DOI QR코드

DOI QR Code

Discovery to Human Disease Research: Proteo-Metabolomics Analysis

  • Minjoong Joo (Basilbiotech) ;
  • Jeong-Hun Mok (Department of Medical Device Management and Research, SAIHST, Sungkyunkwan University) ;
  • Van-An Duong (College of Pharmacy, Gachon University) ;
  • Jong-Moon Park (Basilbiotech) ;
  • Hookeun Lee (College of Pharmacy, Gachon University)
  • 투고 : 2024.02.29
  • 심사 : 2024.04.04
  • 발행 : 2024.06.30

초록

The advancement of high-throughput omics technologies and systems biology is essential for understanding complex biological mechanisms and diseases. The integration of proteomics and metabolomics provides comprehensive insights into cellular functions and disease pathology, driven by developments in mass spectrometry (MS) technologies, including electrospray ionization (ESI). These advancements are crucial for interpreting biological systems effectively. However, integrating these technologies poses challenges. Compared to genomic, proteomics and metabolomics have limitations in throughput, and data integration. This review examines developments in MS equipped electrospray ionization (ESI), and their importance in the effective interpretation of biological mechanisms. The review also discusses developments in sample preparation, such as Simultaneous Metabolite, Protein, Lipid Extraction (SIMPLEX), analytical techniques, and data analysis, highlighting the application of these technologies in the study of cancer or Huntington's disease, underscoring the potential for personalized medicine and diagnostic accuracy. Efforts by the Clinical Proteomic Tumor Analysis Consortium (CPTAC) and integrative data analysis methods such as O2PLS and OnPLS extract statistical similarities between metabolomic and proteomic data. System modeling techniques that mathematically explain and predict system responses are also covered. This practical application also shows significant improvements in cancer research, diagnostic accuracy and therapeutic targeting for diseases like pancreatic ductal adenocarcinoma, non-small cell lung cancer, and Huntington's disease. These approaches enable researchers to develop standardized protocols, and interoperable software and databases, expanding multi-omics research application in clinical practice.

키워드

과제정보

This work was a grant from the National Research Foundation (NRF-2022M3H9A2086450) funded by the Korean Ministry of Science, National Research Foundation of Korea (NRF) (No. 2017M3D9A1073784), and ICT (MSIT) and Korea Evaluation Institute Of Industrial Technology (KEIT) (No. 20018578).

참고문헌

  1. Breitling, R. Front Physiol 2010, 1, 9. https://doi.org/10.3389/fphys.2010.00009 
  2. Hillmer, R.A. PLoS Pathog 2015, 11, e1004786. https://doi.org/10.1371/journal.ppat.1004786 
