生物データサイエンスグループ

研究課題

臨床検体の多層オミックスデータを計測・解析し、診断画像解析データとの連携からマルチモーダルなデータ解析を行い、早期診断に繋がる、疾患発症に係わる分子メカニズムの推定や患者層別化を行う基盤技術開発に取り組んでいます。また、レセプトデータなどのリアルワールドデータを活用し、得られた発症メカニズムの検証にも取り組んでいます。

研究課題

新規創薬モダリティとしてRNA/DNAが注目されていますが、特にRNAは静的な配列情報・立体構造に加えて、その分子運動により機能を発揮します。核酸の理論計算技術はタンパク質に比して未整備であり、精度・信頼性は未知です。私たちは、国内40社以上の製薬・IT企業と、共同で培ってきた計算技術を、核酸用に再構築し、創薬ソフトウェア群myPrestoに実装し、生命活動を調整する生体分子の運動と相互認識機構を解明する理論的ツールの開発と提供を行います。

研究課題

RNA修飾は様々な疾患で変化していることが知られています。しかし、その計測技術が未熟であり、診断治療への応用は実現していません。そこで私たちは、RNAを中心としたオミクスの修飾情報を計測する新規技術の開発を進めています。またこの技術を用いて計測したオミクスの修飾情報解析を進め、がんをはじめとした様々な疾患の早期診断技術開発、新規治療法開発に取り組んでいます。

研究課題

近年、多くの疾患関連変異情報が得られていますが、それらの多くは、生物学的解釈が難しく、従来とは異なる視点での利活用法や解析技術が求められています。本研究では、疾患関連変異をタンパク質の立体構造上でのクラスタという単位でとらえ、それらを基点としたタンパク質の未発見の機能部位の網羅的探索法を開発しています。疾患関連変異は、タンパク質構造上で機能部位近辺に集積する傾向がある一方、既知の機能部位に紐づかないクラスタは、未発見の機能部位を指し示す可能性があります。また、未発見の機能制御部位は、単純なポケットではなく、動的に生じるリガンド結合部位（クリプトサイト）やアロステリック制御部位の可能性があります。そこで、配列解析や分子動力学計算などを組み合わせることで、新規の機能部位、ひいては、新規創薬標的部位を予測する技術開発を行っています。

研究課題

細胞内には多種多様な分子が存在し、これらが互いに情報をやり取りすることで細胞の状態が決定されます。本研究では、細胞内分子が情報を伝えるネットワークが、細胞の分化や外部環境への適応に伴ってどのように変化するのか、ネットワークの変化が細胞の状態にどのように影響を与えるかを高精度で解析する基盤技術を開発しています。また、これらの研究を通じて多能性幹細胞などにおける分化制御の高精度化を推進しています。

研究課題

細胞外部からの刺激（シグナル）の多くはリン酸化経路によって伝えられ、細胞の挙動を決定しています。このシグナル伝達に関わる様々なタンパク質へのリン酸化活性を、タンパク質アレイを使って一斉に測定し、パスウェイ解析を行う新しい評価系を開発しました。また、この系を用いて新たに94種類の市販薬を投与した細胞でリン酸化活性測定とパスウェイ解析を行った結果を収集し、データベースとして公開しています。

研究課題

単純ヘルペスウイルスAmpliconベクターは、ウイルス粒子からウイルスゲノムを排除し、代わりにプラスミドをパッケージングしており、(１)極めて低い細胞毒性、(２)最大150kbpもの遺伝子積載容量、(３)幅広い種類の細胞への感染能を特徴としたウイルスベクターです。
現在、効率的なベクター産生法の開発および特定の細胞を標的化した遺伝子導入技術の開発に取り組んでいます。またウイルスベクターにより高度な細胞制御を行うことで疾病モデル細胞株から非破壊的に分子情報取得し、低侵襲な疾患の診断に適した分子情報(バイオマーカー)や治療標的候補の探索に取り組んでいます。

