Skip to main content
SpringerLink
Log in

Macrophage Activating Properties of The Tryptophan Catabolite Picolinic Acid

  • Chapter
Developments in Tryptophan and Serotonin Metabolism

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 527))

Abstract

Recent studies have suggested a role for aminoacid catabolites as important regulators of macrophage (M4) activities. We reported previously that picolinic acid (PA), a tryptophan catabolite produced under inflammatory conditions and a costimulus with IFNy of M4) effector functions, is a selective inducer of the M4 inflammatory protein-la (MIP-la) and -113 (MIPs), two CC-chemokines involved in the elicitation of the inflammatory reactions and in the development of the Thl responses. In this study, we have investigated the effects of IFNy on PA-induced MIPs expression and secretion by mouse M4) as well as the regulation of MIP-la/ß receptor, CCR5, by both stimuli alone or in combination. We demonstrated that IFNy inhibited MIPs mRNA stimulation by PA in a dose-and time-dependent fashion, despite its ability to induce other CC- or CXC chemokines. MIPs mRNA down-regulation was associated with decreased intracellular chemokine expression and secretion and was dependent on both mRNA destabilization and gene transcription inhibition. Moreover, IFNy inhibitory effects were stimulus-specific because MIPs induction by PA was either unaffected or increased by the anti-inflammatory cytokines, IL-10 and IL-4, or the pro-inflammatory stimulus, LPS, respectively. In contrast, we found that IFNy increased CCR5 basal expression, whereas PA down-regulated both constitutive and IFNy-induced CCR5 mRNA and protein levels. These results demonstrate that IFNy and PA have reciprocal effects on the production of MIPs chemokines and the expression of their receptor. The concerted action of IFNy and PA on MIP-la/ß chemokine/receptor system is likely to be of pathophysiological significance and to represent an important regulatory mechanism for leukocyte recruitment and distribution into damaged tissues during inflammatory responses.catabolites in AIDS, particularly of PA that, by upregulating MIPs expression, could exert protective effects on the host. This hypothesis is further supported by our most recent data showing that PA inhibits both constitutive and IFNy-induced CCR5 mRNA and protein expression on macrophages (manuscript in preparation).

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 259.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 329.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 329.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. G. Melillo, M. C. Bosco, T. Musso, L. Varesio, Immunobiology of picolinic acid. In:Recent advances in tryptophan researchedited by G. Allegri Filippini, C.V.L. Costa, A.Bertazzo, (Plenum Press, New York, 1996), pp. 135–141.

    Book  Google Scholar 

  2. W.T. Milton and F. Gensheng, Relationship between interferon-y, indoleamine 2,3-dioxygenase, and tryptophan catabolismFASEB J. 52516–2522 (1991).

    Google Scholar 

  3. R.R. Brown, Y. Ozaki, S.P. Datta, E.C. Borden, P.M. Sondel, D.G. Malone, Implications of interferon-induced tryptophan catabolism in cancer, auto-immune diseases and AIDSAdv.Exp.Med.Biol. 294425–435 (1991).

    Article  PubMed  CAS  Google Scholar 

  4. L. Varesio, G. Cox, K. Pulkki, A. Brooks, G. Melillo, Arginineandtryptophan catabolism: the picolinic acid connection. In:Advances in tryptophan researchI. Ishiguro, R. Kido, T. Nagatsu, Y. Nagamura, Y. Ohta, Eds. (Fujita Health University Press, Tokyo, Japan, 1992)pp.309–314.

    Google Scholar 

  5. W. Dai and S.L. Gupta, Molecular cloning, sequencing and expression of human interferon-y-inducible indoleamine 2,3-dioxigenase cDNABiochem.Biophys.Res.Commun. 1681–9 (1990).

    Article  PubMed  CAS  Google Scholar 

  6. Y. Ozaki, M.P. Edelstein, D.S. Duch, Induction of indoleamine 2,3-dioxygenase: a mechanism of the antitumor activity of interferon-gammaProc.Natl.Acad.Sci.USA 851242–1249 (1988).