  3. Cho, C.R.; Labow, M.; Reinhardt, M.; van Oostrum, J.; Peitsch, M.C. The application of systems biology to drug discovery Curr Opin Chem Biol 2006, 10, 294. https://doi.org/10.1016/j.cbpa.2006.06.025 
  4. Cisek, K.; Krochmal, M.; Klein, J.; Mischak, H Nephrol Dial Transplant 2016, 31, 2003. https://doi.org/10.1093/ndt/gfv364 
  5. Hagemann, M.; Hess, W.R. Curr Opin Biotechnol 2018, 49, 94. https://doi.org/10.1016/j.copbio.2017.07.008 
  6. Otero, J.M.; Nielsen, J Biotechnol Bioeng 2010, 105, 439. https://doi.org/10.1002/bit.22592 
  7. Tezel, G.; Wax, M.B. Curr Opin Ophthalmol 2004, 80. https://doi.org/10.1097/00055735-200404000-00003 
  8. Gilchrist, M.; Thorsson, V.; Li, B.; Rust, A.G.; Korb, M.; Roach, J.C.; Kennedy, K.; Hai, T.; Bolouri, H.; Aderem, A. Nature 2006, 441, 173. https://doi.org/10.1038/nature04768 
  9. Bodein, A.; Scott-Boyer, M.-P.; Perin, O.; Le Cao, K.-A.; Droit, A. Nucleic Acids Research 2021, 50, e27. https://doi.org/10.1093/nar/gkab1200 
  10. Thiele, I.; Swainston, N.; Fleming, R.M.; Hoppe, A.; Sahoo, S.; Aurich, M.K.; Haraldsdottir, H.; Mo, M.L.; Rolfsson, O.; Stobbe, M.D.; Thorleifsson, S.G.; Agren, R.; Bolling, C.; Bordel, S.; Chavali, A.K.; Dobson, P.; Dunn, W.B.; Endler, L.; Hala, D.; Hucka, M.; Hull, D.; Jameson, D.; Jamshidi, N.; Jonsson, J.J.; Juty, N.; Keating, S.; Nookaew, I.; Le Novere, N.; Malys, N.; Mazein, A.; Papin, J.A.; Price, N.D.; Selkov, E., Sr.; Sigurdsson, M.I.; Simeonidis, E.; Sonnenschein, N.; Smallbone, K.; Sorokin, A.; van Beek, J.H.; Weichart, D.; Goryanin, I.; Nielsen, J.; Westerhoff, H.V.; Kell, D.B.; Mendes, P.; Palsson, B. Nat Biotechnol 2013, 31, 419. https://doi.org/10.1038/nbt.2488 
  11. Domon, B.; Aebersold, R. Science 2006, 312, 212. https://doi.org/10.1126/science.1124619 
  12. Wanichthanarak, K.; Fahrmann, J.F.; Grapov, D. Biomark Insights 2015, 10, 1. https://doi.org/10.4137/BMI.S29511 
  13. Fiehn, O.; Robertson, D.; Griffin, J.; van der Werf, M.; Nikolau, B.; Morrison, N.; Sumner, L.W.; Goodacre, R.; Hardy, N.W.; Taylor, C.; Fostel, J.; Kristal, B.; Kaddurah-Daouk, R.; Mendes, P.; van Ommen, B.; Lindon, J.C.; Sansone, S.-A. Metabolomics 2007, 3, 175. https://doi.org/10.1007/s11306-007-0070-6 
  14. Becker, S.; Kortz, L.; Helmschrodt, C.; Thiery, J.; Ceglarek, U. Journal of Chromatography B 2012, 883-884, 68. https://doi.org/10.1016/j.jchromb.2011.10.018 
  15. Beale, D.J.; Pinu, F.R.; Kouremenos, K.A.; Poojary, M.M.; Narayana, V.K.; Boughton, B.A.; Kanojia, K.; Dayalan, S.; Jones, O.A.H.; Dias, D.A. Metabolomics 2018, 14, 152. https://doi.org/10.1007/s11306-018-1449-2 
  16. Zenati, R.A.; Giddey, A.D.; Al-Hroub, H.M.; Hagyousif, Y.A.; El-Huneidi, W.; Bustanji, Y.; Abu-Gharbieh, E.; Alqudah, M.A.; Shara, M.; Abuhelwa, A.Y. International Journal of Molecular Sciences 2023, 24, 1354. https://doi.org/10.3390/ijms24021354 
  17. Van Pijkeren, A.; Egger, A.-S.; Hotze, M.; Zimmermann, E.; Kipura, T.; Grander, J.; Gollowitzer, A.; Koeberle, A.; Bischoff, R.; Thedieck, K. Journal of Proteome Research 2023, 22, 951. https://doi.org/10.1021/acs.jproteome.2c00758 
