Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Chromosomal rearrangements after ex vivo Epstein–Barr virus (EBV) infection of human B cells

Oncogene volume 29, pages 503–515 (2010)Cite this article

Abstract

The Epstein–Barr virus (EBV) is carried by more than 90% of the adult world population and has been implicated in several human malignancies. Its ability to induce unlimited in vitro proliferation of B cells is frequently used to generate lymphoblastoid cell lines (LCLs). In this study, we have investigated the evolution of two LCLs up to 25 weeks after EBV infection. LCLs were karyotyped once a month by spectral karyotyping (SKY). LCLs but not mitogen-activated B cells showed evidence of DNA damage and DNA damage response within the first 2 weeks. After 4 weeks, the former, but not the latter, showed a high level of non-clonal structural aberrations, mainly deletions, fragments, dicentric chromosomes and unbalanced translocations. Genomic instability decreased thereafter over time. Nonrandom aneuploidy 12 weeks after infection showed clonal evolution in culture. After 25 weeks post-infection, most cells exhibited karyotypic stability. Chromosomal aberrations were compatible with telomere dysfunction, although in the absence of telomere shortening. The telomere capping protein TRF2 was partially displaced from telomeres in EBV-infected cells, suggesting an EBV-mediated uncapping problem. In conclusion, this study suggests that DNA damage and telomere dysfunction contribute to EBV-related chromosomal instability in early LCLs.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  • Aubert G, Lansdorp PM . (2008). Telomeres and aging. Physiol Rev 88: 557–579.

    Article  CAS  PubMed  Google Scholar 

  • Belfiore MC, Natoni A, Barzellotti R, Merendino N, Pessina G, Ghibelli L et al. (2007). Involvement of 5-lipoxygenase in survival of Epstein–Barr virus (EBV)-converted B lymphoma cells. Cancer Lett 254: 236–243.

    Article  CAS  PubMed  Google Scholar 

  • Caporali A, Wark L, Vermolen BJ, Garini Y, Mai S . (2007). Telomeric aggregates and end-to-end chromosomal fusions require myc box II. Oncogene 26: 1398–1406.

    Article  CAS  PubMed  Google Scholar 

  • Cerimele F, Battle T, Lynch R, Frank DA, Murad E, Cohen C et al. (2005). Reactive oxygen signaling and MAPK activation distinguish Epstein–Barr Virus (EBV)-positive versus EBV-negative Burkitt's lymphoma. Proc Natl Acad Sci USA 102: 175–179.

    Article  CAS  PubMed  Google Scholar 

  • Chuang TC, Moshir S, Garini Y, Chuang AY, Young IT, Vermolen B et al. (2004). The three-dimensional organization of telomeres in the nucleus of mammalian cells. BMC Biol 2: 12.

    Article  PubMed  PubMed Central  Google Scholar 

  • Ciobanu N, Wiernik PH . (1986). Malignant lymphomas, AIDS, and the pathogenic role of Epstein–Barr virus. Mt Sinai J Med 53: 627–638.

    CAS  PubMed  Google Scholar 

  • Counter CM, Botelho FM, Wang P, Harley CB, Bacchetti S . (1994). Stabilization of short telomeres and telomerase activity accompany immortalization of Epstein–Barr virus-transformed human B lymphocytes. J Virol 68: 3410–3414.

    CAS  PubMed  PubMed Central  Google Scholar 

  • de Lange T . (2005). Shelterin: the protein complex that shapes and safeguards human telomeres. Genes Dev 19: 2100–2110.

    Article  CAS  PubMed  Google Scholar 

  • De Vos WH, Hoebe RA, Joss GH, Haffmans W, Baatout S, Van Oostveldt P et al. (2009). Controlled light exposure microscopy reveals dynamic telomere microterritories throughout the cell cycle. Cytometry A 75: 428–439.

    Article  PubMed  Google Scholar 

  • Diehl V, Krause P, Hellriegel KP, Busche M, Schedel I, Laskewitz E . (1977). Lymphoid cell lines: in vitro cell markers in correlation to tumorigenicity in nude mice. Haematol Blood Transfus 20: 289–296.

    CAS  PubMed  Google Scholar 

  • Dolcetti R, Masucci MG . (2003). Epstein–Barr virus: induction and control of cell transformation. J Cell Physiol 196: 207–218.

    Article  CAS  PubMed  Google Scholar 

  • Gargouri B, Van Pelt J, El Feki Ael F, Attia H, Lassoued S . (2009). Induction of Epstein–Barr virus (EBV) lytic cycle in vitro causes oxidative stress in lymphoblastoid B cell lines. Mol Cell Biochem 324: 55–63.