    Article  PubMed  CAS  Google Scholar 

  7. J.M. Carlin, E.C. Borden, G.L. Byrne, Interferon-induced indoleamine 2,3-dioxigenase activity inhibitsClamydia psittacireplication in human macrophagesJ.Interferon Res. 9329–335 (1999).

    Article  Google Scholar 

  8. E.R. Pfefferkom, Interferon-gamma blocks the growth ofToxoplasma gondiiin human fibroblasts by inducing the host cells to degrade tryptophanProc.Natl.Acad.Sci.USA 81908–916 (1984).

    Article  Google Scholar 

  9. T.F. Pais and R. Appelberg, Macrophage control of mycobacterial growth induced by picolinic acid is dependent on host cell apoptosisJ.Immunol. 164389–397 (2000).

    PubMed  CAS  Google Scholar 

  10. H.W. Murray, A. Szuro-Sudol, D. Wellner, M.J. Oca, A.M. Granger, D.M. Libby, C.D. Rothermel, B.J. Rubin, Role of tryptophan degradation in respiratory burst-independent antimicrobial activity of gamma interferon-stimulated human macrophages/nfect./mmun.57, 845–850 (1989).

    CAS  Google Scholar 

  11. L. Varesio, A. Soleti, D. Radzioch, K. Putkki, A. Brooks, G.L. Gusella, M.C. Bosco, G.Fomi, Picolinic acid and its influence on the immune system. In:L-tryptophan current prospects in medicine and drug safety.H. S. Walter Kochen, Ed. (Walter de Gruyter, Berlin, New York, 1994), pp. 99–110.

    Google Scholar 

  12. L. Varesio, L. Espinoza-Delgado, L. Gusella, G.W. Cox, G. Melillo, T. Musso, M.C. Bosco, Role of cytokines in the activation of monocytes. In:Human cytokines: their role in disease and therapy.B. B. Aggarwal and R. K. Puri, Eds. (Blackwell Scientific Publication, Inc., Cambridge, MA, 1995), pp. 55–69.

    Google Scholar 

  13. D.H. Munn, E. Shafizadeh, J.T. Attwood, I. Bondarev, A. Pashine, A.L. Mellor, Inhibition of T cell proliferation by macrophage tryptophan catabolismJ.Exp.Med.189, 1363–1372 (1999).

    Article  PubMed  CAS  Google Scholar 

  14. K.M. Kopydlowski, C.A. Salkowski, M.J. Cody, N. Van Rooijen, J. Major, T.A. Hamilton, S.N. Vogel. Regulation of macrophage chemokine expression by lipopolysaccharide in vitro and in vivoJ.Immunol.163, 1537–1544 (1999).

    PubMed  CAS  Google Scholar 

  15. M.M. Shi, J. J. Godleski, J.D. Paulauskis. Regulation of macrophage inflammatory protein -1 alpha mRNA by oxidative stressJ.Biol.Chem.271, 5878–5883 (1996).

    Article  PubMed  CAS  Google Scholar 

  16. D.M. Paulnock, K.P. Demick, S.P. Coller. Analysis of interferon-gamma-dependent and-independent pathways of macrophage activationJ.Leukoc.Biol. 67677–682 (2000).

    PubMed  CAS  Google Scholar 

  17. A. Mehler Formation of picolinic and quinolinic acids following enzimatic oxidation of 3- hydroxyanthranilate to quinolateJ.Biol.Chem. 218241–250 (1956).

    Google Scholar 

  18. T. Rebello, B. Lonnerdal, L. Hurley, Picolinic acid in milk, pancreatic juice and intestine:inadequate for role in zinc absorpionAm.J.Clin.Nutr. 351–9 (1982).

    PubMed  CAS  Google Scholar 

  19. G.W. Evans and P. E. Johnson, Characterization and quantitation of a zinc binding ligand in human milkPediatr.Res. 14867–871 (1980).

    Article  Google Scholar 

  20. C. Dazzi, G. Candiano, S. Massazza, A. Ponzetto, L. Varesio, New high-performance liquid chromatografy method for the detection of picolinic acid in biological fluidsJ.Chromatogr.B751, 61–68 (2001).