  18. Mardis, E.R Annu Rev Genomics Hum Genet 2008, 9, 387. https://doi.org/10.1146/annurev.genom.9.081307.164359 
  19. LaFramboise, T. Nucleic Acids Res 2009, 37, 4181. https://doi.org/10.1093/nar/gkp552 
  20. Wang, Z.; Gerstein, M.; Snyder, M Nat Rev Genet 2009, 10, 57. https://doi.org/10.1038/nrg2484 
  21. Nassar, A.F.; Wu, T.; Nassar, S.F.; Wisnewski, A.V. Drug Discov Today 2017, 22, 463. https://doi.org/10.1016/j.drudis.2016.11.020 
  22. Ludwig, C.; Gillet, L.; Rosenberger, G.; Amon, S.; Collins, B.C.; Aebersold, R. Mol Syst Biol 2018, 14, e8126. https://doi.org/10.15252/msb.20178126 
  23. Yizhak, K.; Benyamini, T.; Liebermeister, W.; Ruppin, E.; Shlomi, T. Bioinformatics 2010, 26, i255. https://doi.org/10.1093/bioinformatics/btq183 
  24. Shannon, P.; Markiel, A.; Ozier, O.; Baliga, N.S.; Wang, J.T.; Ramage, D.; Amin, N.; Schwikowski, B.; Ideker, T. Genome Res 2003, 13, 2498. https://doi.org/10.1101/gr.1239303 
  25. Cohen, A.; Bont, L.; Engelhard, D.; Moore, E.; Fernandez, D.; Kreisberg-Greenblatt, R.; Oved, K.; Eden, E.; Hays, J.P. Future Microbiol 2015, 10, 365. https://doi.org/10.2217/fmb.14.127 
  26. Chen, R.; Mias, G.I.; Li-Pook-Than, J.; Jiang, L.; Lam, H.Y.; Chen, R.; Miriami, E.; Karczewski, K.J.; Hariharan, M.; Dewey, F.E.; Cheng, Y.; Clark, M.J.; Im, H.; Habegger, L.; Balasubramanian, S.; O'Huallachain, M.; Dudley, J.T.; Hillenmeyer, S.; Haraksingh, R.; Sharon, D.; Euskirchen, G.; Lacroute, P.; Bettinger, K.; Boyle, A.P.; Kasowski, M.; Grubert, F.; Seki, S.; Garcia, M.; Whirl-Carrillo, M.; Gallardo, M.; Blasco, M.A.; Greenberg, P.L.; Snyder, P.; Klein, T.E.; Altman, R.B.; Butte, A.J.; Ashley, E.A.; Gerstein, M.; Nadeau, K.C.; Tang, H.; Snyder, M. Cell 2012, 148, 1293. https://doi.org/10.1016/j.cell.2012.02.009 
  27. Gunther, O.P.; Shin, H.; Ng, R.T.; McMaster, W.R.; McManus, B.M.; Keown, P.A.; Tebbutt, S.J.; KA, L.C. Omics 2014, 18, 682. https://doi.org/10.1089/omi.2014.0062 
  28. Schloss, P.D. mBio 2018, 9. https://doi.org/10.1128/mBio.00525-18 
  29. Sun, Y.V.; Hu, Y.J Adv Genet 2016, 93, 147. https://doi.org/10.1016/bs.adgen.2015.11.004 
  30. Zhang, Y.; Xu, S.; Wen, Z.; Gao, J.; Li, S.; Weissman, S.M.; Pan, X. Cell Mol Life Sci 2022, 79, 466. https://doi.org/10.1007/s00018-022-04482-0 
  31. Mok, J.H.; Joo, M.; Cho, S.; Duong, V.A.; Song, H.; Park, J.M.; Lee, H. Metabolites 2024, 14. https://doi.org/10.3390/metabo14010034 
  32. Qin, S.; Bai, Y.; Liu, H. Se Pu 2021, 39, 142. https://doi.org/10.3724/sp.J.1123.2020.08030 
  33. Patel, M.K.; Pandey, S.; Kumar, M.; Haque, M.I.; Pal, S.; Yadav, N.S. Plants (Basel) 2021, 10. https://doi.org/10.3390/plants10112409 
  34. Fischer, R.; Bowness, P.; Kessler, B.M. Proteomics 2013, 13, 3371. https://doi.org/10.1002/pmic.201300192 