    Article  CAS  PubMed  Google Scholar 

  • Garrone P, Neidhardt EM, Garcia E, Galibert L, van Kooten C, Banchereau J . (1995). Fas ligation induces apoptosis of CD40-activated human B lymphocytes. J Exp Med 182: 1265–1273.

    Article  CAS  PubMed  Google Scholar 

  • Gordon J, Walker L, Guy G, Brown G, Rowe M, Rickinson A . (1986). Control of human B-lymphocyte replication. II. Transforming Epstein–Barr virus exploits three distinct viral signals to undermine three separate control points in B-cell growth. Immunology 58: 591–595.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Gruhne B, Sompallae R, Marescotti D, Kamranvar SA, Gastaldello S, Masucci MG . (2009). The Epstein–Barr virus nuclear antigen-1 promotes genomic instability via induction of reactive oxygen species. Proc Natl Acad Sci USA 106: 2313–2318.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gunven P, Klein G, Henle G, Henle W, Clifford P . (1970). Epstein–Barr virus in Burkitt's lymphoma and nasopharyngeal carcinoma. Antibodies to EBV associated membrane and viral capsid antigens in Burkitt lymphoma patients. Nature 228: 1053–1056.

    Article  CAS  PubMed  Google Scholar 

  • Henle G, Henle W, Diehl V . (1968). Relation of Burkitt's tumor-associated herpes-type virus to infectious mononucleosis. Proc Natl Acad Sci USA 59: 94–101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Henle W, Henle G . (1973a). Epstein–Barr virus-related serology in Hodgkin's disease. Natl Cancer Inst Monogr 36: 79–84.

    CAS  PubMed  Google Scholar 

  • Henle W, Henle G . (1973b). Evidence for an oncogenic potential of the Epstein–Barr virus. Cancer Res 33: 1419–1423.

    CAS  PubMed  Google Scholar 

  • Henle W, Henle G . (1979). Seroepidemiology of the virus. In: Epstein MA, Achong BG (eds). The Epstein–Barr Virus. Springer-Verlag: Berlin, Germany. pp 61–78.

    Chapter  Google Scholar 

  • Henle W, Hummeler K, Henle G . (1966). Antibody coating and agglutination of virus particles separated from the EB3 line of Burkitt lymphoma cells. J Bacteriol 92: 269–271.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hopwood PA, Brooks L, Parratt R, Hunt BJ, Bokhari M, Thomas JA et al. (2002). Persistent Epstein–Barr virus infection: unrestricted latent and lytic viral gene expression in healthy immunosuppressed transplant recipients. Transplantation 74: 194–202.

    Article  CAS  PubMed  Google Scholar 

  • Hu BT, Insel RA . (1999). Up-regulation of telomerase in human B lymphocytes occurs independently of cellular proliferation and with expression of the telomerase catalytic subunit. Eur J Immunol 29: 3745–3753.

    Article  CAS  PubMed  Google Scholar 

  • Igarashi H, Sakaguchi N . (1997). Telomerase activity is induced in human peripheral B lymphocytes by the stimulation to antigen receptor. Blood 89: 1299–1307.

    CAS  PubMed  Google Scholar 

  • Jeon JP, Shim SM, Nam HY, Baik SY, Kim JW, Han BG . (2007). Copy number increase of 1p36.33 and mitochondrial genome amplification in Epstein–Barr virus-transformed lymphoblastoid cell lines. Cancer Genet Cytogenet 173: 122–130.

    Article  CAS  PubMed  Google Scholar 

  • Joncas J, Boucher J, Granger-Julien M, Filion C . (1974). Epstein–Barr virus infection in the neonatal period and in childhood. Can Med Assoc J 110: 33–37.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Jung D, Neron S, Lemieux R, Roy A, Richard M . (2001). Telomere-independent reduction of human B lymphocyte: proliferation during long-term culture. Immunol Invest 30: 157–168.

    Article  CAS  PubMed  Google Scholar 

  • Kabore AF, Sun J, Hu X, McCrea K, Johnston JB, Gibson SB . (2006). The TRAIL apoptotic pathway mediates proteasome inhibitor induced apoptosis in primary chronic lymphocytic leukemia cells. Apoptosis 11: 1175–1193.

    Article  CAS  PubMed  Google Scholar 

  • Kamranvar SA, Gruhne B, Szeles A, Masucci MG . (2007). Epstein–Barr virus promotes genomic instability in Burkitt's lymphoma. Oncogene 26: 5115–5123.

