Details of the Researcher

PHOTO

Kazunori Yamada
Section
Unprecedented-scale Data Analytics Center
Job title
Professor
Degree

  • 博士（生命科学）（東京大学）

  • 修士（薬学）（九州大学）

Research Interests 3

  • Artificial intelligence

  • Machine learning

  • Sequence analysis

Research Areas 2

  • Informatics / Intelligent informatics /

  • Informatics / Biological, health, and medical informatics /

Papers 40

  1. Simulating Metabolic Pathways to Enhance Interpretations of Metabolome Genome-wide Association Studies Peer-reviewed

    Kodate S, Sato M, Hishinuma E, Kojima K, Motoike IN, ToMMo Study Group, Koshiba S, Yamamoto M, Yamada KD, Kinoshita K

    Scientific Reports　2025

  2. Effect of Cumulative Exposure on the Efficacy of Paroxetine: a Population Pharmacokinetic-pharmacodynamic and Machine Learning Analyses Peer-reviewed

    Shigetome K, Egarashi T, Tomita T, Higa N, Iwashita K, Morita K, Nishimura M, Kankeko T, Maeda H, Yamada KD, Kajiwara-Morita A, Oniki K, Yasui-Furukori N, Saruwatari J

    Pharmacometrics and Systems Pharmacology　2025

  3. GPS: A Probabilistic Distributional Similarity with Gumbel Priors for Set-to-Set Matching Peer-reviewed

    Lin F, Liu H, Zhang Z, Morales J, Zhang HK, Yamada KD, Kolachalama V, Saligrama V

    International Conference on Learning Representations　2025

  4. Learning Random Numbers to Realize Appendable Memory System for Artificial Intelligence to Acquire New Knowledge after Deployment Peer-reviewed

    Kubota A, Kodate S, Li Y, Lin F, Fukuda H, Baladram MS, Yamada KD

    Interdisciplinary Information Sciences　2025

  5. Loss Distillation via Gradient Matching for Point Cloud Completion with Weighted Chamfer Distance Peer-reviewed

    Lin F, Liu H, Zhou H, Hou S, Yamada KD, Fischer GS, Li Y, Zhang H, Zhang Z

    IEEE/RSJ International Conference on Intelligent Robots and Systems　2024

  6. Question generation for English reading comprehension exercises using Transformers Peer-reviewed

    Maas A, Yamada KD, Nagahama T, Kawada T, Horita T

    Letters on Informatics and Interdisciplinary Research　2024

  7. InfoCD: A contrastive chamfer distance loss for point cloud completion Peer-reviewed

    Lin F, Yue Y, Zhang Z, Hou S, Yamada KD, Kolachalama VB, Saligrama V

    Advances in Neural Information Processing Systems　2023

  8. Hyperbolic chamfer distance for point cloud completion Peer-reviewed

    Lin F, Yue Y, Hou S, Yu X, Xu Y, Yamada KD, Zhang Z

    International Conference on Computer Vision　2023

  9. Serum fatty acid composition balance by fuzzy c-means method in individuals with or without metabolic dysfunction-associated fatty liver disease Peer-reviewed

    Nagase Y, Satoh T, Shigetome K, Tokumaru N, Matsumoto E, Yamada KD, Imafuku T, Watanabe H, Maruyama T, Ogata Y, Yoshida M, Saruwatari J, Oniki K

    Nutrients　15　(4)　809-809　2023

    Publisher: MDPI AG

    DOI： 10.3390/nu15040809 　

    eISSN： 2072-6643

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    Circulating fatty acid composition is assumed to play an important role in metabolic dysfunction-associated fatty liver disease (MAFLD) pathogenesis. This study aimed to investigate the association between the overall balance of serum fatty acid composition and MAFLD prevalence. This cross-sectional study involved 400 Japanese individuals recruited from a health-screening program. We measured fatty acids in serum lipids using gas chromatography–mass spectrometry. The serum fatty acid composition balance was evaluated using fuzzy c-means clustering, which assigns individual data points to multiple clusters and calculates the percentage of data points belonging to multiple clusters, and serum fatty acid mass%. The participants were classified into four characteristic subclasses (i.e., Clusters 1, 2, 3, and 4), and the specific serum fatty acid composition balance (i.e., Cluster 4) was associated with a higher MAFLD prevalence. We suggest that the fuzzy c-means method can be used to determine the circulating fatty acid composition balance and highlight the importance of focusing on this balance when examining the relationship between MAFLD and serum fatty acids.

