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Toyama Y.,University of Tokyo | Toyama Y.,AOMi Inc | Kano H.,University of Tokyo | Mase Y.,University of Tokyo | And 5 more authors.
Nature Communications | Year: 2017

Heterotrimeric guanine-nucleotide-binding proteins (G proteins) serve as molecular switches in signalling pathways, by coupling the activation of cell surface receptors to intracellular responses. Mutations in the G protein α-subunit (Gα) that accelerate guanosine diphosphate (GDP) dissociation cause hyperactivation of the downstream effector proteins, leading to oncogenesis. However, the structural mechanism of the accelerated GDP dissociation has remained unclear. Here, we use magnetic field-dependent nuclear magnetic resonance relaxation analyses to investigate the structural and dynamic properties of GDP bound Gα on a microsecond timescale. We show that Gα rapidly exchanges between a ground-state conformation, which tightly binds to GDP and an excited conformation with reduced GDP affinity. The oncogenic D150N mutation accelerates GDP dissociation by shifting the equilibrium towards the excited conformation. ©The Author(s) 2017.

Amo R.,RIKEN | Amo R.,Waseda University | Aizawa H.,RIKEN | Aizawa H.,Japan Science and Technology Agency | And 8 more authors.
Journal of Neuroscience | Year: 2010

The mammalian habenula consists of the medial and lateral habenulae. Recent behavioral and electrophysiological studies suggested that the lateral habenula plays a pivotal role in controlling motor and cognitive behaviors by influencing the activity of dopaminergic and serotonergic neurons. Despite the functional significance, manipulating neural activity in this pathway remains difficult because of the absence of a genetically accessible animal model such as zebrafish. To address the level of lateral habenula conservation in zebrafish, we applied the tract-tracing technique to GFP(green fluorescent protein)-expressing transgenic zebrafish to identify habenular neurons that project to the raphe nuclei, a major target of the mammalian lateral habenula. Axonal tracing in live and fixed fish showed projection of zebrafish ventral habenula axons to the ventral part of the median raphe, but not to the interpeduncular nucleus where the dorsal habenula projected. The ventral habenula expressed protocadherin 10a, a specific marker of the rat lateral habenula, whereas the dorsal habenula showed no such expression. Gene expression analyses revealed that the ventromedially positioned ventral habenula in the adult originated from the region of primordium lateral to the dorsal habenula during development. This suggested that zebrafish habenulae emerge during development with mediolateral orientation similar to that of the mammalian medial and lateral habenulae. These findings indicated that the lateral habenular pathways are evolutionarily conserved pathways and might control adaptive behaviors in vertebrates through the regulation of monoaminergic activities. Copyright © 2010 the authors.

Azehara S.,Chuo University | Nakata T.,AOMi Inc | Kato T.,Chuo University
Advances in Intelligent Systems and Computing | Year: 2018

Experiment was conducted on the memory in the impression of video. I used a TV commercial (TVCM) to use it as an video. Based on the author’s previous research, we conducted experiments using NIRS this time. Focusing on the impression of TVCM, the presence or absence of memory fixation in impression was measured by using a task of removing visual/audio infor-mation other than impression factors. As a result, impression and suggestion of brain region related to memory was obtained. © Springer International Publishing AG 2018.

Katsuda T.,National Cancer Center Research Institute | Katsuda T.,University of Tokyo | Tsuchiya R.,AOMi Inc | Kosaka N.,National Cancer Center Research Institute | And 7 more authors.
Scientific Reports | Year: 2013

Alzheimer's disease (AD) is characterized by the accumulation of β-amyloid peptide (Aβ) in the brain because of an imbalance between Aβ production and clearance. Neprilysin (NEP) is the most important Aβ-degrading enzyme in the brain. Thus, researchers have explored virus-mediated NEP gene delivery. However, such strategies may entail unexpected risks, and thus exploration of a new possibility for NEP delivery is also required. Here, we show that human adipose tissue-derived mesenchymal stem cells (ADSCs) secrete exosomes carrying enzymatically active NEP. The NEP-specific activity level of 1 μg protein from ADSC-derived exosomes was equivalent to that of ∼ 0.3 ng of recombinant human NEP. Of note, ADSC-derived exosomes were transferred into N2a cells, and were suggested to decrease both secreted and intracellular Aβ levels in the N2a cells. Importantly, these characteristics were more pronounced in ADSCs than bone marrow-derived mesenchymal stem cells, suggesting the therapeutic relevance of ADSC-derived exosomes for AD.

Urata H.,Chuo University | Sakamoto T.,AOMi Inc | Kato T.,Chuo University
Advances in Intelligent Systems and Computing | Year: 2018

Recently, methods for motivating people who do not have an exercise habit have been attracting public attention, because lifestyle-related diseases are becoming a serious issue. While few people possess such a habit, frequent physical exercise is necessary in order to prevent lifestyle-related diseases. To address this issue, it is important to increase motivation for physical exercise. Yet, effective methods for creating this motivation have not been established. This research aims to clarify effective methods for motivating people who lack an exercise habit. We focus on the sense of value for physical exercise, and its use for motivation. The study results succeeded in increasing the amount of physical exercise completed by the subjects. © Springer International Publishing AG 2018.