    Article  CAS  Google Scholar 

  21. L. Varesio, M. Clayton, E. Blasi, R. Ruffmann, D. Radzioch, Picolinic acid, a catabolite of L-tryptophan, as the second signal in the activation of IFN-gamma primed macrophagesJ.Immunol. 1454265–4272 (1990).

    PubMed  CAS  Google Scholar 

  22. G. Melillo, G. Cox, A. Biragyn, L. Sheftler, L. Varesio, Regulation of nitric oxide synthase mRNA expression by interferon-gamma and picolinic acidJ.Biol.Chem. 2698128–8135 (1994).

    PubMed  CAS  Google Scholar 

  23. R. Ruffmann, R. Schlick, M. Chingos, W. Budzynsky, L. Varesio, Antiproliferative activity of picolinic acid due to macrophage activationDrugs.Exp.Clin.Res. 13607–611 (1987).

    PubMed  CAS  Google Scholar 

  24. J. Fernandez-Pol, V. Bono, G. Johnson, Control of growth by picolinic acid: differential response of normal and transformed cellsProc.Natl.Acad.Sci.USA7, 2889–2895 (1977).

    Article  Google Scholar 

  25. J. Plowman, S.D. Harrison, D. Dykes, K.D. Paull, V.L. Narayanan, H.K. Tobol, J. Martin, D.P. Griswold, Preclinical antitumor activity of an a-picoline derivate, penclomedine (NSC 388720), on human and murine tumorsCancer Res 491909–1915 (1989).

    PubMed  CAS  Google Scholar 

  26. S.W. Leuthauser, L.W. Oberley, T.D. Oberley, Antitumor activity of picolinic acid in CBA/J miceJ.Natl.Cancer Inst 68123–129 (1982).

    PubMed  CAS  Google Scholar 

  27. E. Blasi, R. Mazzolla, L. Pitzurra, R. Barluzzi, F. Bistoni, Protective effect of picolinic acid on mice intracerebrally infected with lethal doses ofCandida albicans Antimicrob. Agents Chemother37, 2422–2426 (1993).

    Article  PubMed  CAS  Google Scholar 

  28. E. Blasi, D. Radzioch, L. Varesio, Inibition of retroviral mRNA expression in the murine macrophage cell line GG2EE by biologic response modifiersJ./mmunol. 1412153–2160 (1988).

    CAS  Google Scholar 

  29. G. Melillo, T. Musso, A. Sica, L. S. Taylor, G. Cox, L. Varesio, A hypoxia responsive element mediates a novel pathway of activation of the inducible nitric oxide synthase promoterJ.Exp.Med. 1821683–1693 (1995).

    Article  PubMed  CAS  Google Scholar 

  30. G. Melillo, G. Cox, D. Radzioch, L. Varesio, Picolinic acid, a catabolite of L-tryptophan, is a costimulus for the induction of reactive nitrogen intermediate production in murine macrophagesJ.Immunol. 1504031–4039 (1993).

    PubMed  CAS  Google Scholar 

  31. C.F. Nathan and J.B. Hibbs, Role of nitric oxide synthesis in macrophage antimicrobial activityCurr.Opin.lmmunol. 365–70 (1991).

    Article  CAS  Google Scholar 

  32. T. Springer, Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigmCell76, 301–314 (1994).

    Article  PubMed  CAS  Google Scholar 

  33. A. Ben-Baruk, D. Michiel, J. Oppenheim, Signals and receptor involved in the recruitment of inflammatory cellsJ.Biol.Chem.270, 11703–11706 (1995).

    Article  Google Scholar 

  34. M. Baggiolini, B. Dewald, B. Moser, Interleukin 8 and related chemotactic cytokines: CXC and CC chemokinesAdv.Immunol.55, 97–179 (1994).