  10. Identifying latent traits of questions for controllable machine generation Peer-reviewed

    Maas A, Kawada T, Yamada K, Nagahama T, Horita T

    EdMedia + Innovate Learning　2022

  11. Redox imaging of dextran sodium sulfate-induced colitis mice treated with nitric oxide synthase inhibitors Peer-reviewed

    Yasukawa K, Yamada K, Tokuda H, Koyama S, Utsumi H

    Advances in Redox Research　6　100047-100047　2022

    Publisher: Elsevier BV

    DOI： 10.1016/j.arres.2022.100047 　

    ISSN： 2667-1379

  12. Relation is an option for processing context information Peer-reviewed

    Yamada KD, Baladram MS, Lin F

    Frontiers in Artificial Intelligence　5　2022

    Publisher: Frontiers Media SA

    DOI： 10.3389/frai.2022.924688 　

    eISSN： 2624-8212

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    Attention mechanisms are one of the most frequently used architectures in the development of artificial intelligence because they can process contextual information efficiently. Various artificial intelligence architectures, such as Transformer for processing natural language, image data, etc., include the Attention. Various improvements have been made to enhance its performance since Attention is a powerful component to realize artificial intelligence. The time complexity of Attention depends on the square of the input sequence length. Developing methods to improve the time complexity of Attention is one of the most popular research topics. Attention is a mechanism that conveys contextual information of input sequences to downstream networks. Thus, if one wants to improve the performance of processing contextual information, the focus should not be confined only on improving Attention but also on devising other similar mechanisms as possible alternatives. In this study, we devised an alternative mechanism called “Relation” that can understand the context information of sequential data. Relation is easy to implement, and its time complexity depends only on the length of the sequences; a comparison of the performance of Relation and Attention on several benchmark datasets showed that the context processing capability of Relation is comparable to that of Attention but with less computation time. Processing contextual information at high speeds would be useful because natural language processing and biological sequence processing sometimes deal with very long sequences. Hence, Relation is an ideal option for processing context information.

  13. Cosmos Propagation Network: Deep learning model for point cloud completion Peer-reviewed

    Lin F, Xu Y, Zhang Z, Gao C, Yamada KD

    Neurocomputing　507　221-234　2022

    Publisher: Elsevier BV

    DOI： 10.1016/j.neucom.2022.08.007 　

    ISSN： 0925-2312

  14. Progress in research on implementing machine consciousness Peer-reviewed

    Yamada KD, Baladram MS, Lin F

    Interdisciplinary Information Sciences　28　(1)　95-105　2022

    Publisher: Graduate School of Information Sciences, Tohoku University

    DOI： 10.4036/iis.2022.r.02 　

    ISSN： 1340-9050

    eISSN： 1347-6157

  15. An effective convolutional neural network for visualized understanding transboundary air pollution based on Himawari-8 satellite images Peer-reviewed

    Lin F, Gao C, Yamada KD

    IEEE Geoscience and Remote Sensing Letters　19　1-5　2022

    DOI： 10.1109/LGRS.2021.3102939 　

  16. Developing a novel recurrent neural network architecture with fewer parameters and good learning performance Peer-reviewed

    Yamada KD, Lin F, Nakamura T

    Interdisciplinary Information Sciences　27　(1)　25-40　2021

    Publisher: Graduate School of Information Sciences, Tohoku University

    DOI： 10.4036/iis.2020.r.01 　

    ISSN： 1340-9050

    eISSN： 1347-6157

  17. Introduction to supervised machine learning for data science Peer-reviewed

    Baladram MS, Koike A, Yamada KD

    Interdisciplinary Information Sciences　26　(1)　87-121　2020

    Publisher: Graduate School of Information Sciences, Tohoku University

    DOI： 10.4036/iis.2020.a.03 　

    ISSN： 1340-9050

    eISSN： 1347-6157

  18. In vivo redox imaging of dextran sodium sulfate-induced colitis in mice using Overhauser-enhanced magnetic resonance imaging International-journal Peer-reviewed