Wada M.,AOMi Inc | Wada M.,Fujitsu Limited | Kanamori E.,AOMi Inc | Kanamori E.,Hitachi Solutions | And 2 more authors.
Journal of Chemical Information and Modeling | Year: 2011

We developed a new protocol for in silico drug screening for G-protein-coupled receptors (GPCRs) using a set of "universal active probes" (UAPs) with an ensemble docking procedure. UAPs are drug-like compounds, which are actual active compounds of a variety of known proteins. The current targets were nine human GPCRs whose three-dimensional (3D) structures are unknown, plus three GPCRs, namely β2-adrenergic receptor (ADRB2), A2A adenosine receptor (A2A), and dopamine D3 receptor (D3), whose 3D structures are known. Homology-based models of the GPCRs were constructed based on the crystal structures with careful sequence inspection. After subsequent molecular dynamics (MD) simulation taking into account the explicit lipid membrane molecules with periodic boundary conditions, we obtained multiple model structures of the GPCRs. For each target structure, docking-screening calculations were carried out via the ensemble docking procedure, using both true active compounds of the target proteins and the UAPs with the multiple target screening (MTS) method. Consequently, the multiple model structures showed various screening results with both poor and high hit ratios, the latter of which could be identified as promising for use in in silico screening to find candidate compounds to interact with the proteins. We found that the hit ratio of true active compounds showed a positive correlation to that of the UAPs. Thus, we could retrieve appropriate target structures from the GPCR models by applying the UAPs, even if no active compound is known for the GPCRs. Namely, the screening result that showed a high hit ratio for the UAPs could be used to identify actual hit compounds for the target GPCRs. © 2011 American Chemical Society.

Maruyama Y.,Japan National Institute of Advanced Industrial Science and Technology | Kawamura Y.,AOMi Inc | Nishikawa T.,Hitachi Ltd. | Isogai T.,University of Tokyo | And 2 more authors.
Nucleic Acids Research | Year: 2012

The Human Gene and Protein Database (HGPD; is a unique database that stores information on a set of human Gateway entry clones in addition to protein expression and protein synthesis data. The HGPD was launched in November 2008, and 33 275 human Gateway entry clones have been constructed from the open reading frames (ORFs) of full-length cDNA, thus representing the largest collection in the world. Recently, research objectives have focused on the development of new medicines and the establishment of novel diagnostic methods and medical treatments. And, studies using proteins and protein information, which are closely related to gene function, have been undertaken. For this update, we constructed an additional 9974 human Gateway entry clones, giving a total of 43 249. This set of human Gateway entry clones was named the Human Proteome Expression Resource, known as the 'HuPEX'. In addition, we also classified the clones into 10 groups according to protein function. Moreover, in vivo cellular localization data of proteins for 32 651 human Gateway entry clones were included for retrieval from the HGPD. In 'Information Overview', which presents the search results, the ORF region of each cDNA is now displayed allowing the Gateway entry clones to be searched more easily. © The Author(s) 2011. Published by Oxford University Press.

Handa N.,Shinshushinmachi Fossil Museum | Nakada K.,Josai University | Anso J.,AOMi Inc | Matsuoka A.,Niigata University
Newsletters on Stratigraphy | Year: 2014

The definition of the Global Boundary Stratotype Section and Point (GSSP) of the Bathonian/ Callovian (Middle Jurassic) boundary is under debate in Europe. The sections that include the Bathonian/ Callovian boundary are still limited in East Asia. In Japan, the Middle Jurassic Kaizara Formation, which is located within the Tetori Group, is exposed in Fukui Prefecture, central Japan. This formation contains abundant ammonite fossils. On the basis of ammonite fossils, the Kaizara Formation has been assigned to the late Bathonian to early Callovian age. Therefore, the Kaizara Formation is an important formation encompassing the Bathonian/Callovian boundary in East Asia. However, the fossil-bearing horizons have not been observed clearly in previous studies. In the present study, a detailed analysis of the molluscan fossil-bearing horizons of the Kaizara Formation was conducted utilizing three stratigraphic successions. On the basis of seven identified genera and nine species of ammonites, the presence of three successive assemblage zones first proposed by a previous study is confirmed: the Pseudoneuqueniceras yokoyamai, the Kepplerites japonicus, and the Oxycerites assemblage zones. Of these, the Pseudoneuqueniceras yokoyamai Assemblage Zone was assumed to correspond to the Orbis- Oppeli Zone (late Bathonian), and the Kepplerites assemblage Zone was assumed to be comparable to the early Callovian age. These results indicate that the Bathonian/Callovian boundary lies within the middle part of the Kaizara Formation. © 2014 Gebrüder Borntraeger, Stuttgart, Germany.

Ono K.,AOMi Inc | Ono K.,Japan National Institute of Advanced Industrial Science and Technology | Ueda H.,AOMi Inc | Yoshizawa Y.,AOMi Inc | And 5 more authors.
Journal of Medicinal Chemistry | Year: 2010

GPVI is a key receptor for collagen-induced platelet activation. Loss or inhibition of GPVI causes only mildly prolonged bleeding times but prevents arterial thrombus formation in animal models. Therefore, GPVI is considered to be a potent target molecule for therapy of thrombotic diseases. Recently, it was reported that the AT1-receptor antagonist losartan (DuP-753) and EXP3179 inhibit platelet adhesion and aggregation via GPVI. However, it is still not clear how losartan is associated with inhibition of binding between GPVI and collagen at the molecular level. Here, we show by NMR that losartan directly interacts with the hydrophobic region consisting of strands C and E in the N-terminal Ig-like domain of GPVI. A reliable GPVI-losartan complex model is presented by using a combination of NMR data and in silico tools. These data indicated that the phenyl group with the tetrazole ring in losartan plays a crucial role in the interaction with GPVI. © 2010 American Chemical Society.

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