業績リスト

• Kusano, T; Sotani, Y; Takeda, R; Hatano, A; Kawata, K; Kano, R; Matsumoto, M; Kano, Y; Hoshino, D.
  Time-series transcriptomics reveals distinctive mRNA expression dynamics associated with gene ontology specificity and protein expression in skeletal muscle after electrical stimulation-induced resistance exercise.
  FASEB J. 2024 Nov 30;38(22):e70153. doi:10.1096/fj.202401420RR
• Sato, T; Abe, K; Koseki, J; Seto, M; Yokoyama, J; Akashi, T; Terada, M; Kadowaki, K; Yoshida, S; Yamashiki, YA; Shimamura, T.
  Survivability and life support in sealed mini-ecosystems with simulated planetary soils.
  SCI REP. 2024 Nov 1;14(1):26322. doi: 10.1038/s41598-024-75328-x
• Yoshinori, F; Imai, K; Horton, P.
  Prediction of mitochondrial targeting signals and their cleavage sites.
  METHODS ENZYMOL. 2024 Sep 11. doi: 10.1016/bs.mie.2024.07.026
• Fujii, Y; Kamata, K; Gerdol, M; Hasan, I; Rajia, S; Kawsar, SMA; Padma, S; Chatterjee, BP; Ohkawa, M; Ishiwata, R; Yoshimoto, S; Yamada, M; Matsuzaki, N; Yamamoto, K; Niimi, Y; Miyanishi, N; Konno, M;Pallavicini, A; Kawasaki, T; Ogawa, Y; Ozeki, Y; Fujita, H.
  Multifunctional Cell Regulation Activities of the Mussel Lectin SeviL: Induction of Macrophage Polarization toward the M1 Functional Phenotype.
  MARINE DRUGS. 2024 Jun 11;22(6):269. doi: 10.3390/md22060269
• Watanabe, A; Koyano, F; Imai, K; Hizukuri, Y; Ogiwara, S; Ito, T; Miyamoto, J; Shibuya, C; Kimura, M; Toriumi, K; Motono, C; Arai, M; Tanaka, K; Akiyama, Y; Yamano, K; Matsuda, N.
  The origin of esterase activity of Parkinsons disease causative factor DJ-1 implied by evolutionary trace analysis of its prokaryotic homolog HchA.
  J BIOL CHEM. 2024 Jun 13:107476. doi: 10.1016/j.jbc.2024.107476
• Higo, J; Bekker, GJ; Kamiya, N; Fukuda, I; Fukunishi, Y;.
  Binding free-energy landscapes of small molecule binder and non-binder to FMN riboswitch: All-atom molecular dynamics.
  BIOPHYS PHYSICOBIOL. 2023 Dec 13;20(4):e200047. doi: 10.2142/biophysico.bppb-v20.0047
• Bekker, GJ; Fukunishi, Y; Higo, J; Kamiya, N.
  Binding Mechanism of Riboswitch to Natural Ligand Elucidated by McMD-Based Dynamic Docking Simulations.
  ACS OMEGA. 2024 Jan 10;9(3):3412-3422. doi: 10.1021/acsomega.3c06826 eCollection
• Germany, EM; Thewasano, N; Imai, K; Maruno, Y; Bamert, RS; Stubenrauch, CJ; Dunstan, RA; Ding, Y; Nakajima, Y; Lai, X; Webb, CT; Hidaka, K; Tan, KS; Shen, H; Lithgow, T; Shiota, T.
  Dual recognition of multiple signals in bacterial outer membrane proteins enhances assembly and maintains membrane integrity.
  ELIFE. 2024 Jan 16;12:RP90274. doi: 10.7554/eLife.90274
• Shimizu, R; Murai, K; Tanaka, K; Sato, Y; Takeda, N; Nakasyo, S; Shirasaki, T; Kawaguchi, K; Shimakami, T; Nio, K; Nakaya, Y; Kagiwada, H Horimoto, K; Mizokami, M; Kaneko, S; Murata, K; Yamashita, T; Honda, M.
  Nucleos(t)ide analogs for hepatitis B virus infection differentially regulate the growth factor signaling in hepatocytes.
  HEPATOL COMMUN. 2024 Jan 5;8(1):e0351. doi: 10.1097/HC9.0000000000000351
• Fukuda, I; Moritsugu, K; Higo, J; Fukunishi, Y.
  A cutoff-based method with charge-distribution-data driven pair potentials for efficiently estimating electrostatic interactions in molecular systems.