    Yasukawa K, Hirago A, Yamada K, Tun X, Ohkuma K, Utsumi H

    Free Radical Biology and Medicine　136　1-11　2019

    DOI： 10.1016/j.freeradbiomed.2019.03.025 　

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    In ulcerative colitis, an inflammatory bowel disease of unknown cause, diagnosis of the degree and location of colitis at an early stage is required to control the symptoms. Changes in redox status, including the production of reactive oxygen and nitrogen species (RONS), have been associated with ulcerative colitis in humans and dextran sodium sulfate (DSS)-induced colitis in rodents. In this study, the in vivo redox status of colons of DSS-induced colitis mice were monitored by Overhauser-enhanced magnetic resonance imaging (OMRI), and the relationship between redox status and colitis development was investigated. Colitis was induced by administering 5% DSS in drinking water to male Slc:ICR mice, which are a strain classified as closed colony outbred mice (5-week-old, 25-30 g). On the 3rd day of the DSS challenge, when no symptoms of colitis were displayed, the contrast decays of 15N-CmP and 14N-CxP tended to show enhancement in the whole colon and were not altered by DMSO. On the 5th day of the DSS challenge, with histological damage of the rectum being displayed, the contrast decay of 15N-CmP was significantly enhanced not only in the rectum, but also in the proximal colon, and this was suppressed by DMSO. On the 7th day of the DSS challenge, with the mice displaying severe colitis symptoms, the image contrasts of 15N-labeled 3-carbamoyl-2,2,5,5-tetramethylpyrrolidine-1-oxyl (15N-CmP) and 14N-labeled 3-carboxyl-2,2,5,5-tetramethylpyrrolidine-1-oxyl (14N-CxP) showed much faster decay than those of healthy mice, while the increased decays of both probes were restored by the membrane-permeable reactive oxygen species (ROS) scavenger dimethyl sulfoxide (DMSO). Image differencing between the decay rate images of 15N-CmP and 14N-CxP showed the DSS-induced redox imbalance spreading over the whole colon, and a histogram of the difference image showed a smaller peak and broader distribution with the DSS treatment. These data indicate that ROS are produced intracellularly in the distal and proximal colon in the initiation stage of DSS-induced colitis, and that ROS are produced intracellularly and extracellularly in the advanced stage of DSS-induced colitis.

  19. MAFFT online service: multiple sequence alignment, interactive sequence choice and visualization Peer-reviewed

    Katoh K, Rozewicki J, Yamada KD

    Briefings in Bioinformatics　20　(4)　1160-1166　2019

    DOI： 10.1093/bib/bbx108 　

    ISSN： 1467-5463

    eISSN： 1477-4054

  20. De novo profile generation based on sequence context specificity with the long short-term memory network Peer-reviewed

    Yamada KD, Kinoshita K

    BMC Bioinformatics　2018

    DOI： 10.1186/s12859-018-2284-1 　

  21. Parallelization of MAFFT for large-scale multiple sequence alignments Peer-reviewed

    Nakamura T, Yamada KD, Tomii K, Katoh K

    Bioinformatics　34　(14)　2490-2492　2018

    DOI： 10.1093/bioinformatics/bty121 　

    ISSN： 1367-4803

    eISSN： 1460-2059

  22. Derivative-free neural network for optimizing the scoring functions associated with dynamic programming of pairwise-profile alignment Peer-reviewed

    Yamada KD

    Algorithms for molecular biology　2018

    DOI： 10.1186/s13015-018-0123-6 　

  23. Designing better diffracting crystals of biotin carboxyl carrier protein from Pyrococcus horikoshii by a mutation based on crystal-packing propensity of amino acids International-journal Peer-reviewed

    Yamada KD, Kunishima N, Matsuura Y, Nakai K, Naitow H, Fukasawa Y, Tomii K

    Acta Crystallographica Section D　73　(Pt 9)　757-766　2017

    DOI： 10.1107/S2059798317010932 　

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    An alternative rational approach to improve protein crystals by using single-site mutation of surface residues is proposed based on the results of a statistical analysis using a compiled data set of 918 independent crystal structures, thereby reflecting not only the entropic effect but also other effects upon protein crystallization. This analysis reveals a clear difference in the crystal-packing propensity of amino acids depending on the secondary-structural class. To verify this result, a systematic crystallization experiment was performed with the biotin carboxyl carrier protein from Pyrococcus horikoshii OT3 (PhBCCP). Six single-site mutations were examined: Ala138 on the surface of a β-sheet was mutated to Ile, Tyr, Arg, Gln, Val and Lys. In agreement with prediction, it was observed that the two mutants (A138I and A138Y) harbouring the residues with the highest crystal-packing propensities for β-sheet at position 138 provided better crystallization scores relative to those of other constructs, including the wild type, and that the crystal-packing propensity for β-sheet provided the best correlation with the ratio of obtaining crystals. Two new crystal forms of these mutants were obtained that diffracted to high resolution, generating novel packing interfaces with the mutated residues (Ile/Tyr). The mutations introduced did not affect the overall structures, indicating that a β-sheet can accommodate a successful mutation if it is carefully selected so as to avoid intramolecular steric hindrance. A significant negative correlation between the ratio of obtaining amorphous precipitate and the crystal-packing propensity was also found.