  35. Santacruz, D.; Enane, F.O.; Fundel-Clemens, K.; Giner, M.; Wolf, G.; Onstein, S.; Klimek, C.; Smith, Z.; Wijayawardena, B.; Viollet, C. SLAS Discov 2022, 27, 140. https://doi.org/10.1016/j.slasd.2022.01.002 
  36. Wang, Z.; Ma, H.; Smith, K.; Wu, S. Int J Mass Spectrom 2018, 427, 43. https://doi.org/10.1016/j.ijms.2017.09.001 
  37. Loo, R.R.; Dales, N.; Andrews, P.C. Methods Mol Biol 1996, 61, 141. https://doi.org/10.1385/0-89603-345-7:141 
  38. Zhang, X. Molecular & Cellular Proteomics 2015, 14, 2441. https://doi.org/10.1074/mcp.R114.042572 
  39. Coman, C.; Solari, F.A.; Hentschel, A.; Sickmann, A.; Zahedi, R.P.; Ahrends, R. Mol Cell Proteomics 2016, 15, 1453. https://doi.org/10.1074/mcp.M115.053702 
  40. Nicora, C.D.; Burnum-Johnson, K.E.; Nakayasu, E.S.; Casey, C.P.; White, R.A., 3rd; Roy Chowdhury, T.; Kyle, J.E.; Kim, Y.M.; Smith, R.D.; Metz, T.O.; Jansson, J.K.; Baker, E.S. J Vis Exp 2018. https://doi.org/10.3791/57343 
  41. Koh, H.W.; Fermin, D.; Choi, K.P.; Ewing, R.; Choi, H. bioRxiv 2018, 374520. doi: https://doi.org/10.1101/374520 
  42. Strom, S.P. Methods Mol Biol 2019, 1897, 345. https://doi.org/10.1007/978-1-4939-8935-5_29 
  43. O'Rourke, M.B.; Padula, M.P. Biotechniques 2016, 229. https://doi.org/10.2144/000114414 
  44. Coscia, F.; Lengyel, E.; Duraiswamy, J.; Ashcroft, B.; Bassani-Sternberg, M.; Wierer, M.; Johnson, A.; Wroblewski, K.; Montag, A.; Yamada, S.D.; Lopez-Mendez, B.; Nilsson, J.; Mund, A.; Mann, M.; Curtis, M. Cell 2018, 175, 159. https://doi.org/10.1016/j.cell.2018.08.065 
  45. Behnke, J.-S.; Urner, L.H. Analytical and Bioanalytical Chemistry 2023, 415, 3897. https://doi.org/10.1007/s00216-023-04584-z 
  46. Chetwynd, A.J.; Dunn, W.B.; Rodriguez-Blanco, G. Adv Exp Med Biol 2017, 965, 19. https://doi.org/10.1007/978-3-319-47656-8_2 
  47. Broadhurst, D.I.; Kell, D.B. Metabolomics 2006, 2, 171. https://doi.org/10.1007/s11306-006-0037-z 
  48. Ren, S.; Hinzman, A.A.; Kang, E.L.; Szczesniak, R.D.; Lu, L.J. Metabolomics 2015, 11, 1492. https://doi.org/10.1007/s11306-015-0823-6 
  49. Chen, S.; Hoene, M.; Li, J.; Li, Y.; Zhao, X.; Haring, H.-U.; Schleicher, E.D.; Weigert, C.; Xu, G.; Lehmann, R. Journal of Chromatography A 2013, 1298, 9. https://doi.org/10.1016/j.chroma.2013.05.019 
  50. Lee, D.Y.; Kind, T.; Yoon, Y.-R.; Fiehn, O.; Liu, K.-H. Chemistry 2014, 406, 7275. https://doi.org/10.1007/s00216-014-8124-x 
  51. Ulmer, C.Z.; Jones, C.M.; Yost, R.A.; Garrett, T.J.; Bowden, J.A. Analytica Chimica Acta 2018, 1037, 351. https://doi.org/10.1016/j.aca.2018.08.004 
  52. Beale, D.J.; Karpe, A.V.; McLeod, J.D.; Gondalia, S.V.; Muster, T.H.; Othman, M.Z.; Palombo, E.A.; Joshi, D. Water Res 2016, 88, 346. https://doi.org/10.1016/j.watres.2015.10.029 
  53. Turnbaugh, P.J.; Gordon, J.I. Cell 2008, 134, 708. https://doi.org/10.1016/j.cell.2008.08.025 