  J CHEM PHYS. 2023 Dec 21;159(23):234116. doi: 10.1063/5.0172270
• Watanabe, Y; Iwasaki, Y; Sasaki, K; Motono, C; Imai, K; Suzuki, K.
  Atg15 is a vacuolar phospholipase that disintegrates organelle membranes.
  CELL REP. 2023 Dec 15:113567. doi: 10.1016/j.celrep.2023.113567
• Maeda, F; Adachi, S; Natsume, T.
  Non-destructive and efficient method for obtaining miRNA information in cells by artificial extracellular vesicles.
  SCI REP. 2023 Dec 14;13(1):22231. doi: 10.1038/s41598-023-48995-5
• Ohkawa, M; Konno, M.
  RNA Modification Related Diseases and Sensing Methods.
  APPLIED SCIENCES-BASEL. 2023 13(11) 6376. doi: 10.3390/app13116376
• Shin, WH; Kumazawa, K; Imai, K; Hirokawa, T; Kihara, D.
  Quantitative comparison of protein-protein interaction interface using physicochemical feature-based descriptors of surface patches.
  FRONT MOL BIOSCI. 2023 Feb 6;10:1110567. doi: 10.3389/fmolb.2023.1110567
• Takeda, H; Busto, JV; Lindau, C; Tsutsumi, A; Tomii, K; Imai, K; Yamamori, Y; Hirokawa, T; Motono, C; Ganesan, I; Wenz, LS; Becker, T; Kikkawa, M; Pfanner, N; Wiedemann, N; Endo, T.
  A multipoint guidance mechanism for β-barrel folding on the SAM complex.
  NAT STRUCT MOL BIOL. 2023 Jan 5. doi: 10.1038/s41594-022-00897-2
• Hayashida, R; Kikuchi, R; Imai, K; Kojima, W; Yamada, T; Iijima, M; Sesaki, H; Tanaka, K; Matsuda, N; Yamano, K.
  Elucidation of ubiquitin-conjugating enzymes that interact with RBR-type ubiquitin ligases using a liquid-liquid phase separation-based method.
  J BIOL CHEM. 2022 Dec 20:102822. doi: 10.1016/j.jbc.2022.102822
• Murotomi, K; Kagiwada, H; Hirano, K; Yamamoto, S; Numata, N; Matsumoto, Y; Kaneko, H; Namihira, M.
  Cyclo-glycylproline attenuates hydrogen peroxide-induced cellular damage mediated by the MDM2-p53 pathway in human neural stem cells.
  J CELL PHYSIOL. 2022 Dec 31. doi: 10.1002/jcp.30940
• Fukunishi, Y; Higo, J; Kasahara, K.
  Computer simulation of molecular recognition in biomolecular system: from in silico screening to generalized ensembles.
  BIOPHYS REV. 2022 Nov 28:1-25. doi: 10.1007/s12551-022-01015-8
• Kato, K; Okazaki, S; Schmitt-Ulms, C; Jiang, K; Zhou, W; Ishikawa, J; Isayama, Y; Adachi, S; Nishizawa, T; Makarova, KS; Koonin, EV; Abudayyeh, OO; Gootenberg, JS; Nishimasu, H.
  RNA-triggered protein cleavage and cell growth arrest by the type III-E CRISPR nuclease-protease.
  SCIENCE. 2022 Nov 25;378(6622):882-889. doi: 10.1126/science.add7347
• Lintuluoto, M; Abe, M; Horioka, Y; Fukunishi, Y; Tamura, H; M, Lintuluoto J.
  Investigation on substrate specificity and catalytic activity of serine protease neuropsin.
  BIOPHYS PHYSICOBIOL. 2022 Sep 22;19:e190040. doi: 10.2142/biophysico.bppb-v19.0040
• Tirta, YK; Adachi, S; Perez, CAG; Adhitama, N; Nong, QD; Natsume, T; Kato, Y; Watanabe, H.
  CELF1 represses Doublesex1 expression via its 5 UTR in the crustacean Daphnia magna.
  PLOS ONE. 2022 Oct 14;17(10):e0275526. doi: 10.1371/journal.pone.0275526
• Sato, R; Suzuki, K; Yasuda, Y; Suenaga, A; Fukui, K.
  RNAapt3D: RNA aptamer 3D-structural modeling database.
  BIOPHYS J. 2022 Sep 22:S0006-3495(22)00773-1. doi: 10.1016/j.bpj.2022.09.023
