Startseite Medizin Attempt at a systemic outlook on aging and carcinogenesis
Artikel
Lizenziert
Nicht lizenziert Erfordert eine Authentifizierung

Attempt at a systemic outlook on aging and carcinogenesis

  • Monika Piwowar , Jacek Dygut , Piotr Piwowar , Leszek Konieczny und Irena Roterman EMAIL logo
Veröffentlicht/Copyright: 2. September 2014
Veröffentlichen auch Sie bei De Gruyter Brill

Abstract

Two of the key problems plaguing humanity – aging and carcinogenesis – are inexorably linked. While their nature seems different, their mechanisms have a lot in common. Evidence suggests that aging is the result of spontaneous synthesis and accumulation of improperly folded proteins in cells, leading to a variety of pathologies. As for carcinogenesis, it is tied to genetic mutations – permanent, covalent changes in the DNA. Both processes are random in character; however, unlike mutations, the accumulation of malformed proteins is not genetically determined. Instead, control over this process hinges upon regulating the protein exchange rate – a phenomenon that seems a likely candidate for the basic aging control mechanism. Although mutations themselves may be counteracted in a controlled manner, their effects typically cannot. The mechanisms of aging and carcinogenesis, while functionally different, remain correlated: an aging cell is rendered more susceptible to mutational changes. The rapidly growing body of information regarding aging and carcinogenesis enables a systemic approach to both these phenomena – an approach that is attempted in this review.


Corresponding author: Irena Roterman, Department of Bioinformatics and Telemedicine, Jagiellonian University – Medical College, Łazarza 16, 31-530 Krakow, Poland, E-mail:

References

1. Chen F, Lam CH, Tsui OK. The surface mobility of glasses. Science 2014;343:975–6.10.1126/science.1248113Suche in Google Scholar PubMed

2. Walter P, Ron D. The unfolded protein response: from stress pathway to homeostatic regulation. Science 2011;334:1081–6.10.1126/science.1209038Suche in Google Scholar PubMed

3. Ross JM, Stewart JB, Hagström E, Brené S, Mourier A, Coppotelli G, et al. Germline mitochondrial DNA mutations aggravate ageing and can impair brain development. Nature 2013;01:412–5.10.1038/nature12474Suche in Google Scholar PubMed PubMed Central

4. Gabuzda D, Yankner BA. Inflamation links ageing to the brain. Nature 2013;497:197–8.10.1038/nature12100Suche in Google Scholar PubMed PubMed Central

5. Nemoto S, Finkel T. Ageing and the mystery at Arles. Nature 2004;429:149–52.10.1038/429149aSuche in Google Scholar PubMed

6. Burhans WC, Weinberger M. DNA replication stress, genome instability and aging. Nucleic Acids Res 2007;35:7545–56.10.1093/nar/gkm1059Suche in Google Scholar PubMed PubMed Central

7. Marchewka A, Dąbrowski Z, Żołądź J. Fizjologia starzenia się. Wydawnictwo Naukowe PWN, Warszawa, 2013 (in Polish).Suche in Google Scholar

8. Shen EZ, Song CQ, Lin Y, Zhang WH, Su PF, Liu WY, et al. Mitoflash frequency in early adulthood predicts lifespan in Caenorhabditis elegans. Nature 2014;508:128–32.10.1038/nature13012Suche in Google Scholar PubMed

9. King NP, Bale JB, Sheffler W, McNamara DE, Gonen S, Gonen T, et al. Accurate design of co-assembling multi-component protein nanomaterials. Nature 2014;510:103–8.10.1038/nature13404Suche in Google Scholar PubMed PubMed Central

10. Dyson HJ, Wright PE. Equilibrium NMR studies of unfolded and partially folded proteins. Nat Struct Biol 1998;5(Suppl):499–503.10.1038/739Suche in Google Scholar PubMed

11. Neudecker P, Robustelli P, Cavalli A, Walsh P, Lundström P, Zarrine-Afsar A, et al. Structure of an intermediate state in protein folding and aggregation. Science 2012;336:362–6.10.1126/science.1214203Suche in Google Scholar PubMed

12. Eliezer D. Visualizing amyloid assembly. Science 2012;336:308–9.10.1126/science.1220356Suche in Google Scholar PubMed