    Article  PubMed  CAS  Google Scholar 

  35. T. Schall, Biology of RANTES/SIS cytokine familyCytokine3, 165–183 (1991).

    Article  PubMed  CAS  Google Scholar 

  36. P. Murphy, Chemokine receptors: structure, functions and role in microbial pathogenesisCytokine Growth Factor Rev. 747–53 (1996).

    Article  PubMed  CAS  Google Scholar 

  37. M. Miller and M. Krangel, Biology and biochemistry of the chemokines: a family of chemotactic and inflammatory cytokinesCrit.Rev.Immunol. 1217–46 (1992).

    PubMed  CAS  Google Scholar 

  38. D. Taub, T.J. Sayers, C.R.D. Carter, J. Ortaldo, a and 13 chemokines induce NK cell migration and enhance NK-mediated cytolysisJ.Immunol. 1553877–3888 (1995).

    PubMed  CAS  Google Scholar 

  39. J.T. Siveke and A. Hamann, Cutting edge: T helper-1 and T helper-2 cells respond differentially to chemokinesJ.Immunol. 160550–554 (1998).

    PubMed  CAS  Google Scholar 

  40. M.R. HortonM.D.Burdick, R. Strieter, C. Bao, P.W. Noble, Regulation of Hyaluronan-induced chemokine gene expression by IL-10 and IFN-gamma in mouse macrophagesJ.Immunol. 1603023–3030 (1998).

    CAS  Google Scholar 

  41. M.C. Bosco, A. Rapisarda, S. Massazza, G. Melillo, H. Young, L. Varesio, The tryptophan catabolite picolinic acid selectively induces the chemokines macrophage-inflammatory protein-la and -l3 in macrophagesJ.Immunol. 1643283–3291 (2000).

    PubMed  CAS  Google Scholar 

  42. W.J. Karpus, N.W. Lukacs, B.L. McRae, R. Strieter, S. Kunkel, S.D. Miller, An important role for the chemokine macrophage inflammatory protein-la in the pathogenesis of the T cell-mediated autoimmune disease, experimental autoimmune encephalomyelitisJ.Immunol. 1555003–5010 (1995).

    PubMed  CAS  Google Scholar 

  43. F. Sallusto, A. Lanzavecchia, C.R. Mackay, Chemokines and chemokine receptors in T-cell priming and Thl/Th2-mediated responsesImmunol.Today 19568–574 (1998).

    Article  PubMed  CAS  Google Scholar 

  44. D. Taub, K. Conlon, A. Lloyd, J. Oppenheim, D. Kelvin, Preferential migration of activated CD4’ and CD8’ T cells in response toMIP-laand MIP-1(3Science 260355–358 (1993).

    Article  PubMed  CAS  Google Scholar 

  45. L.A. DiPietro, M.D. Burdick, Q.E. Low, S. Kunkel, R. StrieterMIP-lalphaas a critical macrophage chemoattractant in murine wound repairJ.Clin.Invest. 1011693–1698 (1998).

    Article  PubMed  CAS  Google Scholar 

  46. A. Rot, M. Krienger, T. Brunner, S. Bischoff, T. Shall, C. Dahinden, RANTES and macrophage protein la induce the migration and activation of normal human eosinophil granulocytesJ.Exp.Med. 1761489–1495 (1992).

    Article  PubMed  CAS  Google Scholar 

  47. D. Cook The role of MIP-1 alpha in inflammation and hematopoiesisJ.Leukoc.Biol. 5961–66 (1996).

    Google Scholar 

  48. S. Schrum, P. Probst, B. Fleischer, P.F. Zipfel, Synthesis of the CC-chemokines MIP-la, M1P-1 3, and RANTES is associated with a type 1 immune responseJ.Immunol. 1573598–3603 (1996).

    PubMed  CAS  Google Scholar 

  49. D. Alberati-Giani, P. Malherbe, P. Ricciardi-Castagnoli, C. Kohler, S. Denis-Donini, A.M. Cesura, Differential regulation of indoleamine 2,3-dioxygenase expression by nitric oxide and inflammatory mediators in IFN-gamma-activated murine macrophages and microglial cellsJ.Immunol. 159419–426 (1997).