  54. Hultman, J.; Waldrop, M.P.; Mackelprang, R.; David, M.M.; McFarland, J.; Blazewicz, S.J.; Harden, J.; Turetsky, M.R.; McGuire, A.D.; Shah, M.B.; VerBerkmoes, N.C.; Lee, L.H.; Mavrommatis, K.; Jansson, J.K. Nature 2015, 521, 208. https://doi.org/10.1038/nature14238 
  55. Wu, P.; Heins, Z.J.; Muller, J.T.; Katsnelson, L.; de Bruijn, I.; Abeshouse, A.A.; Schultz, N.; Fenyo, D.; Gao, JMolecular & Cellular Proteomics 2019, 18, 1893. https://doi.org/10.1074/mcp.TIR119.001673 
  56. Edwards, N.J.; Oberti, M.; Thangudu, R.R.; Cai, S.; McGarvey, P.B.; Jacob, S.; Madhavan, S.; Ketchum, K.A. Journal of proteome research 2015, 14, 2707. https://doi.org/10.1021/pr501254j 
  57. Tang, D.Q.; Zou, L.; Yin, X.X.; Ong, C.N. Mass spectrometry reviews 2016, 35, 574. https://doi.org/10.1002/mas.21445 
  58. Loo, R.O.; Dales, N.; Andrews, P Protein Science 1994, 3, 1975. https://doi.org/10.1002/pro.5560031109 
  59. Jobgen, W.S.; Fried, S.K.; Fu, W.J.; Meininger, C.J.; Wu, G. J Nutr Biochem 2006, 17, 571. https://doi.org/10.1016/j.jnutbio.2005.12.001 
  60. Myung, S.; Lee, Y.J.; Moon, M.H.; Taraszka, J.; Sowell, R.; Koeniger, S.; Hilderbrand, A.E.; Valentine, S.J.; Cherbas, L.; Cherbas, P. Analytical chemistry 2003, 75, 5137. https://doi.org/10.1021/ac030107f 
  61. Liu, Q.; Cobb, J.S.; Johnson, J.L.; Wang, Q.; Agar, J.N. Journal of chromatographic science 2014, 52, 120. https://doi.org/10.1093/chromsci/bms255 
  62. Burkhart, J.M.; Premsler, T.; Sickmann, A. Proteomics 2011, 11, 1049. https://doi.org/10.1002/pmic.201000604 
  63. Tyanova, S.; Temu, T.; Cox, J. Nature protocols 2016, 11, 2301. https://doi.org/10.1038/nprot.2016.136 
  64. Wishart, D.S.; Feunang, Y.D.; Marcu, A.; Guo, A.C.; Liang, K.; Vazquez-Fresno, R.; Sajed, T.; Johnson, D.; Li, C.; Karu, N. Nucleic acids research 2018, 46, D608. https://doi.org/10.1093/nar/gkx1089 
  65. Kim, S.; Thiessen, P.A.; Bolton, E.E.; Chen, J.; Fu, G.; Gindulyte, A.; Han, L.; He, J.; He, S.; Shoemaker, B.A. Nucleic acids research 2016, 44, D1202. https://doi.org/10.1093/nar/gkv951 
  66. Xue, J.; Domingo-Almenara, X.; Guijas, C.; Palermo, A.; Rinschen, M.M.; Isbell, J.; Benton, H.P.; Siuzdak, G. Anal Chem 2020, 92, 6051. https://doi.org/10.1021/acs.analchem.0c00409 
  67. Fischer, R.; Bowness, P.; Kessler, B.M. Proteomics 2013, 13, 3371. https://doi.org/10.1002/pmic.201300192 
  68. Smith, C.A.; Want, E.J.; O'Maille, G.; Abagyan, R.; Siuzdak, G. Analytical chemistry 2006, 78, 779. https://doi.org/10.1021/ac051437y 
  69. Kanehisa, M.; Goto, S.; Kawashima, S.; Nakaya, A. Nucleic acids research 2002, 30, 42. https://doi.org/10.1093/nar/30.1.42 
  70. Dennis, G.; Sherman, B.T.; Hosack, D.A.; Yang, J.; Gao, W.; Lane, H.C.; Lempicki, R.A. Genome Biology 2003, 4, R60. https://doi.org/10.1186/gb-2003-4-9-r60 
  71. Blum, B.C.; Mousavi, F.; Emili, A Mol Omics 2018, 14, 307. https://doi.org/10.1039/c8mo00136g 
  72. Kuo, T.-C.; Tian, T.-F.; Tseng, Y.J. BMC systems biology 2013, 7, 1. https://doi.org/10.1186/1752-0509-7-64 