13. Sunde M, Blake CC. From globular to the fibrous state: protein structure and structural conversion in amyloid formation. Q Rev Biophys 1998;31:1–39.10.1017/S0033583598003400Suche in Google Scholar

14. Stopa B, Jagusiak A, Konieczny L, Piekarska B, Rybarska J, Zemanek G, et al. The use of supramolecular structures as protein ligands. J Mol Model 2013;19:4731–40.10.1007/s00894-012-1744-1Suche in Google Scholar PubMed PubMed Central

15. Konieczny L, Roterman I, Spólik P. Systems biology – strategy of living organisms. New York, Heidelberg, Dordrecht, London: Springer 2014.10.1007/978-3-319-01336-7Suche in Google Scholar

16. Khan Z, Ford MJ, Cusanovich DA, Mitrano A, Pritchard JK, Gilad Y. Primate transcript and protein expression levels evolve under compensatory selection pressures. Science 2013;342:1100–4.10.1126/science.1242379Suche in Google Scholar PubMed PubMed Central

17. Wu L, Candille SI, Choi Y, Xie D, Jiang L, Li-Pook-Than J, et al. Variation and genetic control of protein abundance in humans. Nature 2013;499:79–82.10.1038/nature12223Suche in Google Scholar PubMed PubMed Central

18. Gardner BM, Walter P. Unfolded proteins are Ire1-activating ligands that directly induce the unfolded protein response. Science 2011;333:1891–4.10.1126/science.1209126Suche in Google Scholar PubMed PubMed Central

19. Hollien J, Weissman JS. Decay of endoplasmic reticulum-localized mRNAs during the unfolded protein response. Science 2006;313:104–7.10.1126/science.1129631Suche in Google Scholar PubMed

20. Bass J, Takahashi JS. Circadian integration of metabolism and energetics. Science 2010;330:1349–54.10.1126/science.1195027Suche in Google Scholar PubMed PubMed Central

21. Spólnik P, Konieczny L, Roterman I, Markiewicz M. Biological clock – is the need for a clock a common issue for cells and computers? Bio-Algorithms Med-Syst 2012;8:255–65.10.2478/bams-2012-0014Suche in Google Scholar

22. Jiang H, Ju Z, Rudolph KL. Telomere shortening and aging. Z Gerontol Geriatr 2007;40:314–24.10.1007/s00391-007-0480-0Suche in Google Scholar PubMed

23. Yang H, Rudge DG, Koos JD, Vaidialingam B, Yang HJ, Pavletich NP. mTOR kinase structure, mechanism and regulation. Nature 2013;97:217–23.10.1038/nature12122Suche in Google Scholar PubMed PubMed Central

24. Johnson SC, Yanos ME, Kayser EB, Quintana A, Sangesland M, Castanza A, et al. mTOR inhibition alleviates mitochondrial disease in a mouse model of Leigh syndrome. Science 2013;342:1524–8.10.1126/science.1244360Suche in Google Scholar PubMed PubMed Central

25. Johnson SC, Rabinovitch PS, Kaeberlein M. mTOR is a key modulator of ageing and age-related disease. Nature 2013;493:338–45.10.1038/nature11861Suche in Google Scholar PubMed PubMed Central

26. Lee IH, Kawai Y, Fergusson MM, Rovira II, Bishop AJ, Motoyama N, et al. Atg7 modulates p53 activity to regulate cell cycle and survival during metabolic stress. Science 2012;336:225–8.10.1126/science.1218395Suche in Google Scholar PubMed PubMed Central

27. Chin RM, Fu X, Pai MY, Vergnes L, Hwang H, Deng G, et al. The metabolite α-ketoglutarate extends lifespan by inhibiting ATP synthase and TOR. Nature 2014;509:397–401.10.1038/nature13264Suche in Google Scholar PubMed PubMed Central

28. O’Neill LA, Hardie DG. Metabolism of inflammation limited by AMPK and pseudo-starvation. Nature 2013;493:346–55.10.1038/nature11862Suche in Google Scholar PubMed

29. Michaelis S, Hrycyna CA. A protease for the ages. Science 2013;339:1529–30.10.1126/science.1236764Suche in Google Scholar PubMed

30. Conneely KN, Capell BC, Erdos MR, Sebastiani P, Solovieff N, Swift AJ, et al. Human longevity and common variations in the LMNA gene: a meta-analysis. Aging Cell 2012;11:475–81.10.1111/j.1474-9726.2012.00808.xSuche in Google Scholar PubMed PubMed Central