    Article  CAS  PubMed  Google Scholar 

  • Kataoka H, Tahara H, Watanabe T, Sugawara M, Ide T, Goto M et al. (1997). Immortalization of immunologically committed Epstein–Barr virus-transformed human B-lymphoblastoid cell lines accompanied by a strong telomerase activity. Differentiation 62: 203–211.

    Article  CAS  PubMed  Google Scholar 

  • Kim SH, McQueen PG, Lichtman MK, Shevach EM, Parada LA, Misteli T . (2004). Spatial genome organization during T-cell differentiation. Cytogenet Genome Res 105: 292–301.

    Article  CAS  PubMed  Google Scholar 

  • Knecht H, Sawan B, Lichtensztejn D, Lemieux B, Wellinger RJ, Mai S . (2009). The 3D nuclear organization of telomeres marks the transition from Hodgkin to Reed–Sternberg cells. Leukemia 23: 565–573.

    Article  CAS  PubMed  Google Scholar 

  • Konishi A, de Lange T . (2008). Cell cycle control of telomere protection and NHEJ revealed by a ts mutation in the DNA-binding domain of TRF2. Genes Dev 22: 1221–1230.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lassoued S, Ben Ameur R, Ayadi W, Gargouri B, Ben Mansour R, Attia H . (2008). Epstein–Barr virus induces an oxidative stress during the early stages of infection in B lymphocytes, epithelial, and lymphoblastoid cell lines. Mol Cell Biochem 313: 179–186.

    Article  CAS  PubMed  Google Scholar 

  • Louis SF, Vermolen BJ, Garini Y, Young IT, Guffei A, Lichtensztejn Z et al. (2005). c-Myc induces chromosomal rearrangements through telomere and chromosome remodeling in the interphase nucleus. Proc Natl Acad Sci USA 102: 9613–9618.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mai S, Wiener F . (2002). Murine FISH. In: Beatty B, Mai S, Squire J (eds). FISH: A Practical Approach. Oxford University Press: Oxford. pp 55–67.

    Google Scholar 

  • Mochida A, Gotoh E, Senpuku H, Harada S, Kitamura R, Takahashi T et al. (2005). Telomere size and telomerase activity in Epstein–Barr virus (EBV)-positive and EBV-negative Burkitt's lymphoma cell lines. Arch Virol 150: 2139–2150.

    Article  CAS  PubMed  Google Scholar 

  • Nagele RG, Velasco AQ, Anderson WJ, McMahon DJ, Thomson Z, Fazekas J et al. (2001). Telomere associations in interphase nuclei: possible role in maintenance of interphase chromosome topology. J Cell Sci 114: 377–388.

    CAS  PubMed  Google Scholar 

  • Niederman JC, McCollum RW, Henle G, Henle W . (1968). Infectious mononucleosis. Clinical manifestations in relation to EB virus antibodies. JAMA 203: 205–209.

    Article  CAS  PubMed  Google Scholar 

  • Nilsson K . (1992). Human B-lymphoid cell lines. Hum Cell 5: 25–41.

    CAS  PubMed  Google Scholar 

  • Nilsson K, Giovanella BC, Stehlin JS, Klein G . (1977). Tumorigenicity of human hematopoietic cell lines in athymic nude mice. Int J Cancer 19: 337–344.

    Article  CAS  PubMed  Google Scholar 

  • Nilsson K, Ponten J . (1975). Classification and biological nature of established human hematopoietic cell lines. Int J Cancer 15: 321–341.

    Article  CAS  PubMed  Google Scholar 

  • O’Nions J, Allday MJ . (2004). Proliferation and differentiation in isogenic populations of peripheral B cells activated by Epstein–Barr virus or T cell-derived mitogens. J Gen Virol 85: 881–895.

    Article  PubMed  Google Scholar 

  • Oexle K, Zwirner A . (1997). Advanced telomere shortening in respiratory chain disorders. Hum Mol Genet 6: 905–908.

    Article  CAS  PubMed  Google Scholar 

  • Okano M, Taguchi Y, Nakamine H, Pirruccello SJ, Davis JR, Beisel KW et al. (1990). Characterization of Epstein–Barr virus-induced lymphoproliferation derived from human peripheral blood mononuclear cells transferred to severe combined immunodeficient mice. Am J Pathol 137: 517–522.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Okubo M, Tsurukubo Y, Higaki T, Kawabe T, Goto M, Murase T et al. (2001). Clonal chromosomal aberrations accompanied by strong telomerase activity in immortalization of human B-lymphoblastoid cell lines transformed by Epstein–Barr virus. Cancer Genet Cytogenet 129: 30–34.

