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Computational approaches for microRNA studies: a review

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Abstract

MicroRNAs (miRNAs) are one class of tiny, endogenous RNAs that can regulate messenger RNA (mRNA) expression by targeting homologous sequences in mRNAs. Their aberrant expressions have been observed in many cancers and several miRNAs have been convincingly shown to play important roles in carcinogenesis. Since the discovery of this small regulator, computational methods have been indispensable tools in miRNA gene finding and functional studies. In this review we first briefly outline the biological findings of miRNA genes, such as genomic feature, biogenesis, gene structure, and functional mechanism. We then discuss in detail the three main aspects of miRNA computational studies: miRNA gene finding, miRNA target prediction, and regulation of miRNA genes. Finally, we provide perspectives on some emerging issues, including combinatorial regulation by miRNAs and functional binding sites beyond the 3′-untranslated region (3′UTR) of target mRNAs. Available online resources for miRNA computational studies are also provided.

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Abbreviations

miRNAs:

MicroRNAs

pri-miRNAs:

Primary miRNAs

UTR:

Untranslated region

miRNPs:

Micro-ribonucleoproteins

miRISCs:

miRNA-induced silencing complexes

AGO:

Argonaute

SVM:

Support vector machine

HMM:

Hidden Markov model

HITS-CLIP:

High-throughput sequencing of RNAs isolated by crosslinking immunoprecipitation

TFs:

Transcription factors

Pol II or Pol III:

RNA polymerase II or III

TSS:

Transcription start site

References

  • Addo-Quaye C, Miller W, Axtell MJ (2009) CleaveLand: a pipeline for using degradome data to find cleaved small RNA targets. Bioinformatics 25:130–131

    Article  PubMed  CAS  Google Scholar 

  • Amaral PP, Dinger ME, Mercer TR, Mattick JS (2008) The eukaryotic genome as an RNA machine. Science 319:1787–1789

    Article  PubMed  CAS  Google Scholar 

  • Baek D, Villen J, Shin C, Camargo FD, Gygi SP et al (2008) The impact of microRNAs on protein output. Nature 455:64–71

    Article  PubMed  CAS  Google Scholar 

  • Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116:281–297

    Article  PubMed  CAS  Google Scholar 

  • Baskerville S, Bartel DP (2005) Microarray profiling of microRNAs reveals frequent coexpression with neighboring miRNAs and host genes. RNA 11:241–247

    Article  PubMed  CAS  Google Scholar 

  • Bentwich I, Avniel A, Karov Y, Aharonov R, Gilad S et al (2005) Identification of hundreds of conserved and nonconserved human microRNAs. Nat Genet 37:766–770

    Article  PubMed  CAS  Google Scholar 

  • Berezikov E, Chung WJ, Willis J, Cuppen E, Lai EC (2007) Mammalian mirtron genes. Mol Cell 28:328–336

    Article  PubMed  CAS  Google Scholar 

  • Borchert GM, Lanier W, Davidson BL (2006) RNA polymerase III transcribes human microRNAs. Nat Struct Mol Biol 13:1097–1101

    Article  PubMed  CAS  Google Scholar 

  • Cai X, Hagedorn CH, Cullen BR (2004) Human microRNAs are processed from capped, polyadenylated transcripts that can also function as mRNAs. RNA 10:1957–1966

    Article  PubMed  CAS  Google Scholar 

  • Chang YM, Juan HF, Lee TY, Chang YY, Yeh YM et al (2008) Prediction of human miRNAs using tissue-selective motifs in 3′ UTRs. Proc Natl Acad Sci USA 105:17061–17066

    Article  PubMed  Google Scholar 

  • Chi SW, Zang JB, Mele A, Darnell RB (2009) Argonaute HITS-CLIP decodes microRNA-mRNA interaction maps. Nature 460:479–486

    PubMed  CAS  Google Scholar 

  • Cui C, Griffiths A, Li G, Silva LM, Kramer MF et al (2006) Prediction and identification of herpes simplex virus 1-encoded microRNAs. J Virol 80:5499–5508