  73. Zhou, G.; Xia, J Nucleic Acids Res 2018, 46, W514. https://doi.org/10.1093/nar/gky510
  74. Szklarczyk, D.; Gable, A.L.; Lyon, D.; Junge, A.; Wyder, S.; Huerta-Cepas, J.; Simonovic, M.; Doncheva, N.T.; Morris, J.H.; Bork, P. Nucleic acids research 2019, 47, D607. https://doi.org/10.1093/nar/gky1131 
  75. Douterelo, I.; Boxall, J.B.; Deines, P.; Sekar, R.; Fish, K.E.; Biggs, C.A. Water Res 2014, 65, 134. https://doi.org/10.1016/j.watres.2014.07.008 
  76. Kimes, N.E.; Callaghan, A.V.; Aktas, D.F.; Smith, W.L.; Sunner, J.; Golding, B.; Drozdowska, M.; Hazen, T.C.; Suflita, J.M.; Morris, P.J Frontiers in microbiology 2013, 4, 50. https://doi.org/10.3389/fmicb.2013.00050 
  77. Hultman, J.; Waldrop, M.P.; Mackelprang, R.; David, M.M.; McFarland, J.; Blazewicz, S.J.; Harden, J.; Turetsky, M.R.; McGuire, A.D.; Shah, M.B.; VerBerkmoes, N.C.; Lee, L.H.; Mavrommatis, K.; Jansson, J.K. Nature 2015, 521, 208. https://doi.org/10.1038/nature14238 
  78. Bylesjo, M.; Eriksson, D.; Kusano, M.; Moritz, T.; Trygg, J. The Plant Journal 2007, 52, 1181. https://doi.org/10.1111/j.1365-313X.2007.03293.x 
  79. Trygg, J.; Wold, S. Journal of chemometrics 2003, 17, 53. https://doi.org/10.1002/cem.775 
  80. Reinke, S.N.; Galindo-Prieto, B.; Skotare, T.; Broadhurst, D.I.; Singhania, A.; Horowitz, D.; Djukanovic, R.; Hinks, T.S.; Geladi, P.; Trygg, J. Analytical chemistry 2018, 90, 13400. https://doi.org/10.1021/acs.analchem.8b03205 
  81. Lofstedt, T.; Trygg, J. Journal of Chemometrics 2011, 25, 441. https://doi.org/10.1002/cem.1388 
  82. Rantalainen, M.; Cloarec, O.; Beckonert, O.; Wilson, I.; Jackson, D.; Tonge, R.; Rowlinson, R.; Rayner, S.; Nickson, J.; Wilkinson, R.W. Journal of proteome research 2006, 5, 2642. https://doi.org/10.1021/pr060124w 
  83. Shi, Z.; Mao, B.; Chen, X.; Hao, P.; Guo, S. Cancer Research Communications 2023, 3, 202. https://doi.org/10.1158/2767-9764.Crc-22-0431 
  84. Lourenco, A.; Ferreira, A.; Veiga, N.; Machado, I.; Pereira, M.O.; Azevedo, N.F. PLoS One 2012, 7, e39960. https://doi.org/10.1371/journal.pone.0039960 
  85. Karp, P.D.; Billington, R.; Caspi, R.; Fulcher, C.A.; Latendresse, M.; Kothari, A.; Keseler, I.M.; Krummenacker, M.; Midford, P.E.; Ong, Q.; Ong, W.K.; Paley, S.M.; Subhraveti, P. Brief Bioinform 2019, 20, 1085. https://doi.org/10.1093/bib/bbx085 
  86. Lloyd, C.M.; Halstead, M.D.; Nielsen, P.F Prog Biophys Mol Biol 2004, 85, 433. https://doi.org/10.1016/j.pbiomolbio.2004.01.004 
  87. Stewart, C.; Wheeler, C.; Cena, R.; McMonagle, C.; Cuta, J.; Trent, D. 1977. COBRA-IV: The model and the method. Pacific Northwest National Lab.(PNNL), Richland, WA (United States) 