    Article  CAS  PubMed  Google Scholar 

  • Pallesen G, Hamilton-Dutoit SJ, Rowe M, Young LS . (1991). Expression of Epstein–Barr virus latent gene products in tumour cells of Hodgkin's disease. Lancet 337: 320–322.

    Article  CAS  PubMed  Google Scholar 

  • Purtilo DT . (1980). Epstein–Barr-virus-induced oncogenesis in immune-deficient individuals. Lancet 1: 300–303.

    Article  CAS  PubMed  Google Scholar 

  • Rickinson AB, Young LS, Rowe M . (1987). Influence of the Epstein–Barr virus nuclear antigen EBNA 2 on the growth phenotype of virus-transformed B cells. J Virol 61: 1310–1317.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Rooney CM, Wimperis JZ, Brenner MK, Patterson J, Hoffbrand AV, Prentice HG . (1986). Natural killer cell activity following T-cell depleted allogeneic bone marrow transplantation. Br J Haematol 62: 413–420.

    Article  CAS  PubMed  Google Scholar 

  • Rosen A, Gergely P, Jondal M, Klein G, Britton S . (1977). Polyclonal Ig production after Epstein–Barr virus infection of human lymphocytes in vitro. Nature 267: 52–54.

    Article  CAS  PubMed  Google Scholar 

  • Rowe DT, Rowe M, Evan GI, Wallace LE, Farrell PJ, Rickinson AB . (1986). Restricted expression of EBV latent genes and T-lymphocyte-detected membrane antigen in Burkitt's lymphoma cells. EMBO J 5: 2599–2607.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rowe M, Lear AL, Croom-Carter D, Davies AH, Rickinson AB . (1992). Three pathways of Epstein–Barr virus gene activation from EBNA1-positive latency in B lymphocytes. J Virol 66: 122–131.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Rowe M, Rowe DT, Gregory CD, Young LS, Farrell PJ, Rupani H et al. (1987). Differences in B cell growth phenotype reflect novel patterns of Epstein–Barr virus latent gene expression in Burkitt's lymphoma cells. EMBO J 6: 2743–2751.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rowe M, Young LS, Cadwallader K, Petti L, Kieff E, Rickinson AB . (1989). Distinction between Epstein–Barr virus type A (EBNA 2A) and type B (EBNA 2B) isolates extends to the EBNA 3 family of nuclear proteins. J Virol 63: 1031–1039.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Rowe M, Young LS, Crocker J, Stokes H, Henderson S, Rickinson AB . (1991). Epstein–Barr virus (EBV)-associated lymphoproliferative disease in the SCID mouse model: implications for the pathogenesis of EBV-positive lymphomas in man. J Exp Med 173: 147–158.

    Article  CAS  PubMed  Google Scholar 

  • Steel CM, Philipson J, Arthur E, Gardiner SE, Newton MS, McIntosh RV . (1977). Possibility of EB virus preferentially transforming a subpopulation of human B lymphocytes. Nature 270: 729–731.

    Article  CAS  PubMed  Google Scholar 

  • Sugimoto M, Ide T, Goto M, Furuichi Y . (1999). Reconsideration of senescence, immortalization and telomere maintenance of Epstein–Barr virus-transformed human B-lymphoblastoid cell lines. Mech Ageing Dev 107: 51–60.

    Article  CAS  PubMed  Google Scholar 

  • Tahara H, Tokutake Y, Maeda S, Kataoka H, Watanabe T, Satoh M et al. (1997). Abnormal telomere dynamics of B-lymphoblastoid cell strains from Werner's syndrome patients transformed by Epstein–Barr virus. Oncogene 15: 1911–1920.

    Article  CAS  PubMed  Google Scholar 

  • Takahashi T, Kawabe T, Okazaki Y, Itoh C, Noda K, Tajima M et al. (2003). in vitro establishment of tumorigenic human B-lymphoblastoid cell lines transformed by Epstein–Barr virus. DNA Cell Biol 22: 727–735.

    Article  CAS  PubMed  Google Scholar 

  • Thomas JA, Crawford DH . (1989). Epstein–Barr virus associated B-cell lymphomas in AIDS and after organ transplantation. Lancet 1: 1075–1076.

    Article  CAS  PubMed  Google Scholar 

  • Thomas JA, Hotchin NA, Allday MJ, Amlot P, Rose M, Yacoub M et al. (1990). Immunohistology of Epstein–Barr virus-associated antigens in B cell disorders from immunocompromised individuals. Transplantation 49: 944–953.