    Article  PubMed  CAS  Google Scholar 

  • Dews M, Homayouni A, Yu D, Murphy D, Sevignani C et al (2006) Augmentation of tumor angiogenesis by a Myc-activated microRNA cluster. Nat Genet 38:1060–1065

    Article  PubMed  CAS  Google Scholar 

  • Easow G, Teleman AA, Cohen SM (2007) Isolation of microRNA targets by miRNP immunopurification. RNA 13:1198–1204

    Article  PubMed  CAS  Google Scholar 

  • Enright AJ, John B, Gaul U, Tuschl T, Sander C et al (2003) MicroRNA targets in Drosophila. Genome Biol 5:R1

    Article  PubMed  Google Scholar 

  • Filipowicz W, Bhattacharyya SN, Sonenberg N (2008) Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight? Nat Rev Genet 9:102–114

    Article  PubMed  CAS  Google Scholar 

  • Fontana L, Pelosi E, Greco P, Racanicchi S, Testa U et al (2007) MicroRNAs 17–5p-20a–106a control monocytopoiesis through AML1 targeting and M-CSF receptor upregulation. Nat Cell Biol 9:775–787

    Article  PubMed  CAS  Google Scholar 

  • Forman JJ, Legesse-Miller A, Coller HA (2008) A search for conserved sequences in coding regions reveals that the let-7 microRNA targets Dicer within its coding sequence. Proc Natl Acad Sci USA 105:14879–14884

    Article  PubMed  Google Scholar 

  • Friedlander MR, Chen W, Adamidi C, Maaskola J, Einspanier R et al (2008) Discovering microRNAs from deep sequencing data using miRDeep. Nat Biotechnol 26:407–415

    Article  PubMed  CAS  Google Scholar 

  • German MA, Pillay M, Jeong DH, Hetawal A, Luo S et al (2008) Global identification of microRNA-target RNA pairs by parallel analysis of RNA ends. Nat Biotechnol 26:941–946

    Article  PubMed  CAS  Google Scholar 

  • Giraldez AJ, Cinalli RM, Glasner ME, Enright AJ, Thomson JM et al (2005) MicroRNAs regulate brain morphogenesis in zebrafish. Science 308:833–838

    Article  PubMed  CAS  Google Scholar 

  • Giraldez AJ, Mishima Y, Rihel J, Grocock RJ, Van Dongen S et al (2006) Zebrafish MiR-430 promotes deadenylation and clearance of maternal mRNAs. Science 312:75–79

    Article  PubMed  CAS  Google Scholar 

  • Grun D, Wang YL, Langenberger D, Gunsalus KC, Rajewsky N (2005) microRNA target predictions across seven Drosophila species and comparison to mammalian targets. PLoS Comput Biol 1:e13

    Article  PubMed  CAS  Google Scholar 

  • Grundhoff A, Sullivan CS, Ganem D (2006) A combined computational and microarray-based approach identifies novel microRNAs encoded by human gamma-herpesviruses. RNA 12:733–750

    Article  PubMed  CAS  Google Scholar 

  • Hackenberg M, Sturm M, Langenberger D, Falcon-Perez JM, Aransay AM (2009) miRanalyzer: a microRNA detection and analysis tool for next-generation sequencing experiments. Nucleic Acids Res 37:W68–W76

    Article  PubMed  CAS  Google Scholar 

  • Hammell M, Long D, Zhang L, Lee A, Carmack CS et al (2008) mirWIP: microRNA target prediction based on microRNA-containing ribonucleoprotein-enriched transcripts. Nat Methods 5:813–819

    Article  PubMed  CAS  Google Scholar 

  • Helvik SA, Snove O Jr, Saetrom P (2007) Reliable prediction of Drosha processing sites improves microRNA gene prediction. Bioinformatics 23:142–149

    Article  PubMed  CAS  Google Scholar 

  • Hertel J, Stadler PF (2006) Hairpins in a haystack: recognizing microRNA precursors in comparative genomics data. Bioinformatics 22:e197–e202

    Article  PubMed  CAS  Google Scholar 

  • Hsu PW, Lin LZ, Hsu SD, Hsu JB, Huang HD (2007) ViTa: prediction of host microRNAs targets on viruses. Nucleic Acids Res 35:D381–D385