31. Paul S, Million-Weaver S, Chattopadhyay S, Sokurenko E, Merrikh H. Accelerated gene evolution through replication-transcription conflicts. Nature 2013;495:512–5.10.1038/nature11989Suche in Google Scholar PubMed PubMed Central

32. Wolff S, Dillin A. Ageing: beneficial miscommunication. Nature 2013;497:442–3.10.1038/497442aSuche in Google Scholar PubMed

33. Reiser KM. Nonenzymatic glycation of collagen in aging and diabetes. Proc Soc Exp Biol Med 1998;218:23–37.10.3181/00379727-218-44264Suche in Google Scholar

34. Kasper M, Funk RH. Age-related changes in cells and tissues due to advanced glycation end products (AGEs). Arch Gerontol Geriatr 2001;32:2.10.1016/S0167-4943(01)00103-0Suche in Google Scholar

35. Vazquez A, Liu J, Zhou Y, Oltvai ZN. Catabolic efficiency of aerobic glycolysis: the Warburg effect revisited. BMC Syst Biol 2010;4:58.10.1186/1752-0509-4-58Suche in Google Scholar PubMed PubMed Central

36. Cairns RA, Harris IS, Mak TW. Regulation of cancer cell metabolism. Nat Rev Cancer 2011;11:85–95.10.1038/nrc2981Suche in Google Scholar PubMed

37. de Lange T. Activation of telomerase in a human tumor. Proc Natl Acad Sci USA 1994;91:2882–5.10.1073/pnas.91.8.2882Suche in Google Scholar PubMed PubMed Central

38. Shay JW, Reddel RR, Wright WE. Cancer and telomeres – an ALTernative to telomerase. Science 2012;336:1388–90.10.1126/science.1222394Suche in Google Scholar PubMed

39. Tomita M, Kami K. Systems biology, metabolomics, and cancer metabolism. Science 2012;336:990–1.10.1126/science.1223066Suche in Google Scholar PubMed

40. Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 2009;324:1029–33.10.1126/science.1160809Suche in Google Scholar PubMed PubMed Central

41. Vander Heiden MG, Locasale JW, Swanson KD, Sharfi H, Heffron GJ, Amador-Noguez D, et al. Evidence for an alternative glycolytic pathway in rapidly proliferating cells. Science 2010;329:1492–9.10.1126/science.1188015Suche in Google Scholar PubMed PubMed Central

42. Elsässer SJ, Allis CD, Lewis PW. New epigenetic drivers of cancers. Science 2011;331(6021), 1145–6.10.1126/science.1203280Suche in Google Scholar PubMed

43. Ramiro AR, Jankovic M, Callen E, Difilippantonio S, Chen HT, McBride KM, et al. Role of genomic instability and p53 in AID-induced c-myc-Igh translocations. Nature 2006;440:105–9.10.1038/nature04495Suche in Google Scholar PubMed PubMed Central

44. Lukas J, Lukas C. Molecular biology. Shielding broken DNA for a quick fix. Science 2013;339:652–3.10.1126/science.1234602Suche in Google Scholar PubMed

45. Krivtsov AV, Armstrong SA. Can one cell influence cancer heterogeneity? Science 2012;338:1035–6.10.1126/science.1231594Suche in Google Scholar PubMed

46. Fischer WW. Life before the rise of oxygen. Nature 2008;455:1051–2.10.1038/4551051aSuche in Google Scholar PubMed

47. Srivastava M, Simakov O, Chapman J, Fahey B, Gauthier ME, Mitros T, et al. The Amphimedon queenslandica genome and the evolution of animal complexity. Nature 2010;466:720–6.10.1038/nature09201Suche in Google Scholar PubMed PubMed Central

48. Smith MP, Harper DA. Causes of the Cambrian explosion. Science 2013;341:1355–6.10.1126/science.1239450Suche in Google Scholar PubMed

49. Lyons TW, Reinhard CT, Planavsky NJ. The rise of oxygen in Earth’s early ocean and atmosphere. Nature 2014;506:307–15.10.1038/nature13068Suche in Google Scholar PubMed

50. Eisenhoffer GT, Loftus PD, Yoshigi M, Otsuna H, Chien C-B, Morcos PA, et al. Crowding induces live cell extrusion to maintain homeostatic cell numbers in epithelia. Nature 2012;484:546–9.10.1038/nature10999Suche in Google Scholar PubMed PubMed Central