  24. Identification of the sequence determinants of protein N-terminal acetylation through a decision tree approach International-journal Peer-reviewed

    Yamada KD, Omori S, Nish H, Miyagi M

    BMC Bioinformatics　18　(1)　289-289　2017

    DOI： 10.1186/s12859-017-1699-4 　

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    BACKGROUND: N-terminal acetylation is one of the most common protein modifications in eukaryotes and occurs co-translationally when the N-terminus of the nascent polypeptide is still attached to the ribosome. This modification has been shown to be involved in a wide range of biological phenomena such as protein half-life regulation, protein-protein and protein-membrane interactions, and protein subcellular localization. Thus, accurately predicting which proteins receive an acetyl group based on their protein sequence is expected to facilitate the functional study of this modification. As the occurrence of N-terminal acetylation strongly depends on the context of protein sequences, attempts to understand the sequence determinants of N-terminal acetylation were conducted initially by simply examining the N-terminal sequences of many acetylated and unacetylated proteins and more recently by machine learning approaches. However, a complete understanding of the sequence determinants of this modification remains to be elucidated. RESULTS: We obtained curated N-terminally acetylated and unacetylated sequences from the UniProt database and employed a decision tree algorithm to identify the sequence determinants of N-terminal acetylation for proteins whose initiator methionine (iMet) residues have been removed. The results suggested that the main determinants of N-terminal acetylation are contained within the first five residues following iMet and that the first and second positions are the most important discriminator for the occurrence of this phenomenon. The results also indicated the existence of position-specific preferred and inhibitory residues that determine the occurrence of N-terminal acetylation. The developed predictor software, termed NT-AcPredictor, accurately predicted the N-terminal acetylation, with an overall performance comparable or superior to those of preceding predictors incorporating machine learning algorithms. CONCLUSION: Our machine learning approach based on a decision tree algorithm successfully provided several sequence determinants of N-terminal acetylation for proteins lacking iMet, some of which have not previously been described. Although these sequence determinants remain insufficient to comprehensively predict the occurrence of this modification, indicating that further work on this topic is still required, the developed predictor, NT-AcPredictor, can be used to predict N-terminal acetylation with an accuracy of more than 80%.

  25. Protein sequence-similarity search acceleration using a heuristic algorithm with a sensitive matrix International-journal Peer-reviewed

    Lim K, Yamada KD, Frith MC, Tomii K

    Journal of Structural and Functional Genomics　17　(4)　147-154　2016

    DOI： 10.1007/s10969-016-9210-4 　

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    Protein database search for public databases is a fundamental step in the target selection of proteins in structural and functional genomics and also for inferring protein structure, function, and evolution. Most database search methods employ amino acid substitution matrices to score amino acid pairs. The choice of substitution matrix strongly affects homology detection performance. We earlier proposed a substitution matrix named MIQS that was optimized for distant protein homology search. Herein we further evaluate MIQS in combination with LAST, a heuristic and fast database search tool with a tunable sensitivity parameter m, where larger m denotes higher sensitivity. Results show that MIQS substantially improves the homology detection and alignment quality performance of LAST across diverse m parameters. Against a protein database consisting of approximately 15 million sequences, LAST with m = 105 achieves better homology detection performance than BLASTP, and completes the search 20 times faster. Compared to the most sensitive existing methods being used today, CS-BLAST and SSEARCH, LAST with MIQS and m = 106 shows comparable homology detection performance at 2.0 and 3.9 times greater speed, respectively. Results demonstrate that MIQS-powered LAST is a time-efficient method for sensitive and accurate homology search.

  26. Application of the MAFFT sequence alignment program to large data - reexamination of the usefulness of chained guide trees Peer-reviewed

    Yamada KD, Tomii K, Katoh K

    Bioinformatics　32　(21)　3246-3251　2016

    DOI： 10.1093/bioinformatics/btw412 　

    ISSN： 1367-4803

    eISSN： 1460-2059

  27. Structural characterization of single nucleotide variants at ligand binding sites and enzyme active sites of human proteins Peer-reviewed