    Article  PubMed  CAS  Google Scholar 

  • Huang JC, Babak T, Corson TW, Chua G, Khan S et al (2007a) Using expression profiling data to identify human microRNA targets. Nat Methods 4:1045–1049

    Article  PubMed  CAS  Google Scholar 

  • Huang TH, Fan B, Rothschild MF, Hu ZL, Li K et al (2007b) MiRFinder: an improved approach and software implementation for genome-wide fast microRNA precursor scans. BMC Bioinformatics 8:341

    Article  PubMed  CAS  Google Scholar 

  • Hwang HW, Wentzel EA, Mendell JT (2007) A hexanucleotide element directs microRNA nuclear import. Science 315:97–100

    Article  PubMed  CAS  Google Scholar 

  • Jiang P, Wu H, Wang W, Ma W, Sun X et al (2007) MiPred: classification of real and pseudo microRNA precursors using random forest prediction model with combined features. Nucleic Acids Res 35:W339–W344

    Article  PubMed  Google Scholar 

  • Kertesz M, Iovino N, Unnerstall U, Gaul U, Segal E (2007) The role of site accessibility in microRNA target recognition. Nat Genet 39:1278–1284

    Article  PubMed  CAS  Google Scholar 

  • Kim DH, Saetrom P, Snove O Jr, Rossi JJ (2008) MicroRNA-directed transcriptional gene silencing in mammalian cells. Proc Natl Acad Sci USA 105:16230–16235

    Article  PubMed  Google Scholar 

  • Kim SK, Nam JW, Rhee JK, Lee WJ, Zhang BT (2006) miTarget: microRNA target gene prediction using a support vector machine. BMC Bioinformatics 7:411

    Article  PubMed  CAS  Google Scholar 

  • Kim VN (2005) MicroRNA biogenesis: coordinated cropping and dicing. Nat Rev Mol Cell Biol 6:376–385

    Article  PubMed  CAS  Google Scholar 

  • Kim YK, Yu J, Han TS, Park SY, Namkoong B et al (2009) Functional links between clustered microRNAs: suppression of cell-cycle inhibitors by microRNA clusters in gastric cancer. Nucleic Acids Res 37:1672–1681

    Article  PubMed  CAS  Google Scholar 

  • Kiriakidou M, Nelson PT, Kouranov A, Fitziev P, Bouyioukos C et al (2004) A combined computational-experimental approach predicts human microRNA targets. Genes Dev 18:1165–1178

    Article  PubMed  CAS  Google Scholar 

  • Krek A, Grun D, Poy MN, Wolf R, Rosenberg L et al (2005) Combinatorial microRNA target predictions. Nat Genet 37:495–500

    Article  PubMed  CAS  Google Scholar 

  • Lall S, Grun D, Krek A, Chen K, Wang YL et al (2006) A genome-wide map of conserved microRNA targets in C. elegans. Curr Biol 16:460–471

    Article  PubMed  CAS  Google Scholar 

  • Landgraf P, Rusu M, Sheridan R, Sewer A, Iovino N et al (2007) A mammalian microRNA expression atlas based on small RNA library sequencing. Cell 129:1401–1414

    Article  PubMed  CAS  Google Scholar 

  • Lee J, Li Z, Brower-Sinning R, John B (2007) Regulatory circuit of human microRNA biogenesis. PLoS Comput Biol 3:e67

    Article  PubMed  CAS  Google Scholar 

  • Lee RC, Ambros V (2001) An extensive class of small RNAs in Caenorhabditis elegans. Science 294:862–864

    Article  PubMed  CAS  Google Scholar 

  • Lee RC, Feinbaum RL, Ambros V (1993) The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 75:843–854

    Article  PubMed  CAS  Google Scholar 

  • Lee Y, Jeon K, Lee JT, Kim S, Kim VN (2002) MicroRNA maturation: stepwise processing and subcellular localization. EMBO J 21:4663–4670