51. Vogel G. How do organs know when they have reached the right size? Science 2013;340:1156–7.10.1126/science.340.6137.1156-bSuche in Google Scholar PubMed

52. Marinari E, Mehonic A, Curran S, Gale J, Duke T, Baum B. Live-cell delamination counterbalances epithelial growth to limit tissue overcrowding. Nature 2012;484:542–5.10.1038/nature10984Suche in Google Scholar PubMed

53. Dixon JR, Selvaraj S, Yue F, Kim A, Li Y, Shen Y, et al. Topological domains in mammalian genomes identified by analysis of chromatin interactions. Nature 2012;485:376–80.10.1038/nature11082Suche in Google Scholar

54. Thellin O, Zorzi W, Lakaye B, De Borman B, Coumans B, Hennen G, et al. Housekeeping genes as internal standards: use and limits. J Biotechnol 1999;75:291–5.10.1016/S0168-1656(99)00163-7Suche in Google Scholar

55. Belle MD, Piggins HD. Circadian time redoxed. Science 2012;337:805–6.10.1126/science.1227203Suche in Google Scholar PubMed

56. Kandoth C, McLellan MD, Vandin F, Ye K, Niu B, Lu C, et al. Mutational landscape and significance across 12 major cancer types. Nature 2013;502:333–9.10.1038/nature12634Suche in Google Scholar PubMed PubMed Central

57. Lawrence MS, Stojanov P, Mermel CH, Robinson JT, Garraway LA, Golub TR, et al. Discovery and saturation analysis of cancer genes across 21 tumour types. Nature 2014;505:495–501.10.1038/nature12912Suche in Google Scholar PubMed PubMed Central

58. Muzny DM, Bainbridge MN, Chang K, Dinh HH, Drummond JA, Fowler G, et al. Comprehensive molecular characterization of human colon and rectal cancer. Nature 2012;487:330–7.10.1038/nature11252Suche in Google Scholar PubMed PubMed Central

59. Tamborero D, Gonzalez-Perez A, Perez-Llamas C, Deu-Pons J, Kandoth C, Reimand J, et al. Comprehensive identification of mutational cancer driver genes across 12 tumor types. Sci Rep 2013;3:2650.10.1038/srep02650Suche in Google Scholar PubMed PubMed Central

60. Weinstein JN, Akbani R, Broom BM, Wang W, Verhaak RG, McConkey D, et al. Comprehensive molecular characterization of urothelial bladder carcinoma. Nature 2014;507:315–22.10.1038/nature12965Suche in Google Scholar PubMed PubMed Central

61. Rahman N. Realizing the promise of cancer predisposition genes. Nature 2014;505:302–8. Erratum in: Nature 2014;510:176.10.1038/nature12981Suche in Google Scholar PubMed PubMed Central

62. Hudson T. A clinical perspective. Nature 2013;502:306–7.Suche in Google Scholar

63. Ojesina AI, Lichtenstein L, Freeman SS, Pedamallu CS, Imaz-Rosshandler I, Pugh TJ, et al. Landscape of genomic alterations in cervical carcinomas. Nature 2014;506:371–5.10.1038/nature12881Suche in Google Scholar PubMed PubMed Central

64. Aerts S, Cools J. Mutations close in on gene regulation. Nature 2013;499:35–6.10.1038/499035aSuche in Google Scholar PubMed

65. Dancer JY, Henry SP, Bondaruk J, Lee S, Ayala AG, de Crombrugghe B, et al. Expression of master regulatory genes controlling skeletal development in benign cartilage and bone forming tumors. Hum Pathol 2010;41:1788–93.10.1016/j.humpath.2010.06.008Suche in Google Scholar PubMed PubMed Central

66. Yamada KM, Araki M. Tumor suppressor PTEN: modulator of cell signaling, growth, migration and apoptosis. J Cell Sci 2001;114(Pt 13):2375–82.10.1242/jcs.114.13.2375Suche in Google Scholar PubMed

67. Burke JE, Perisic O, Masson GR, Vadas O, Williams RL. Oncogenic mutations mimic and enhance dynamic events in the natural activation of phosphoinositide 3-kinase p110α (PIK3CA). Proc Natl Acad Sci USA 2012;109:15259–64.10.1073/pnas.1205508109Suche in Google Scholar PubMed PubMed Central