• Li, S; Ikeuchi, K; Kato, M; Buschauer, R; Sugiyama, T; Adachi, S; Kusano, H; Natsume, T; Berninghausen, O; Matsuo, Y; Becker, T; Beckmann, R; Inada, T.
  Sensing of individual stalled 80S ribosomes by Fap1 for nonfunctional rRNA turnover.
  MOL CELL. 2022 Sep 15;82(18):3424-3437.e8. doi: 10.1016/j.molcel.2022.08.018
• Kagiwada, H; Motono, C; Horimoto, K; Fukui, K.
  Phosprof: pathway analysis database of drug response based on phosphorylation activity measurements.
  DATABASE (Oxford). 2022 Aug 22;2022:baac072. doi: 10.1093/database/baac072
• Higo, J; Kasahara, K; Bekker, GJ; Ma, B; Sakuraba, S; Iida, S; Kamiya, N; Fukuda, I; Kono, H; Fukunishi, Y; Nakamura, H.
  Fly casting with ligand sliding and orientational selection supporting complex formation of a GPCR and a middle sized flexible molecule.
  SCI REP. 2022 Aug 13;12(1):13792. doi: 10.1038/s41598-022-17920-7
• Hirata, Y; Oda, AH; Motono, C; Shiro, M; Ohta, K.
  Imputation-free reconstructions of three-dimensional chromosome architectures in human diploid single-cells using allele-specified contacts.
  SCI REP. 2022 Jul 11;12(1):11757. doi: 10.1038/s41598-022-15038-4
• Kose, S; Imai, K; Watanabe, A; Nakai, A; Suzuki, Y; Imamoto, N.
  Lack of Hikeshi activates HSF1 activity under normal conditions and disturbs the heat-shock response.
  LIFE SCI ALLIANCE. 2022 May 17;5(9):e202101241. doi: 10.26508/lsa.202101241
• Maeda, F; Kato, A; Takeshima, K; Shibazaki, M; Sato, R; Shibata,T; Miyake, K; Kozuka-Hata, H; Oyama, M; Shimizu, E; Imoto, S; Miyano, S; Adachi, S; Natsume, T; Takeuchi, K; Maruzuru, Y; Koyanagi, N; Jun, A; Yasushi, K.
  Role of the Orphan Transporter SLC35E1 in the Nuclear Egress of Herpes Simplex Virus 1.
  J VIROL. 2022 Apr 27:e0030622. doi: 10.1128/jvi.00306-22
• Santos, HJ; Hanadate, Y; Imai, K; Watanabe, H; Nozaki, T.
  Entamoeba histolytica EHD1 Is Involved in Mitosome-Endosome Contact.
  MBIO. 2022 Apr 11:e0384921. doi: 10.1128/mbio.03849-21
• Araiso, Y; Imai, K; Endo, T.
  Role of the TOM Complex in Protein Import into Mitochondria: Structural Views.
  ANNU REV BIOCHEM. 2022 Feb 14. doi: 10.1146/annurev-biochem-032620-104527
• Queliconi BB, Kojima W, Kimura M, Imai K, Udagawa C, Motono C, Hirokawa T, Tashiro S, Caaveiro JMM, Tsumoto K, Yamano K, Tanaka K, Matsuda N.
  Unfolding is the driving force for mitochondrial import and degradation of Parkinsons disease-related protein DJ-1.
  J CELL SCI. 2021 Oct 22:jcs.258653. doi: 10.1242/jcs.258653
• Kimura, M; Imai, K; Morinaka, Y; Hosono-Sakuma, Y; Horton, P; Imamoto, N.
  Distinct mutations in importin-β family nucleocytoplasmic transport receptors transportin-SR and importin-13 affect specific cargo binding.
  SCI REP. 2021 Aug 2;11(1):15649. doi: 10.1038/s41598-021-94948-1
• Motono, C; Yanagida, S; Sato, M; Hirokawa, T.
  MDContactCom: a tool to identify differences of protein molecular dynamics from two MD simulation trajectories in terms of interresidue contacts.
  BIOINFORMATICS. 2021 Jul 21:btab538. doi: 10.1093/bioinformatics/btab538
• Kagiwada, H; Kiboku, T; Matsuo, H; Kitazawa, M; Fukui, K; Horimoto, K.