    PubMed  CAS  Google Scholar 

  50. J. Fernandez-Pol, Iron: possible cause of the GI arrest induced by picolinic acidBiochem Biophys Res Commun 78136–141 (1977).

    Article  PubMed  CAS  Google Scholar 

  51. G. Melillo, B. Taylor, A. Brooks, T. Musso, G. Cox, L. Varesio, Functional requirement of the hypoxia responsive element in the activation of the inducible nitric oxide synthase promoter by iron chelator desferrioxamineJ. Biol.Chem. 27212236–12243 (1996).

    Article  Google Scholar 

  52. P. Giardina and R. Grady, Chelation therapy in beta-thalassemia: the benefits and limitation of desferrioxamineSemin.Hematol. 32304–3I2 (1995).

    Google Scholar 

  53. N. Mukaida, Y. Mahe, K. Matsushima, Cooperative interaction of nuclear factor-KB- and cis-regulatory enhancer binding protein-like factor binding elements in activating the interleukin-8 gene by prointlammatory cytokinesJ.Biol.Chem. 26521128–21133 (1990).

    PubMed  CAS  Google Scholar 

  54. A. J. Valente, J. Xie, M. Abramova, U. Wenzel, H. Abbound, D. Graves. A complex element regulates IFNgamma-stimulated monocyte chemoattractant protein-1 gene transcription.J.Immunol. 1613719–3728, 1998.

    PubMed  CAS  Google Scholar 

  55. M. Baggiolini and C. Dahinden, CC chemokines in allergic inflammationImmunol.Today 15127–133 (1994).

    Article  PubMed  CAS  Google Scholar 

  56. Z. Brown, R. Robson, J. Westwick, Regulation and expression of chemokines: potential role in glomerulonephritisJ.Leukocyte Biol. 5975–80 (1996).

    PubMed  CAS  Google Scholar 

  57. M.J.Cameron, G.A. ArreazaM.Grattan, C. Meagher, S.Sharif, M.D.Burdick, Strieter R, Cook D, T.L. Delovitch, Differential expression of CC-chemokines and the CCR5 receptor in the pancreas is associated with progression to type [diabetesJ.Immunol. 1651102–1110 (2000).

    PubMed  CAS  Google Scholar 

  58. S. Gautam, J. M. Tebo, T. Hamilton, IL-4 suppresses cytokine gene expression induced by IFN-y and/or IL-2 in murine peritoneal macrophagesJ.Immunol. 1481725–1732 (1992).

    PubMed  CAS  Google Scholar 

  59. C. Bogdan, Y. Vodovotz, C. Nathan, Macrophage deactivation by interleukin 10JExp.Med. 1741549–1554 (1991).

    Article  CAS  Google Scholar 

  60. Y. Ohmori and T. Hamilton, IFN-gamma selectively inhibits lipopolysaccharide-inducible JE/monocyte chemoattractant protein-1 and KC/GRO/melanoma growth-stimulating activity gene expression in mouse peritoneal macrophagesJ.Immunol. 1532204–2212 (1994).

    PubMed  CAS  Google Scholar 

  61. R. Bonecchi, S. Sozzani, J.T. Stine, W. Luini, G. D’Amico, P. AllavenaD.Chantry, A. Mantovani. Divergent effects of interleukin-4 and interferon-gamma on macrophage-derived chemokine (MDC) production: an amplification circuit of polarized T helper-2 responsesBlood 982668–2671 (1998).

    Google Scholar 

  62. U. Boehm, T. Klamp, M. Groot, J. Howard, Cellular responses to interferon-gammaAnnu.Rev.Immunol. 15749–795 (1997).

    Article  PubMed  CAS  Google Scholar 

  63. Y. Ohmori and T. Hamilton, The interferon-stimulated response element and a KB site mediate synergistic induction of murineIP-10gene transcription by IFN-y and TNF-aJImmunol. 1545235–5239 (1995).

    CAS  Google Scholar 

  64. E. Blasi, D. Bauer, R. Barluzzi, R. Mazzolla, F. Bistoni, Pattern of cytokine gene expression in brains of mice protected by picolinic acid against lethal intracerebral infection withCandida albicans J.Neuroimmunol. 52205–213 (1994).