68. Harbour JW, Onken MD, Roberson ED, Duan S, Cao L, Worley LA, et al. Frequent mutation of BAP1 in metastasizing uveal melanomas. Science 2010;330:1410–3.10.1126/science.1194472Suche in Google Scholar PubMed PubMed Central

69. Ogawara Y, Kishishita S, Obata T, Isazawa Y, Suzuki T, Tanaka K, et al. Akt enhances Mdm2-mediated ubiquitination and degradation of p53. J Biol Chem 2002;277:21843–50.10.1074/jbc.M109745200Suche in Google Scholar PubMed

70. Losman JA, Looper RE, Koivunen P, Lee S, Schneider RK, McMahon C, et al. (R)-2-Hydroxyglutarate is sufficient to promote leukemogenesis and its effects are reversible. Science 2013;339:1621–5.10.1126/science.1231677Suche in Google Scholar PubMed PubMed Central

71. Krall AS, Christofk HR. A metabolic metamorphosis. Nature 2013;496:38–40.10.1038/496038aSuche in Google Scholar PubMed

72. Chen Z, Odstrcil EA, Tu BP, McKnight SL. Restriction of DNA replication to the reductive phase of the metabolic cycle protects genome integrity. Science 2007;316:1916–9.10.1126/science.1140958Suche in Google Scholar PubMed

73. Son J, Lyssiotis CA, Ying H, Wang X, Hua S, Ligorio M, et al. Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway. Nature 2013;496:101–5.10.1038/nature12040Suche in Google Scholar PubMed PubMed Central

74. Levine AJ, Puzio-Kuter AM. The control of the metabolic switch in cancers by oncogenes and tumor suppressor genes. Science 2010;330:1340–4.10.1126/science.1193494Suche in Google Scholar PubMed

75. Gut P, Verdin E. The nexus of chromatin regulation and intermediary metabolism. Nature 2013;502:489–98.10.1038/nature12752Suche in Google Scholar PubMed

76. Maddocks OD, Berkers CR, Mason SM, Zheng L, Blyth K, Gottlieb E, et al. Serine starvation induces stress and p53-dependent metabolic remodelling in cancer cells. Nature 2013;493:542–6.10.1038/nature11743Suche in Google Scholar PubMed PubMed Central

77. Zoncu R, Bar-Peled L, Efeyan A, Wang S, Sancak Y, Sabatini DM. mTORC1 senses lysosomal amino acids through an inside-out mechanism that requires the vacuolar H(+)-ATPase. Science 2011;334:678–83.10.1126/science.1207056Suche in Google Scholar PubMed PubMed Central

78. Purvis JE, Karhohs KW, Mock C, Batchelor E, Loewer A, Lahav G. p53 dynamics control cell fate. Science 2012;336:1440–4.10.1126/science.1218351Suche in Google Scholar PubMed PubMed Central

79. Hsieh AC, Liu Y, Edlind MP, Ingolia NT, Janes MR, Sher A, et al. The translational landscape of mTOR signalling steers cancer initiation and metastasis. Nature 2012;485:55–61.10.1038/nature10912Suche in Google Scholar PubMed PubMed Central

80. Keller KE, Tan IS, Lee YS. SAICAR stimulates pyruvate kinase isoform M2 and promotes cancer cell survival in glucose-limited conditions. Science 2012;338:1069–72.10.1126/science.1224409Suche in Google Scholar PubMed PubMed Central

81. Mattaini KR, Vander Heiden MG. Glycosylation to adapt to stress. Science 2012;337:925–6.10.1126/science.1227513Suche in Google Scholar PubMed

82. Bass J. Circadian topology of metabolism. Nature 2012;491:348–56.10.1038/nature11704Suche in Google Scholar PubMed

83. Starobinets H, Debnath J. A suppression switch. Nature 2013;504:225–6.10.1038/nature12841Suche in Google Scholar PubMed

84. Dominissini D, He C. Damage prevention targeted Nature 2014;508:191–2.10.1038/nature13221Suche in Google Scholar PubMed

85. Suvà ML, Riggi N, Bernstein BE. Epigenetic reprogramming in cancer. Science 2013;339:1567–70.10.1126/science.1230184Suche in Google Scholar PubMed PubMed Central