  Assessing the activation/inhibition of tyrosine kinase-related pathways with a newly developed platform.
  PROTEOMICS. 2021 Jun 21:e2000251. doi: 10.1002/pmic.202000251
• Amemiya, T; Horimoto, K; Fukui, K.
  Application of multiple omics and network projection analyses to drug repositioning for pathogenic mosquito-borne viruses.
  SCI REP. 2021 May 12;11(1):10136. doi: 10.1038/s41598-021-89171-x
• Kohrogi, K; Hino, S; Sakamoto, A; Anan, K; Takase, R; Araki, H; Hino, Y; Araki, K; Sato, T; Nakamura, K; Nakao, M
  LSD1 defines erythroleukemia metabolism by controlling the lineage-specific transcription factors GATA1 and C/EBP
  Blood Adv. 2021 May 11;5(9):2305-2318. doi: 10.1182/bloodadvances.2020003521
• Ohashi, H; Watashi, K; Saso, W; Shionoya, K; Iwanami, S; Hirokawa, T; Shirai, T; Kanaya, S; Ito, Y; Kim, KS; Nomura, T; Suzuki, T; Nishioka, K; Ando, S; Ejima, K; Koizumi, Y; Tanaka, T; Aoki, S; Kuramochi, K; Suzuki, T; Hashiguchi, T; Maenaka, K; Matano, T; Muramatsu, M; Saijo, M; Aihara, K; Iwami, S; Takeda, M; McKeating, JA; Wakita, T
  Potential anti-COVID-19 agents, Cepharanthine and Nelfinavir, and their usage for combination treatment.
  ISCIENCE. 2021 Mar 26:102367. doi: 10.1016/j.isci.2021.102367
• Koiwai K, Morohashi K, Inaba K, Ebihara K, Kojima H, Okabe T, Yoshino R, Hirokawa T, Nampo T, Fujikawa Y, Inoue H, Yumoto F, Senda T, Niwa R
  Non-steroidal inhibitors of Drosophila melanogaster steroidogenic glutathione S-transferase Noppera-bo
  J Pestic Sci. 2021 Feb 20;46(1):75-87. doi: 10.1584/jpestics.D20-072
• Kojima W, Yamano K, Kosako H, Imai K, Kikuchi R, Tanaka K, Matsuda N
  Mammalian BCAS3 and C16orf70 associate with the phagophore assembly site in response to selective and non-selective autophagy.
  AUTOPHAGY. 2021 Jan 26:1-26. doi: 10.1080/15548627.2021.1874133
• Takeda H, Tsutsumi A, Nishizawa T, Lindau C, Busto JV, Wenz LS, Ellenrieder L, Imai K, Straub SP, Mossmann W, Qiu J, Yamamori Y, Tomii K, Suzuki J, Murata T, Ogasawara S, Nureki O, Becker T, Pfanner N, Wiedemann N, Kikkawa M, Endo T
  Mitochondrial sorting and assembly machinery operates by β-barrel switching.
  NATURE. 2021 Jan 6. doi: 10.1038/s41586-020-03113-7
• Sasaki S, Ma Y, Ishizuka T, Bao HL, Hirokawa T, Xu Y, Tera M, Nagasawa K
  Linear consecutive hexaoxazoles as G4 ligands inducing chair-type anti-parallel topology of a telomeric G-quadruplex.
  RSC ADVANCES 10 (71) 43319-43323; doi: 10.1039/d0ra09413g DEC 7
• Imai K, Nakai K
  Tools for the Recognition of Sorting Signals and the Prediction of Subcellular Localization of Proteins From Their Amino Acid Sequences.
  FRONT GENET 2020 Nov 25;11:607812. doi: 10.3389/fgene.2020.607812. eCollection
• Sakamoto K, Masutani T, Hirokawa T
  Generation of KS-58 as the first K-Ras(G12D)-inhibitory peptide presenting anti-cancer activity in vivo.
  SCI REP. 10(1):21671 (2020) doi: 10.1038/s41598-020-78712-5
• Araiso Y, Imai K, Endo T
  Structural snapshot of the mitochondrial protein import gate
  FEBS J. 2020 Dec 10. doi: 10.1111/febs.15661
• Shin WH, Kumazawa K, Imai K, Hirokawa T, Kihara D
  Current Challenges and Opportunities in Designing Protein-Protein Interaction Targeted Drugs