    Article  PubMed  CAS  Google Scholar 

  • Lee Y, Kim M, Han J, Yeom KH, Lee S et al (2004) MicroRNA genes are transcribed by RNA polymerase II. EMBO J 23:4051–4060

    Article  PubMed  CAS  Google Scholar 

  • Lewis BP, Shih IH, Jones-Rhoades MW, Bartel DP, Burge CB (2003) Prediction of mammalian microRNA targets. Cell 115:787–798

    Article  PubMed  CAS  Google Scholar 

  • Lewis BP, Burge CB, Bartel DP (2005) Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 120:15–20

    Article  PubMed  CAS  Google Scholar 

  • Li SC, Shiau CK, Lin WC (2008) Vir-Mir db: prediction of viral microRNA candidate hairpins. Nucleic Acids Res 36:D184–D189

    Article  PubMed  CAS  Google Scholar 

  • Lim LP, Lau NC, Weinstein EG, Abdelhakim A, Yekta S et al (2003) The microRNAs of Caenorhabditis elegans. Genes Dev 17:991–1008

    Article  PubMed  CAS  Google Scholar 

  • Lim LP, Lau NC, Garrett-Engele P, Grimson A, Schelter JM et al (2005) Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs. Nature 433:769–773

    Article  PubMed  CAS  Google Scholar 

  • Lindow M, Gorodkin J (2007) Principles and limitations of computational microRNA gene and target finding. DNA Cell Biol 26:339–351

    Article  PubMed  CAS  Google Scholar 

  • Linsen SE, de Wit E, Janssens G, Heater S, Chapman L et al (2009) Limitations and possibilities of small RNA digital gene expression profiling. Nat Methods 6:474–476

    Article  PubMed  CAS  Google Scholar 

  • Long D, Lee R, Williams P, Chan CY, Ambros V et al (2007) Potent effect of target structure on microRNA function. Nat Struct Mol Biol 14:287–294

    Article  PubMed  CAS  Google Scholar 

  • Lytle JR, Yario TA, Steitz JA (2007) Target mRNAs are repressed as efficiently by microRNA-binding sites in the 5′ UTR as in the 3′ UTR. Proc Natl Acad Sci USA 104:9667–9672

    Article  PubMed  CAS  Google Scholar 

  • Marson A, Levine SS, Cole MF, Frampton GM, Brambrink T et al (2008) Connecting microRNA genes to the core transcriptional regulatory circuitry of embryonic stem cells. Cell 134:521–533

    Article  PubMed  CAS  Google Scholar 

  • Martinez NJ, Ow MC, Barrasa MI, Hammell M, Sequerra R et al (2008) A C. elegans genome-scale microRNA network contains composite feedback motifs with high flux capacity. Genes Dev 22:2535–2549

    Article  PubMed  CAS  Google Scholar 

  • Maziere P, Enright AJ (2007) Prediction of microRNA targets. Drug Discov Today 12:452–458

    Article  PubMed  CAS  Google Scholar 

  • Megraw M, Sethupathy P, Corda B, Hatzigeorgiou AG (2007) miRGen: a database for the study of animal microRNA genomic organization and function. Nucleic Acids Res 35:D149–D155

    Article  PubMed  CAS  Google Scholar 

  • Milo R, Shen-Orr S, Itzkovitz S, Kashtan N, Chklovskii D et al (2002) Network motifs: simple building blocks of complex networks. Science 298:824–827

    Article  PubMed  CAS  Google Scholar 

  • Miranda KC, Huynh T, Tay Y, Ang YS, Tam WL et al (2006) A pattern-based method for the identification of microRNA binding sites and their corresponding heteroduplexes. Cell 126:1203–1217

    Article  PubMed  CAS  Google Scholar 

  • Nam JW, Kim J, Kim SK, Zhang BT (2006) ProMiR II: a web server for the probabilistic prediction of clustered, nonclustered, conserved and nonconserved microRNAs. Nucleic Acids Res 34:W455–W458

    Article  PubMed  CAS  Google Scholar 

  • Ng KL, Mishra SK (2007) De novo SVM classification of precursor microRNAs from genomic pseudo hairpins using global and intrinsic folding measures. Bioinformatics 23:1321–1330