    Yamada KD, Nishi H, Nakata J, Kinoshita K

    Biophysics and Physicobiology　13　157-163　2016

    Publisher: The Biophysical Society of Japan

    DOI： 10.2142/biophysico.13.0_157 　

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    <p>Functional sites on proteins play an important role in various molecular interactions and reactions between proteins and other molecules. Thus, mutations in functional sites can severely affect the overall phenotype. Progress of genome sequencing projects has yielded a wealth of information on single nucleotide variants (SNVs), especially those with less than 1% minor allele frequency (rare variants). To understand the functional influence of genetic variants at a protein level, we investigated the relationship between SNVs and protein functional sites in terms of minor allele frequency and the structural position of variants. As a result, we observed that SNVs were less abundant at ligand binding sites, which is consistent with a previous study on SNVs and protein interaction sites. Additionally, we found that non-rare variants tended to be located slightly apart from enzyme active sites. Examination of non-rare variants revealed that most of the mutations resulted in moderate changes of the physico-chemical properties of amino acids, suggesting the existence of functional constraints. In conclusion, this study shows that the mapping of genetic variants on protein structures could be a powerful approach to evaluate the functional impact of rare genetic variations.</p>

  28. Identification of hepta-histidine as a candidate drug for Huntington’s disease by in silico-in vitro-in vivo-integrated screens of chemical libraries International-journal Peer-reviewed

    Imamura T, Fujita K, Tagawa K, Ikura T, Chen X, Homma H, Tamura T, Mao Y, Taniguchi JB, Motoki K, Nakabayashi M, Ito N, Yamada K, Tomii K, Okano H, Kaye J, Finkbeiner S, Okazawa H

    Scientific Reports　6　33861-33861　2016

    DOI： 10.1038/srep33861 　

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    We identified drug seeds for treating Huntington's disease (HD) by combining in vitro single molecule fluorescence spectroscopy, in silico molecular docking simulations, and in vivo fly and mouse HD models to screen for inhibitors of abnormal interactions between mutant Htt and physiological Ku70, an essential DNA damage repair protein in neurons whose function is known to be impaired by mutant Htt. From 19,468 and 3,010,321 chemicals in actual and virtual libraries, fifty-six chemicals were selected from combined in vitro-in silico screens; six of these were further confirmed to have an in vivo effect on lifespan in a fly HD model, and two chemicals exerted an in vivo effect on the lifespan, body weight and motor function in a mouse HD model. Two oligopeptides, hepta-histidine (7H) and Angiotensin III, rescued the morphological abnormalities of primary neurons differentiated from iPS cells of human HD patients. For these selected drug seeds, we proposed a possible common structure. Unexpectedly, the selected chemicals enhanced rather than inhibited Htt aggregation, as indicated by dynamic light scattering analysis. Taken together, these integrated screens revealed a new pathway for the molecular targeted therapy of HD.

  29. Intrinsically disordered region of influenza A NP regulates viral genome packaging via interactions with viral RNA and host PI(4,5)P2 International-journal Peer-reviewed

    Kakisaka M, Yamada K, Yamaji-Hasegawa A, Kobayashi T, Aida Y

    Virology　496　116-126　2016

    DOI： 10.1016/j.virol.2016.05.018 　

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    To be incorporated into progeny virions, the viral genome must be transported to the inner leaflet of the plasma membrane (PM) and accumulate there. Some viruses utilize lipid components to assemble at the PM. For example, simian virus 40 (SV40) targets the ganglioside GM1 and human immunodeficiency virus type 1 (HIV-1) utilizes phosphatidylinositol (4,5) bisphosphate [PI(4,5)P2]. Recent studies clearly indicate that Rab11-mediated recycling endosomes are required for influenza A virus (IAV) trafficking of vRNPs to the PM but it remains unclear how IAV vRNP localized or accumulate underneath the PM for viral genome incorporation into progeny virions. In this study, we found that the second intrinsically disordered region (IDR2) of NP regulates two binding steps involved in viral genome packaging. First, IDR2 facilitates NP oligomer binding to viral RNA to form vRNP. Secondly, vRNP assemble by interacting with PI(4,5)P2 at the PM via IDR2. These findings suggest that PI(4,5)P2 functions as the determinant of vRNP accumulation at the PM.

  30. Prediction of homo- and hetero-protein complexes by protein docking and template-based modeling: a CASP-CAPRI experiment Peer-reviewed