  Adv Appl Bioinform Chem. 2020 Nov 12;13:11-25. doi: 10.2147/AABC.S235542
• Nguyen HN, Suzuki K, Kimura Y, Hirokawa T, Murakami-Tonami Y, Abe H
  SYNTHESIS AND BIOLOGICAL EVALUATION OF NMDI14 DERIVATIVES AS ANTI-MESOTHELIOMA AGENTS
  HETEROCYCLES 100 (2) 253-266; (2020) doi: 10.3987/COM-19-14191
• Santos HJ, Chiba Y, Makiuchi T, Arakawa S, Murakami Y, Tomii K, Imai K, Nozaki T
  Import of Entamoeba histolytica Mitosomal ATP Sulfurylase Relies on Internal Targeting Sequences
  Microorganisms. 8(8):1229. (2020) doi: 10.3390/microorganisms8081229
• Nakagita T, Taketani C, Narukawa M, Hirokawa T, Kobayashi T, Misaka T
  Ibuprofen, a nonsteroidal anti-inflammatory drug, is a potent inhibitor of the human sweet taste receptor
  Chem Senses. bjaa057 (2020) doi: 10.1093/chemse/bjaa057
• Tomonari T, Sato Y, Tanaka H, Tanaka T, Fujino Y, Mitsui Y, Hirao A, Taniguchi T, Okamoto K, Sogabe M, Miyamoto H, Muguruma N, Kagiwada H, Kitazawa M, Fukui K, Horimoto K, Takayama T
  Potential use of lenvatinib for patients with unresectable hepatocellular carcinoma including after treatment with sorafenib: Real-world evidence and in vitro assessment via protein phosphorylation array
  Oncotarget. 11: 2531-2542 (2020) doi: 10.18632/oncotarget.27640
• Manabe T, Yasuda H, Terai H, Kagiwada H, Hamamoto J, Ebisudani T, Kobayashi K, Masuzawa K, Ikemura S, Kawada I, Hayashi Y, Fukui K, Horimoto K, Fukunaga K, Soejima K
  IGF2 Autocrine-Mediated IGF1R Activation Is a Clinically Relevant Mechanism of Osimertinib Resistance in Lung Cancer
  Molecular Cancer Res. 18: 549-559 (2020) doi: 10.1158/1541-7786.MCR-19-0956
• Koiwai K, Inaba K, Morohashi K, Enya S, Arai R, Kojima H, Okabe T, Fujikawa Y, Inoue H, Yoshino R, Hirokawa T, Kato K, Fukuzawa K, Shimada-Niwa Y, Nakamura A, Yumoto F, Senda T, Niwa R
  An integrated approach to unravel a crucial structural property required for the function of the insect steroidogenic Halloween protein Noppera-bo
  J Biol Chem. 0: 0 (2020) doi: 10.1074/jbc.RA119.011463
• Kagamu H, Kitano S, Yamaguchi O, Yoshimura K, Horimoto K, Kitazawa M, Fukui K, Shiono A, Mouri A, Nishihara F, Miura Y, Hashimoto K, Murayama Y, Kaira K, Kobayashi K
  CD4(+) T-cell Immunity in the Peripheral Blood Correlates with Response to Anti-PD-1 Therapy
  Cancer Immunology Res. 8 8: 334-344 (2020) doi: 10.1158/2326-6066.CIR-19-0574
• Adachi K, Yamada T, Ishizuka H, Oki M, Tsunogae S, Shimada N, Chiba O, Orihara T, Hidaka M, Hirokawa T, Odagi M, Konoki K, Yotsu-Yamashita M, Nagasawa K
  Synthesis of C12-Keto Saxitoxin Derivatives with Unusual Inhibitory Activity Against Voltage-Gated Sodium Channels
  Chemistry. 26: 2025-2033 (2020) doi: 10.1002/chem.201904184
• Kitazawa M, Hatta T, Sasaki Y,Fukui K, Ogawa K, Fukuda E, Goshima N, Okita N, Yamada Y, Nakagama H,Natsume T, Horimoto K
  Promotion of the Warburg effect is associated with poor benefit from adjuvant chemotherapy in colorectal cancer
  Cancer Sci. 111: 658-666 (2020) doi: 10.1111/cas.14275
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  A prospective compound screening contest identified broader inhibitors for Sirtuin 1
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