    Article  PubMed  CAS  Google Scholar 

  • Okamura K, Hagen JW, Duan H, Tyler DM, Lai EC (2007) The mirtron pathway generates microRNA-class regulatory RNAs in Drosophila. Cell 130:89–100

    Article  PubMed  CAS  Google Scholar 

  • Okamura K, Phillips MD, Tyler DM, Duan H, Chou YT et al (2008) The regulatory activity of microRNA* species has substantial influence on microRNA and 3′ UTR evolution. Nat Struct Mol Biol 15:354–363

    Article  PubMed  CAS  Google Scholar 

  • Olson AJ, Brennecke J, Aravin AA, Hannon GJ, Sachidanandam R (2008) Analysis of large-scale sequencing of small RNAs. Pac Symp Biocomput 126-136

  • Ozsolak F, Poling LL, Wang Z, Liu H, Liu XS et al (2008) Chromatin structure analyses identify miRNA promoters. Genes Dev 22:3172–3183

    Article  PubMed  CAS  Google Scholar 

  • Papadopoulos GL, Reczko M, Simossis VA, Sethupathy P, Hatzigeorgiou AG (2009) The database of experimentally supported targets: a functional update of TarBase. Nucleic Acids Res 37:D155–D158

    Article  PubMed  CAS  Google Scholar 

  • Pfeffer S, Zavolan M, Grasser FA, Chien M, Russo JJ et al (2004) Identification of virus-encoded microRNAs. Science 304:734–736

    Article  PubMed  CAS  Google Scholar 

  • Pfeffer S, Sewer A, Lagos-Quintana M, Sheridan R, Sander C et al (2005) Identification of microRNAs of the herpesvirus family. Nat Methods 2:269–276

    Article  PubMed  CAS  Google Scholar 

  • Place RF, Li LC, Pookot D, Noonan EJ, Dahiya R (2008) MicroRNA-373 induces expression of genes with complementary promoter sequences. Proc Natl Acad Sci USA 105:1608–1613

    Article  PubMed  Google Scholar 

  • Rehmsmeier M, Steffen P, Hochsmann M, Giegerich R (2004) Fast and effective prediction of microRNA/target duplexes. RNA 10:1507–1517

    Article  PubMed  CAS  Google Scholar 

  • Ruby JG, Jan CH, Bartel DP (2007) Intronic microRNA precursors that bypass Drosha processing. Nature 448:83–86

    Article  PubMed  CAS  Google Scholar 

  • Rusinov V, Baev V, Minkov IN, Tabler M (2005) MicroInspector: a web tool for detection of miRNA binding sites in an RNA sequence. Nucleic Acids Res 33:W696–W700

    Article  PubMed  CAS  Google Scholar 

  • Saetrom O, Snove O Jr, Saetrom P (2005) Weighted sequence motifs as an improved seeding step in microRNA target prediction algorithms. RNA 11:995–1003

    Article  PubMed  CAS  Google Scholar 

  • Saini HK, Griffiths-Jones S, Enright AJ (2007) Genomic analysis of human microRNA transcripts. Proc Natl Acad Sci USA 104:17719–17724

    Article  PubMed  Google Scholar 

  • Selbach M, Schwanhausser B, Thierfelder N, Fang Z, Khanin R et al (2008) Widespread changes in protein synthesis induced by microRNAs. Nature 455:58–63

    Article  PubMed  CAS  Google Scholar 

  • Sethupathy P, Megraw M, Hatzigeorgiou AG (2006) A guide through present computational approaches for the identification of mammalian microRNA targets. Nat Methods 3:881–886

    Article  PubMed  CAS  Google Scholar 

  • Sewer A, Paul N, Landgraf P, Aravin A, Pfeffer S et al (2005) Identification of clustered microRNAs using an ab initio prediction method. BMC Bioinformatics 6:267

    Article  PubMed  CAS  Google Scholar 

  • Sullivan CS, Ganem D (2005) MicroRNAs and viral infection. Mol Cell 20:3–7

    Article  PubMed  CAS  Google Scholar 

  • Tay Y, Zhang J, Thomson AM, Lim B, Rigoutsos I (2008) MicroRNAs to Nanog, Oct4 and Sox2 coding regions modulate embryonic stem cell differentiation. Nature 455:1124–1128