    Article  CAS  PubMed  Google Scholar 

  • Thorley-Lawson DA . (2001). Epstein–Barr virus: exploiting the immune system. Nat Rev Immunol 1: 75–82.

    Article  CAS  PubMed  Google Scholar 

  • Thorley-Lawson DA, Gross A . (2004). Persistence of the Epstein–Barr virus and the origins of associated lymphomas. N Engl J Med 350: 1328–1337.

    Article  CAS  PubMed  Google Scholar 

  • van Steensel B, Smogorzewska A, de Lange T . (1998). TRF2 protects human telomeres from end-to-end fusions. Cell 92: 401–413.

    Article  CAS  PubMed  Google Scholar 

  • Verdun RE, Crabbe L, Haggblom C, Karlseder J . (2005). Functional human telomeres are recognized as DNA damage in G2 of the cell cycle. Mol Cell 20: 551–561.

    Article  CAS  PubMed  Google Scholar 

  • Verdun RE, Karlseder J . (2006). The DNA damage machinery and homologous recombination pathway act consecutively to protect human telomeres. Cell 127: 709–720.

    Article  CAS  PubMed  Google Scholar 

  • Vermolen BJ, Garini Y, Mai S, Mougey V, Fest T, Chuang TC et al. (2005). Characterizing the three-dimensional organization of telomeres. Cytometry A 67: 144–150.

    Article  CAS  PubMed  Google Scholar 

  • Walter J, Moller P, Moldenhauer G, Schirrmacher V, Pawlita M, Wolf J . (1992). Local growth of a Burkitt's lymphoma versus disseminated invasive growth of the autologous EBV-immortalized lymphoblastoid cells and their somatic cell hybrids in SCID mice. Int J Cancer 50: 265–273.

    Article  CAS  PubMed  Google Scholar 

  • Wang F, Gregory CD, Rowe M, Rickinson AB, Wang D, Birkenbach M et al. (1987). Epstein–Barr virus nuclear antigen 2 specifically induces expression of the B-cell activation antigen CD23. Proc Natl Acad Sci USA 84: 3452–3456.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Weierich C, Brero A, Stein S, von Hase J, Cremer C, Cremer T et al. (2003). Three-dimensional arrangements of centromeres and telomeres in nuclei of human and murine lymphocytes. Chromosome Res 11: 485–502.

    Article  CAS  PubMed  Google Scholar 

  • Weng NP, Granger L, Hodes RJ . (1997). Telomere lengthening and telomerase activation during human B cell differentiation. Proc Natl Acad Sci USA 94: 10827–10832.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Young LS, Deacon EM, Rowe M, Crocker J, Herbst H, Niedobitek G et al. (1991). Epstein–Barr virus latent genes in tumour cells of Hodgkin's disease. Lancet 337: 1617.

    Article  CAS  PubMed  Google Scholar 

  • Young LS, Murray PG . (2003). Epstein–Barr virus and oncogenesis: from latent genes to tumours. Oncogene 22: 5108–5121.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Mary Cheang for statistical analyses, and Ludger Klewes, Brenda Kuschak and Sabine Hombach-Klonisch for technical help. This study was supported by the Canadian Cancer Society and the National Cancer Institute of Canada (SM), the Swedish Cancer Society (GK), the Canadian Institutes of Health Research Strategic Training Program ‘Innovative Technologies in Multidisciplinary Health Research Training’ fellowships (SL and EW) and by a Manitoba Health Research Council post-doctoral fellowship (SL).

Author information

Author notes

  1. E Wiechec and A G dos Santos Silva: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Physiology, Manitoba Institute of Cell Biology, University of Manitoba, Winnipeg, Manitoba, Canada

    S Lacoste, A G dos Santos Silva, A Guffei & S Mai

  2. Department of Human Genetics, University of Aarhus, Aarhus C, Denmark

    E Wiechec

  3. Department of Pathology, Hematopathology Laboratory, Health Sciences Centre, Winnipeg, Manitoba, Canada

    G Williams

  4. Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden

    M Lowbeer, K Benedek, M Henriksson & G Klein

Authors
  1. S Lacoste
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. E Wiechec
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A G dos Santos Silva
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A Guffei
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. G Williams
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. M Lowbeer
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. K Benedek
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. M Henriksson
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. G Klein
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. S Mai
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to S Mai.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lacoste, S., Wiechec, E., dos Santos Silva, A. et al. Chromosomal rearrangements after ex vivo Epstein–Barr virus (EBV) infection of human B cells. Oncogene 29, 503–515 (2010). https://doi.org/10.1038/onc.2009.359

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2009.359

Keywords

This article is cited by

Search

Advanced search

Quick links