    Article  PubMed  CAS  Google Scholar 

  65. W.J. Karpus and R. Ransohoff, Cutting edge commentary:chemokine regulation of experimental autoimmune encephalomyelitis: temporal and spatial expression patterns govern disease pathogenesisJImmunol.161, 2667–2671 (1998).

    CAS  Google Scholar 

  66. A.E. Koch, S. Kunkel, L.A. Harlow, D.D. Mazarakis, G.K. Haines, M.D. Burdick, R.M. Pope, R. Strieter, Macrophage inflammatory protein-lalpha: a novel chemotactic cytokine for macrophages in rheumatoid arthritisJ.Clin.lnvest. 93921–929 (1994).

    Article  CAS  Google Scholar 

  67. F. Cocchi, A. Devico, A. Garzino-Demo, S. Arya, R. Gallo, P. Lusso. Identification of RANTES, MIP la and MIP lß as the major HIV-suppressive factors produced by CD8’ T cells.Science 2701811–1815, 1995.

    Article  PubMed  CAS  Google Scholar 

  68. G. Alkhatib, C. Combadiere, C. C. Broder, Y. Feng, P. E. Kennedy, P. Murphy, E. A. Berger. CC CKR5: a RANTES, MIP-lalphaMIP-1 betareceptor as a fusion cofactor for macrophage-tropic HIV-1.Science 2721955–1958, 1996.

    Article  PubMed  CAS  Google Scholar 

  69. H. Schmidtmayerova, S. L. H. Nottet, G. Nuovo, T. Raabe, C. R. Flanagan, L. Dubrovsky, H. E. Gendelman, A. Cerami, M. Bykrinsky, B. Sherry. Human immunodeficiency virus type 1 infection alters chemokine f3 peptide expression in human monocytes: implication for recruitment of leukocytes into brain and lymph nodes.Proc.Natl.Acad.Sci. USA 93700–709, 1996.

    Article  PubMed  CAS  Google Scholar 

  70. D. Fuchs, A. Forsman, L. Hagberg, M. Larsson, G. Norkrans, G. ReibneggerE.R. Werner, H. Wachter. Immune activation and decreased tryptophan in patients with HIV-1 infection.J.Interferon Res. 10599–605, 1990.

    Article  PubMed  CAS  Google Scholar 

  71. C. L. Achim, M. P. Heyes, C. A. Wiley. Quantitation of human immunodeficiency virus, immune activation factors, and quinolinic acid in AIDS brain.J.Clin.lnvest. 912769–2775, 1993.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. G.Gaslini Institute, 16147 Genova, Laboratory of Molecular Biology, Italy

    Maria Carla Bosco

Authors
  1. Maria Carla Bosco
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Annamaria Rapisarda
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gioia Reffo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Stefano Massazza
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sandra Pastorino
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Luigi Varesio
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. University of Padova, Padova, Italy

    Graziella Allegri , Carlo V. L. Costa  & Eugenio Ragazzi ,  & 

  2. University of Hamburg, Hamburg, Germany

    Hans Steinhart

  3. Istituto G. Gaslini, Genova Quarto, Italy

    Luigi Varesio

Rights and permissions

Reprints and permissions

Copyright information

© 2003 Springer Science+Business Media New York

About this chapter

Cite this chapter

Bosco, M.C., Rapisarda, A., Reffo, G., Massazza, S., Pastorino, S., Varesio, L. (2003). Macrophage Activating Properties of The Tryptophan Catabolite Picolinic Acid. In: Allegri, G., Costa, C.V.L., Ragazzi, E., Steinhart, H., Varesio, L. (eds) Developments in Tryptophan and Serotonin Metabolism. Advances in Experimental Medicine and Biology, vol 527. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-0135-0_6

Download citation

  • DOI: https://doi.org/10.1007/978-1-4615-0135-0_6

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-1-4613-4939-6

  • Online ISBN: 978-1-4615-0135-0

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation