rs1006737 may be associated with schizophrenia through its detrimental effect on endophenotypic traits.
Psychoneuroendocrinology | 2014
Takashi Fujii; Hiroaki Hori; Miho Ota; Kotaro Hattori; Toshiya Teraishi; Daimei Sasayama; Noriko Yamamoto; Teruhiko Higuchi; Hiroshi Kunugi
Regulation of hypothalamic-pituitary-adrenal (HPA) axis reactivity plays an important role in the development of stress-related psychiatric disorders. FK506 binding protein 5 (FKBP5) modulates HPA axis reactivity via glucocorticoid receptor (GR; NR3C1) sensitivity and signaling. The T allele of the single nucleotide polymorphism, FKBP5 rs1360780 (C/T), is associated with higher FKBP5 induction by glucocorticoids. In the present study, we performed the dexamethasone/corticotropin releasing hormone (DEX/CRH) test and quantitative real-time PCR analysis of peripheral blood mononuclear cell (PBMC) cDNA samples in 174 and 278 non-clinical individuals, respectively. We found increased suppression of the stress hormone (cortisol) response to the DEX/CRH test (P=0.0016) in aged (>50 years) individuals carrying the T allele compared with aged non-T allele carriers. T carriers showed significant age-related changes in GR and FKBP5 mRNA expression levels in PBMCs (P=0.0013 and P=0.00048, respectively). Our results indicate that FKBP5 rs1360780 regulates HPA axis reactivity and expression levels of GR and FKBP5 in PBMCs in an age-dependent manner. Because these phenotypes of aged T carriers are similar to endophenotypes of people with post-traumatic stress disorder, our findings may be useful for determining the molecular mechanisms, treatment, and preventive strategies for this disease.
Behavioral and Brain Functions | 2011
Daimei Sasayama; Hiroaki Hori; Yoshimi Iijima; Toshiya Teraishi; Kotaro Hattori; Miho Ota; Takashi Fujii; Teruhiko Higuchi; Naoji Amano; Hiroshi Kunugi
BackgroundRecently, hypothalamus-pituitary-adrenal (HPA) axis function assessed with the combined dexamethasone (DEX)/corticotropin releasing hormone (CRH) test has been shown to be associated with response to antidepressant treatment. A polymorphism (rs16944) in the interleukin-1beta (IL-1β) gene has also been reported to be associated with the medication response in depression. These findings prompted us to examine the possible association between IL-1β gene polymorphisms and HPA axis function assessed with the DEX/CRH test.MethodsDEX/CRH test was performed in 179 healthy volunteers (45 males: mean age 40.5 ± 15.8 years; 134 females: mean age 47.1 ± 13.2 years). Five tagging single nucleotide polymorphisms (SNPs) of IL-1β gene (rs2853550, rs1143634, rs1143633, rs1143630, rs16944) were selected at an r2 threshold of 0.80 with a minor allele frequency > 0.1. Genotyping was performed by the TaqMan allelic discrimination assay. A two-way factorial analysis of variance (ANOVA) was performed with the DEX/CRH test results as the dependent variable and genotype and gender as independent variables. To account for multiple testing, P values < 0.01 were considered statistically significant for associations between the genotypes and the cortisol levels.ResultsThe cortisol levels after DEX administration (DST-Cortisol) showed significant associations with the genotypes of rs16944 (P = 0.00049) and rs1143633 (P = 0.0060), with no significant gender effect or genotype × gender interaction. On the other hand, cortisol levels after CRH administration (DEX/CRH-Cortisol) were affected by gender but were not significantly influenced by the genotype of the examined SNPs, with no significant genotype × gender interaction.ConclusionsOur results suggest that genetic variations in the IL-1β gene contribute to the HPA axis alteration assessed by DST-Cortisol in healthy subjects. On the other hand, no significant associations of the IL-1β gene polymorphisms with the DEX/CRH-Cortisol were observed. Confirmation of our findings in futures studies may add new insight into the communication between the immune system and the HPA axis.
Current Molecular Pharmacology | 2009
Takashi Fujii; Hiroshi Kunugi
The p75 neurotrophin receptor (p75NTR) was originally identified as a low-affinity receptor for neurotrophins. Recent studies have revealed that p75NTR can promote cell death or survival and modulate neurite outgrowth depending on the operative ligands and co-receptors. Up-regulation and ligand activation of p75NTR have been shown to be involved in neuronal cell death in cultured cells and animal models of neurodegenerative diseases. The levels of proneurotrophins, which bind to p75NTR to promote neuronal death, have been found to be increased in postmortem brains of patients with Alzheimers disease. Furthermore, there is some evidence for the involvement of this molecule in psychiatric diseases, such as depression and schizophrenia. Mice lacking p75NTR have been shown to have several alterations in central nervous system and cognitive function. Notably, recent progress in genome-based drug discovery has enabled the identification of peptides and non-peptide small molecules targeting p75NTR, which may be potentially beneficial in the treatment of neuropsychiatric diseases. In this review, we focus on recent findings on p75NTR as a therapeutic target for neuropsychiatric diseases.
Nature Communications | 2017
Takashi Fujii; Keiichi Namba
Muscle contraction is driven by cyclic association and dissociation of myosin head of the thick filament with thin actin filament coupled with ATP binding and hydrolysis by myosin. However, because of the absence of actomyosin rigour structure at high resolution, it still remains unclear how the strong binding of myosin to actin filament triggers the release of hydrolysis products and how ATP binding causes their dissociation. Here we report the structure of mammalian skeletal muscle actomyosin rigour complex at 5.2u2009Å resolution by electron cryomicroscopy. Comparison with the structures of myosin in various states shows a distinctly large conformational change, providing insights into the ATPase-coupled reaction cycle of actomyosin. Based on our observations, we hypothesize that asymmetric binding along the actin filament could function as a Brownian ratchet by favouring directionally biased thermal motions of myosin and actin.
Scientific Reports | 2015
Takashi Fujii; Miho Ota; Hiroaki Hori; Kotaro Hattori; Toshiya Teraishi; Junko Matsuo; Yukiko Kinoshita; Ikki Ishida; Anna Nagashima; Hiroshi Kunugi
The common single nucleotide polymorphism (SNP) rs1360780 (C/T) of the FK506 Binding Protein 5 (FKBP5) gene has been reported to be associated with an altered response of the hypothalamic-pituitary-adrenal (HPA) axis and the development of stress-related psychiatric disorders such as posttraumatic stress disorder (PTSD). In the present study, we examined whether this SNP is associated with cognitive function in a non-clinical population. The full versions of the Wechsler Memory Scale-Revised and Wechsler Adult Intelligence Scale-Revised were administered to 742 and 627 Japanese individuals, respectively, followed by genotyping of rs1360780 by the TaqMan 5′-exonuclease allelic discrimination assay. For both cognitive tests, we found significantly poorer attention/concentration (working memory) in aged (>50 years old) individuals carrying the T allele compared with their counterparts. This finding accords with an altered HPA axis and vulnerability to stress-related psychiatric disorders.