    Article  PubMed  CAS  Google Scholar 

  • Thadani R, Tammi MT (2006) MicroTar: predicting microRNA targets from RNA duplexes. BMC Bioinformatics 7 Suppl 5:S20

    Article  PubMed  CAS  Google Scholar 

  • van Dongen S, Abreu-Goodger C, Enright AJ (2008) Detecting microRNA binding and siRNA off-target effects from expression data. Nat Methods 5:1023–1025

    Article  PubMed  CAS  Google Scholar 

  • Wang X, Zhang J, Li F, Gu J, He T et al (2005) MicroRNA identification based on sequence and structure alignment. Bioinformatics 21:3610–3614

    Article  PubMed  CAS  Google Scholar 

  • Xu J, Wong C (2008) A computational screen for mouse signaling pathways targeted by microRNA clusters. RNA 14:1276–1283

    Article  PubMed  CAS  Google Scholar 

  • Xue C, Li F, He T, Liu GP, Li Y et al (2005) Classification of real and pseudo microRNA precursors using local structure-sequence features and support vector machine. BMC Bioinformatics 6:310

    Article  PubMed  CAS  Google Scholar 

  • Yousef M, Nebozhyn M, Shatkay H, Kanterakis S, Showe LC et al (2006) Combining multi-species genomic data for microRNA identification using a Naive Bayes classifier. Bioinformatics 22:1325–1334

    Article  PubMed  CAS  Google Scholar 

  • Yousef M, Jung S, Kossenkov AV, Showe LC, Showe MK (2007) Naive Bayes for microRNA target predictions–machine learning for microRNA targets. Bioinformatics 23:2987–2992

    Article  PubMed  CAS  Google Scholar 

  • Yu X, Lin J, Zack DJ, Mendell JT, Qian J (2008) Analysis of regulatory network topology reveals functionally distinct classes of microRNAs. Nucleic Acids Res 36:6494–6503

    Article  PubMed  CAS  Google Scholar 

  • Yuan X, Liu C, Yang P, He S, Liao Q et al (2009) Clustered microRNAs’ coordination in regulating protein-protein interaction network. BMC Syst Biol 3:65

    Article  PubMed  CAS  Google Scholar 

  • Zhang L, Ding L, Cheung TH, Dong MQ, Chen J et al (2007) Systematic identification of C. elegans miRISC proteins, miRNAs, and mRNA targets by their interactions with GW182 proteins AIN-1 and AIN-2. Mol Cell 28:598–613

    Article  PubMed  CAS  Google Scholar 

  • Zhao Y, Samal E, Srivastava D (2005) Serum response factor regulates a muscle-specific microRNA that targets Hand2 during cardiogenesis. Nature 436:214–220

    Article  PubMed  CAS  Google Scholar 

  • Zhou X, Ruan J, Wang G, Zhang W (2007) Characterization and identification of microRNA core promoters in four model species. PLoS Comput Biol 3:e37

    Article  PubMed  CAS  Google Scholar 

  • Ziegelbauer JM, Sullivan CS, Ganem D (2009) Tandem array-based expression screens identify host mRNA targets of virus-encoded microRNAs. Nat Genet 41:130–134

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We apologize for the failure to cite many of the important and relevant papers in this field due to space limitations. We thank Dr. Baowei Peng and Ms. Jian Fan for critical reading of the manuscript. This work was partially supported by the National Natural Science Foundation of China (Grant No. 60601010), the Science Foundation of the education department of Henan province (Grant No. 2006210002), and the Award for Outstanding Young Teacher of Tongji University (No.TJYQ08014).

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Correspondence to Jianzhen Xu.

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L. Li and J. Xu contributed equally to this work.

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Li, L., Xu, J., Yang, D. et al. Computational approaches for microRNA studies: a review. Mamm Genome 21, 1–12 (2010). https://doi.org/10.1007/s00335-009-9241-2

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