    Lensink MF, Velankar S, Kryshtafovych A, Huang SY, Schneidman-Duhovny D, Sali A, Segura J, Fernandez-Fuentes N, Viswanath S, Elber R, Grudinin S, Popov P, Neveu E, Lee H, Baek M, Park S, Heo L, Rie Lee G, Seok C, Qin S, Zhou HX, Ritchie DW, Maigret B, Devignes MD, Ghoorah A, Torchala M, Chaleil RA, Bates PA, Ben-Zeev E, Eisenstein M, Negi SS, Weng Z, Vreven T, Pierce BG, Borrman TM, Yu J, Ochsenbein F, Guerois R, Vangone A, Rodrigues JP, van Zundert G, Nellen M, Xue L, Karaca E, Melquiond AS, Visscher K, Kastritis PL, Bonvin AM, Xu X, Qiu L, Yan C, Li J, Ma Z, Cheng J, Zou X, Shen Y, Peterson LX, Kim HR, Roy A, Han X, Esquivel-Rodriguez J, Kihara D, Yu X, Bruce NJ, Fuller JC, Wade RC, Anishchenko I, Kundrotas PJ, Vakser IA, Imai K, Yamada K, Oda T, Nakamura T, Tomii K, Pallara C, Romero-Durana M, Jiménez-García B, Moal IH, Férnandez-Recio J, Joung JY, Kim JY, Joo K, Lee J, Kozakov D, Vajda S, Mottarella S, Hall DR, Beglov D, Mamonov A, Xia B, Bohnuud T, Del Carpio CA, Ichiishi E, Marze N, Kuroda D, Roy Burman SS, Gray JJ, Chermak E, Cavallo L, Oliva R, Tovchigrechko A, Wodak SJ

    Proteins　84　(S1)　323-348　2016

    Publisher: Wiley

    DOI： 10.1002/prot.25007 　

    ISSN： 0887-3585

    eISSN： 1097-0134

  31. Systematic exploration of an efficient amino acid substitution matrix: MIQS Peer-reviewed

    Tomii K, Yamada K

    Methods in Molecular Biology　2016

    DOI： 10.1007/978-1-4939-3572-7_11 　

  32. A new genotype of bovine leukemia virus in South America identified by NGS-based whole genome sequencing and molecular evolutionary genetic analysis Peer-reviewed

    Polat M, Takeshima SN, Hosomichi K, Kim J, Miyasaka T, Yamada K, Arainga M, Murakami T, Matsumoto Y, de la Barra Diaz V, Panei CJ, González ET, Kanemaki M, Onuma M, Giovambattista G, Aida Y

    Retrovirology　13　2016

    DOI： 10.1186/s12977-016-0239-z 　

    eISSN： 1742-4690

  33. Refinement of Amino Acid Substitution Matrix for Detecting Distant Relationships of Proteins Peer-reviewed

    Yamada K, Tomii K

    Seibutsu Butsuri　55　(3)　133-136　2015

    Publisher: Biophysical Society of Japan

    DOI： 10.2142/biophys.55.133 　

    ISSN： 0582-4052

    eISSN： 1347-4219

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    Amino acid similarity search methods are fundamental tools for inferring protein structure and function. Optimization of amino acid substitution matrices is indispensable to improve search performance. We explored matrices that are ideal for detecting distantly related proteins in the PCA subspace that represents a set of typical existing matrices, and derived a novel sensitive matrix: MIQS. Test results show that the MIQS detection performance is superior to those of existing matrices and other sequence comparison methods. This refinement of the amino acid substitution matrix might influence many fields of sequence analysis. MIQS is available at http://csas.cbrc.jp/Ssearch/.

  34. A novel antiviral target structure involved in the RNA binding, dimerization, and nuclear export functions of the influenza A virus nucleoprotein International-journal Peer-reviewed

    Kakisaka M, Sasaki Y, Yamada K, Kondoh Y, Hikono H, Osada H, Tomii K, Saito T, Aida Y

    PLOS Pathogens　11　(7)　e1005062　2015

    DOI： 10.1371/journal.ppat.1005062 　

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    Developing antiviral therapies for influenza A virus (IAV) infection is an ongoing process because of the rapid rate of antigenic mutation and the emergence of drug-resistant viruses. The ideal strategy is to develop drugs that target well-conserved, functionally restricted, and unique surface structures without affecting host cell function. We recently identified the antiviral compound, RK424, by screening a library of 50,000 compounds using cell-based infection assays. RK424 showed potent antiviral activity against many different subtypes of IAV in vitro and partially protected mice from a lethal dose of A/WSN/1933 (H1N1) virus in vivo. Here, we show that RK424 inhibits viral ribonucleoprotein complex (vRNP) activity, causing the viral nucleoprotein (NP) to accumulate in the cell nucleus. In silico docking analysis revealed that RK424 bound to a small pocket in the viral NP. This pocket was surrounded by three functionally important domains: the RNA binding groove, the NP dimer interface, and nuclear export signal (NES) 3, indicating that it may be involved in the RNA binding, oligomerization, and nuclear export functions of NP. The accuracy of this binding model was confirmed in a NP-RK424 binding assay incorporating photo-cross-linked RK424 affinity beads and in a plaque assay evaluating the structure-activity relationship of RK424. Surface plasmon resonance (SPR) and pull-down assays showed that RK424 inhibited both the NP-RNA and NP-NP interactions, whereas size exclusion chromatography showed that RK424 disrupted viral RNA-induced NP oligomerization. In addition, in vitro nuclear export assays confirmed that RK424 inhibited nuclear export of NP. The amino acid residues comprising the NP pocket play a crucial role in viral replication and are highly conserved in more than 7,000 NP sequences from avian, human, and swine influenza viruses. Furthermore, we found that the NP pocket has a surface structure different from that of the pocket in host molecules. Taken together, these results describe a promising new approach to developing influenza virus drugs that target a novel pocket structure within NP.