86. Filippakopoulos P, Qi J, Picaud S, Shen Y, Smith WB, Fedorov O, et al. Selective inhibition of BET bromodomains. Nature 2010;468:1067–73.10.1038/nature09504Suche in Google Scholar PubMed PubMed Central

87. Versteeg R. Tumours outside the mutation box. Nature 2014;506:438–9.10.1038/nature13061Suche in Google Scholar PubMed

88. Kolodner RD, Cleveland DW, Putnam CD. Aneuploidy drives a mutator phenotype in cancer. Science 2011;333:942–3.10.1126/science.1211154Suche in Google Scholar PubMed PubMed Central

89. Martincorena I, Seshasayee AS, Luscombe NM. Evidence of non-random mutation rates suggests an evolutionary risk management strategy. Nature 2012;485:95–8.10.1038/nature10995Suche in Google Scholar PubMed

90. Albert FW, Treusch S, Shockley AH, Bloom JS, Kruglyak L. Genetics of single-cell protein abundance variation in large yeast populations. Nature 2014;506:494–7.10.1038/nature12904Suche in Google Scholar PubMed PubMed Central

91. Smagulova F, Gregoretti IV, Brick K, Khil P, Camerini-Otero RD, Petukhova GV. Genome-wide analysis reveals novel molecular features of mouse recombination hotspots. Nature 2011;472:375–8.10.1038/nature09869Suche in Google Scholar PubMed PubMed Central

92. Ruark E, Snape K, Humburg P, Loveday C, Bajrami I, Brough R, et al. Mosaic PPM1D mutations are associated with predisposition to breast and ovarian cancer. Nature 2013;493:406–10.10.1038/nature11725Suche in Google Scholar PubMed PubMed Central

93. Silvente-Poirot S, Poirot M. Cholesterol and cancer, in the balance. Science 2014;343:1445–6.10.1126/science.1252787Suche in Google Scholar PubMed

94. Nelson ER, Wardell SE, Jasper JS, Park S, Suchindran S, Howe MK, et al. 27-Hydroxycholesterol links hypercholesterolemia and breast cancer pathophysiology. Science 2013;342:1094–8.10.1126/science.1241908Suche in Google Scholar PubMed PubMed Central

95. Ryan KK, Seeley RJ. Food as a hormone. Science 2013;339:918–9.10.1126/science.1234062Suche in Google Scholar PubMed PubMed Central

96. Goossens T, Klein U, Küppers R. Frequent occurrence of deletions and duplications during somatic hypermutation: implications for oncogene translocations and heavy chain disease. Proc Natl Acad Sci USA 1998;95:2463–8.10.1073/pnas.95.5.2463Suche in Google Scholar PubMed PubMed Central

97. Deweerdt S. Naked ambition. Nature 2014;509:S60–1.10.1038/509S60aSuche in Google Scholar PubMed

98. Jones S, Wang TL, Shih Ie, Mao TL, Nakayama K, Roden R, et al. Frequent mutations of chromatin remodeling gene ARID1A in ovarian clear cell carcinoma. Science 2010;330:228–31.10.1126/science.1196333Suche in Google Scholar PubMed PubMed Central

99. Stieglitz B, Rana RR, Koliopoulos MG, Morris-Davies AC, Schaeffer V, Christodoulou E, et al. Structural basis for ligase-specific conjugation of linear ubiquitin chains by HOIP. Nature 2013;503:422–6.10.1038/nature12638Suche in Google Scholar PubMed PubMed Central

100. Rivkin E, Almeida SM, Ceccarelli DF, Juang YC, MacLean TA, Srikumar T, et al. The linear ubiquitin-specific deubiquitinase gumby regulates angiogenesis. Nature 2013;498:318–24.10.1038/nature12296Suche in Google Scholar PubMed PubMed Central

101. Matouschek A, Finley D. An ancient portal to proteolysis. Science 2012;337:813–4.10.1126/science.1227301Suche in Google Scholar PubMed PubMed Central


Supplemental Material

The online version of this article (DOI: 10.1515/bams-2014-0012) offers supplementary material, available to authorized users.


Received: 2014-7-15
Accepted: 2014-8-6
Published Online: 2014-9-2
Published in Print: 2014-9-30

©2014 by De Gruyter

Heruntergeladen am 26.12.2025 von https://www.degruyterbrill.com/document/doi/10.1515/bams-2014-0012/pdf
Button zum nach oben scrollen