  88. Heirendt, L.; Arreckx, S.; Pfau, T.; Mendoza, S.N.; Richelle, A.; Heinken, A.; Haraldsdottir, H.S.; Wachowiak, J.; Keating, S.M.; Vlasov, V.; Magnusdottir, S.; Ng, C.Y.; Preciat, G.; Zagare, A.; Chan, S.H.J.; Aurich, M.K.; Clancy, C.M.; Modamio, J.; Sauls, J.T.; Noronha, A.; Bordbar, A.; Cousins, B.; El Assal, D.C.; Valcarcel, L.V.; Apaolaza, I.; Ghaderi, S.; Ahookhosh, M.; Ben Guebila, M.; Kostromins, A.; Sompairac, N.; Le, H.M.; Ma, D.; Sun, Y.; Wang, L.; Yurkovich, J.T.; Oliveira, M.A.P.; Vuong, P.T.; El Assal, L.P.; Kuperstein, I.; Zinovyev, A.; Hinton, H.S.; Bryant, W.A.; Aragon Artacho, F.J.; Planes, F.J.; Stalidzans, E.; Maass, A.; Vempala, S.; Hucka, M.; Saunders, M.A.; Maranas, C.D.; Lewis, N.E.; Sauter, T.; Palsson, B.O.; Thiele, I.; Fleming, R.M.T. Nat Protoc 2019, 14, 639. https://doi.org/10.1038/s41596-018-0098-2 
  89. Noronha, A.; Modamio, J.; Jarosz, Y.; Guerard, E.; Sompairac, N.; Preciat, G.; Danielsdottir, A.D.; Krecke, M.; Merten, D.; Haraldsdottir, H.S.; Heinken, A.; Heirendt, L.; Magnusdottir, S.; Ravcheev, D.A.; Sahoo, S.; Gawron, P.; Friscioni, L.; Garcia, B.; Prendergast, M.; Puente, A.; Rodrigues, M.; Roy, A.; Rouquaya, M.; Wiltgen, L.; Zagare, A.; John, E.; Krueger, M.; Kuperstein, I.; Zinovyev, A.; Schneider, R.; Fleming, R.M.T.; Thiele, I. Nucleic Acids Res 2019, 47, D614. https://doi.org/10.1093/nar/gky992 
  90. Xia, T.; Hemert, J.V.; Dickerson, J.A. Bioinformatics 2010, 26, 2995. https://doi.org/10.1093/bioinformatics/btq583 
  91. Tomita, M.; Hashimoto, K.; Takahashi, K.; Shimizu, T.S.; Matsuzaki, Y.; Miyoshi, F.; Saito, K.; Tanida, S.; Yugi, K.; Venter, J.C.; Hutchison, C.A., 3rd. Bioinformatics 1999, 15, 72. https://doi.org/10.1093/bioinformatics/15.1.72 
  92. King, Z.A.; Drager, A.; Ebrahim, A.; Sonnenschein, N.; Lewis, N.E.; Palsson, B.O. PLoS Comput Biol 2015, 11, e1004321. https://doi.org/10.1371/journal.pcbi.1004321 
  93. Vasaikar, S.V.; Straub, P.; Wang, J.; Zhang, Bs Nucleic Acids Research 2017, 46, D956. https://doi.org/10.1093/nar/gkx1090 
  94. Ahsan, S.; Draghici, S. Curr Protoc Bioinformatics 2017, 57, 7.15.1. https://doi.org/10.1002/cpbi.24 
  95. Pang, Z.; Chong, J.; Zhou, G.; de Lima Morais, D.A.; Chang, L.; Barrette, M.; Gauthier, C.; Jacques, P.-E.; Li, S.; Xia, J. Nucleic acids research 2021, 49, W388. https://doi.org/10.1093/nar/gkab382 
  96. Rohart, F.; Gautier, B.; Singh, A.; Le Cao, K.A PLoS Comput Biol 2017, 13, e1005752. https://doi.org/10.1371/journal.pcbi.1005752 
  97. Wierling, C.; Herwig, R.; Lehrach, H. Brief Funct Genomic Proteomic 2007, 6, 240. https://doi.org/10.1093/bfgp/elm027 
  98. Shapiro, B.E.; Levchenko, A.; Meyerowitz, E.M.; Wold, B.J.; Mjolsness, E.D. Bioinformatics 2003, 19, 677. https://doi.org/10.1093/bioinformatics/btg042 
  99. Orth, J.D.; Thiele, I.; Palsson, B.ONature biotechnology 2010, 28, 245. https://doi.org/10.1038/nbt.1614 
  100. Varma, A.; Palsson, B.O Appl Environ Microbiol 1994, 60, 3724. https://doi.org/10.1128/aem.60.10.3724-3731.1994 