  35. PoSSuM v.2.0: data update and a new function for investigating ligand analogs and target proteins of small-molecule drugs Peer-reviewed

    Ito JI, Ikeda K, Yamada K, Mizuguchi K, Tomii K

    Nucleic Acids Research (NAR)　2015

    DOI： 10.1093/nar/gku1144 　

  36. Comparative analysis of seven viral nuclear export signals (NESs) reveals the crucial role of nuclear export mediated by the third NES consensus sequence of nucleoprotein (NP) in influenza A virus replication International-journal Peer-reviewed

    Chutiwitoonchai N, Kakisaka M, Yamada K, Aida Y

    PLOS ONE　9　(8)　e105081　2014

    DOI： 10.1371/journal.pone.0105081 　

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    The assembly of influenza virus progeny virions requires machinery that exports viral genomic ribonucleoproteins from the cell nucleus. Currently, seven nuclear export signal (NES) consensus sequences have been identified in different viral proteins, including NS1, NS2, M1, and NP. The present study examined the roles of viral NES consensus sequences and their significance in terms of viral replication and nuclear export. Mutation of the NP-NES3 consensus sequence resulted in a failure to rescue viruses using a reverse genetics approach, whereas mutation of the NS2-NES1 and NS2-NES2 sequences led to a strong reduction in viral replication kinetics compared with the wild-type sequence. While the viral replication kinetics for other NES mutant viruses were also lower than those of the wild-type, the difference was not so marked. Immunofluorescence analysis after transient expression of NP-NES3, NS2-NES1, or NS2-NES2 proteins in host cells showed that they accumulated in the cell nucleus. These results suggest that the NP-NES3 consensus sequence is mostly required for viral replication. Therefore, each of the hydrophobic (Φ) residues within this NES consensus sequence (Φ1, Φ2, Φ3, or Φ4) was mutated, and its viral replication and nuclear export function were analyzed. No viruses harboring NP-NES3 Φ2 or Φ3 mutants could be rescued. Consistent with this, the NP-NES3 Φ2 and Φ3 mutants showed reduced binding affinity with CRM1 in a pull-down assay, and both accumulated in the cell nucleus. Indeed, a nuclear export assay revealed that these mutant proteins showed lower nuclear export activity than the wild-type protein. Moreover, the Φ2 and Φ3 residues (along with other Φ residues) within the NP-NES3 consensus were highly conserved among different influenza A viruses, including human, avian, and swine. Taken together, these results suggest that the Φ2 and Φ3 residues within the NP-NES3 protein are important for its nuclear export function during viral replication.

  37. Revisiting amino acid substitution matrices for identifying distantly related proteins Peer-reviewed

    Yamada K, Tomii K

    Bioinformatics　2014

    DOI： 10.1093/bioinformatics/btt694 　

  38. Importin α3/Qip1 is involved in multiplication of mutant influenza virus with alanine mutation at amino acid 9 independently of nuclear transport function International-journal Peer-reviewed

    Sasaki Y, Hagiwara K, Kakisaka M, Yamada K, Murakami T, Aida Y

    PLOS ONE　8　(1)　e55765　2013

    DOI： 10.1371/journal.pone.0055765 　

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    The nucleoprotein (NP) of influenza A virus is transported into the nucleus via the classical importin α/β pathway, and proceeds via nuclear localization signals (NLSs) recognized by importin α molecules. Although NP binds to importin α isoforms Rch1, Qip1 and NPI-1, the role of each individual isoform during the nuclear transport of NP and replication of the influenza virus remains unknown. In this study, we examined the contribution of importin α isoforms for nuclear localization of NP and viral growth using a panel of NP mutants containing serial alanine replacements within an unconventional NLS of NP. Alanine mutation at amino acid 8 (R8A) caused a significant reduction in the nuclear localization and binding to the three importin isoforms. The R8A NP mutant virus did not generate by reverse-genetics approach. This indicates that position 8 is the main site that mediates nuclear localization via interactions with Rch1, Qip1 and NPI-1, and subsequent viral production. This was confirmed by the finding that the conservation of amino acid 8 in human- and avian-origin influenza virus NP was necessary for virus propagation. By contrast, another mutant, S9A NP, which localized in the nucleus, caused a reduction in viral growth and vRNA transcription, suggesting that the unconventional NLS within NP may be associated with nuclear transport, vRNA transcription and viral replication through independent pathways. Interestingly, the N-terminal 110-amino acid region, which contained the unconventional NLS with S9A mutation, mainly bound to Qip1. Furthermore, activities of vRNA transcription and replication of S9A NP mutants were decreased by silencing Qip1 in without changing nuclear localization, indicating that Qip1 involves in multiplication of S9A mutant virus independently of nuclear transport function. Collectively, our results demonstrate the unconventional NLS within NP might have the additional ability to regulate the viral replication that is independent of nuclear localization activity via interactions with Qip1.

  39. Identification of a novel compound with antiviral activity against influenza A virus depending on PA subunit of viral RNA polymerase International-journal Peer-reviewed

    Yamada K, Koyama H, Hagiwara K, Ueda A, Sasaki Y, Kanesashi SN, Ueno R, Nakamura HK, Kuwata K, Shimizu K, Suzuki M, Aida Y

    Microbes and Infection　14　(9)　740-7　2012

    DOI： 10.1016/j.micinf.2012.02.012 　

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    Influenza viruses have developed resistance to current drugs, creating a need for new antiviral targets and new drugs to treat influenza virus infections. In this study, computational and experimental screening of an extensive compound library identified THC19, which was able to suppress influenza virus replication. This compound had no cytotoxic effects and did not disrupt cell cycle progression or induce apoptosis in MDCK cells as confirmed by WST-1 assays, flow cytometry analysis, and caspase-3 assays. Time-of-addition experiments showed that THC19 acts at a relatively early stage of the viral lifecycle. Subsequent mini-genome assays revealed that THC19 inhibited viral genome replication and/or transcription, suggesting that it interferes with one or more of the viral components that form the ribonucleoprotein complexes, namely polymerase basic 2 (PB2), polymerase basic 1 (PB1), polymerase acidic (PA), nucleoprotein (NP) and viral RNA. Finally, mini-genome assays where PB2, PB1, PA or NP from A/WSN/33 (H1N1) virus were replaced with those from A/Udorn/307/1972 (H3N2) virus effectively demonstrated that THC19 inhibited viral multiplication in a manner dependent upon the PA subunit. Taken together, these results suggest that influenza virus PA protein is a potential target for, and may aid the development of, novel compounds that inhibit influenza A virus replication.

  40. Discovery of novel antiviral agents directed against the influenza A virus nucleoprotein using photo-cross-linked chemical arrays International-journal Peer-reviewed

    Hagiwara K, Kondoh Y, Ueda A, Yamada K, Goto H, Watanabe T, Nakata T, Osada H, Aida Y

    Biochemical and Biophysical Research Communications　394　(3)　721-7　2010

    DOI： 10.1016/j.bbrc.2010.03.058 　

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    The nucleoprotein (NP) of the influenza virus is expressed in the early stage of infection and plays important roles in numerous steps of viral replication. NP is relatively well conserved compared with viral surface spike proteins. This study experimentally demonstrates that NP is a novel target for the development of new antiviral drugs against the influenza virus. First, artificial analogs of mycalamide A in a chemical array bound specifically with high affinity to NP. Second, the compounds inhibited multiplication of the influenza virus. Furthermore, surface plasmon resonance imaging experiments demonstrated that the binding activity of each compound to NP correlated with its antiviral activity. Finally, it was shown that these compounds bound NP within the N-terminal 110-amino acid region but their binding abilities were dramatically reduced when the N-terminal 13-amino acid tail was deleted, suggesting that the compounds might bind to this region, which mediates the nuclear transport of NP and its binding to viral RNA. These data suggest that compound binding to the N-terminal 13-amino acid tail region may inhibit viral replication by inhibiting the functions of NP. Collectively, these results strongly suggest that chemical arrays are convenient tools for the screening of viral product inhibitors.

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Research Projects 2

  1. 人工知能で目指すアミノ酸配列類似性検索法の高速化および高感度化研究 Competitive

    山田和範

    2018/04 - 2020/03

  2. MAFFT多重アラインメントプログラムの大量配列データへの対応と機能拡張 Competitive

    加藤和貴

    2016/04 - 2020/03