  101. Schilling, C.H.; Edwards, J.S.; Letscher, D.; Palsson, B.O. Biotechnol Bioeng 2000, 71, 286. https://doi.org/10.1002/1097-0290(2000)71:43.3.CO;2-I 
  102. Varma, A.; Palsson, B.O Bio/technology 1994, 12, 994. https://doi.org/10.1038/nbt1094-994 
  103. Lee, I.D.; Palsson, B.O. Comput Methods Programs Biomed 1992, 38, 195. https://doi.org/10.1016/0169-2607(92)90102-d 
  104. Brunk, E.; Sahoo, S.; Zielinski, D.C.; Altunkaya, A.; Drager, A.; Mih, N.; Gatto, F.; Nilsson, A.; Preciat Gonzalez, G.A.; Aurich, M.K.; Prlic, A.; Sastry, A.; Danielsdottir, A.D.; Heinken, A.; Noronha, A.; Rose, P.W.; Burley, S.K.; Fleming, R.M.T.; Nielsen, J.; Thiele, I.; Palsson, B.O Nat Biotechnol 2018, 36, 272. https://doi.org/10.1038/nbt.4072 
  105. Bauer, E.; Thiele, I NPJ Syst Biol Appl 2018, 4, 27. https://doi.org/10.1038/s41540-018-0063-2 
  106. Erickson, A.R.; Cantarel, B.L.; Lamendella, R.; Darzi, Y.; Mongodin, E.F.; Pan, C.; Shah, M.; Halfvarson, J.; Tysk, C.; Henrissat, B.; Raes, J.; Verberkmoes, N.C.; Fraser, C.M.; Hettich, R.L.; Jansson, J.K. PLoS One 2012, 7, e49138. https://doi.org/10.1371/journal.pone.0049138 
  107. Noecker, C.; Eng, A.; Srinivasan, S.; Theriot, C.M.; Young, V.B.; Jansson, J.K.; Fredricks, D.N.; Borenstein, E MSystems 2016, 1. https://doi.org/10.1128/msystems.00013-15 
  108. Fondi, M.; Lio, P. Microbiol Res 2015, 171, 52. https://doi.org/10.1016/j.micres.2015.01.003 
  109. Kikuchi, J.; Ito, K.; Date, Y Prog Nucl Magn Reson Spectrosc 2018, 104, 56. https://doi.org/10.1016/j.pnmrs.2017.11.003 
  110. Yachie-Kinoshita, A.; Nishino, T.; Shimo, H.; Suematsu, M.; Tomita, M J Biomed Biotechnol 2010, 2010, 642420. https://doi.org/10.1155/2010/642420 
  111. Bansal, N.; Gupta, A.; Sankhwar, S.N. Cancer Biomark 2015, 15, 339. https://doi.org/10.3233/CBM-150479 
  112. Huang, H.; van Dullemen, L.F.; Akhtar, M.Z.; Faro, M.-L.L.; Yu, Z.; Valli, A.; Dona, A.; Thezenas, M.-L.; Charles, P.D.; Fischer, R. Scientific Reports 2018, 8, 8539. https://doi.org/10.1038/s41598-018-26804-8 
  113. Gonzalez-Borja, I.; Viudez, A.; Goni, S.; Santamaria, E.; Carrasco-Garcia, E.; Perez-Sanz, J.; Hernandez-Garcia, I.; Sala-Elarre, P.; Arrazubi, V.; Oyaga-Iriarte, E.; Zarate, R.; Arevalo, S.; Sayar, O.; Vera, R.; Fernandez-Irigoyen, J. Cancers (Basel) 2019, 11, 1052. https://doi.org/10.3390/cancers11081052 
  114. Unger, K.; Mehta, K.Y.; Kaur, P.; Wang, Y.; Menon, S.S.; Jain, S.K.; Moonjelly, R.A.; Suman, S.; Datta, K.; Singh, R.; Fogel, P.; Cheema, A.K. Oncotarget 2018, 9, 23078. https://doi.org/10.18632/oncotarget.25212 
  115. Yan, S.; Bhawal, R.; Yin, Z.; Thannhauser, T.W.; Zhang, S. Molecular Horticulture 2022, 2, 17. https://doi.org/10.1186/s43897-022-00038-9 
  116. Blanchet, L.; Smolinska, A. 2016. Data Fusion in Metabolomics and Proteomics for Biomarker Discovery. In Statistical Analysis in Proteomics. K. Jung, editor. New York, NY: Springer New York. 209.https://doi.org/10.1007/978-1-4939-3106-4_14