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:

CSF concentrations of brain tryptophan and kynurenines during immune stimulation with IFN-α: relationship to CNS immune responses and depression

Molecular Psychiatry volume 15, pages 393–403 (2010)Cite this article

Abstract

Cytokine-induced activation of indoleamine 2,3-dioxygenase (IDO) catabolizes L-tryptophan (TRP) into L-kynurenine (KYN), which is metabolized to quinolinic acid (QUIN) and kynurenic acid (KA). QUIN and KA are neuroactive and may contribute to the behavioral changes experienced by some patients during exposure to inflammatory stimuli such as interferon (IFN)-α. A relationship between depressive symptoms and peripheral blood TRP, KYN and KA during treatment with IFN-α has been described. However, whether peripheral blood changes in these IDO catabolites are manifest in the brain and whether they are related to central nervous system cytokine responses and/or behavior is unknown. Accordingly, TRP, KYN, QUIN and KA were measured in cerebrospinal fluid (CSF) and blood along with CSF concentrations of relevant cytokines, chemokines and soluble cytokine receptors in 27 patients with hepatitis C after ∼12 weeks of either treatment with IFN-α (n=16) or no treatment (n=11). Depressive symptoms were assessed using the Montgomery–Asberg Depression Rating Scale. IFN-α significantly increased peripheral blood KYN, which was accompanied by marked increases in CSF KYN. Increased CSF KYN was in turn associated with significant increases in CSF QUIN and KA. Despite significant decreases in peripheral blood TRP, IFN-α had no effect on CSF TRP concentrations. Increases in CSF KYN and QUIN were correlated with increased CSF IFN-α, soluble tumor necrosis factor-α receptor 2 and monocyte chemoattractant protein-1 as well as increased depressive symptoms. In conclusion, peripheral administration of IFN-α activated IDO in concert with central cytokine responses, resulting in increased brain KYN and QUIN, which correlated with depressive symptoms.

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

Access options

Buy this article

  • Purchase on SpringerLink
  • 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

Similar content being viewed by others

References

  1. Dantzer R, O’Connor JC, Freund GG, Johnson RW, Kelley KW . From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci 2008; 9: 46–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Miller GE, Rohleder N, Cole SW . Chronic interpersonal stress predicts activation of pro- and anti-inflammatory signaling pathways 6 months later. Psychosom Med 2009; 71: 57–62.

    Article  PubMed  Google Scholar 

  3. Anisman H, Merali Z, Hayley S . Neurotransmitter, peptide and cytokine processes in relation to depressive disorder: comorbidity between depression and neurodegenerative disorders. Prog Neurobiol 2008; 85: 1–74.

    Article  CAS  PubMed  Google Scholar 

  4. Yirmiya R . Endotoxin produces a depressive-like episode in rats. Brain Res 1996; 711: 163–174.

    Article  CAS  PubMed  Google Scholar 

  5. Zorrilla EP, Luborsky L, McKay JR, Rosenthal R, Houldin A, Tax A et al. The relationship of depression and stressors to immunological assays: a meta-analytic review. Brain Behav Immun 2001; 15: 199–226.

    Article  CAS  PubMed  Google Scholar 

  6. Reichenberg A, Yirmiya R, Schuld A, Kraus T, Haack M, Morag A et al. Cytokine-associated emotional and cognitive disturbances in humans. Arch Gen Psychiatry 2001; 58: 445–452.

    Article  CAS  PubMed  Google Scholar 

  7. Brydon L, Harrison NA, Walker C, Steptoe A, Critchley HD . Peripheral inflammation is associated with altered substantia nigra activity and psychomotor slowing in humans. Biol Psychiatry 2008; 63: 1022–1029.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Capuron L, Fornwalt FB, Knight BT, Harvey PD, Ninan PT, Miller AH . Does cytokine-induced depression differ from idiopathic major depression in medically healthy individuals?. J Affect Disord (in press).

  9. Tyring S, Gottlieb A, Papp K, Gordon K, Leonardi C, Wang A et al. Etanercept and clinical outcomes, fatigue, and depression in psoriasis: double-blind placebo-controlled randomised phase III trial. Lancet 2006; 367: 29–35.

    Article  CAS  PubMed  Google Scholar 

  10. Muller N, Schwarz MJ, Dehning S, Douhe A, Cerovecki A, Goldstein-Muller B et al. The cyclooxygenase-2 inhibitor celecoxib has therapeutic effects in major depression: results of a double-blind, randomized, placebo controlled, add-on pilot study to reboxetine. Mol Psychiatry 2006; 11: 680–684.

    Article  CAS  PubMed  Google Scholar 

  11. Miller AH, Maletic V, Raison CL . Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol Psychiatry 2009; 65: 732–741.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Felger JC, Alagbe O, Hu F, Mook D, Freeman AA, Sanchez MM et al. Effects of interferon-alpha on rhesus monkeys: a nonhuman primate model of cytokine-induced depression. Biol Psychiatry 2007; 62: 1324–1333.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Raison CL, Borisov AS, Majer M, Drake DF, Pagnoni G, Woolwine BJ et al. Activation of central nervous system inflammatory pathways by interferon-alpha: relationship to monoamines and depression. Biol Psychiatry 2009; 65: 296–303.

    Article  CAS  PubMed  Google Scholar 

  14. Quan N, Banks WA . Brain-immune communication pathways. Brain Behav Immun 2007; 21: 727–735.

    Article  CAS  PubMed  Google Scholar 

  15. D’Mello C, Le T, Swain MG . Cerebral microglia recruit monocytes into the brain in response to tumor necrosis factor alpha signaling during peripheral organ inflammation. J Neurosci 2009; 29: 2089–2102.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Weidenfeld J, Yirmiya R . Effects of bacterial endotoxin on the glucocorticoid feedback regulation of adrenocortical response to stress. Neuroimmunomodulation 1996; 3: 352–357.

    Article  CAS  PubMed  Google Scholar 

  17. Capuron L, Raison CL, Musselman DL, Lawson DH, Nemeroff CB, Miller AH . Association of exaggerated HPA axis response to the initial injection of interferon-alpha with development of depression during interferon-alpha therapy. Am J Psychiatry 2003; 160: 1342–1345.

    Article  PubMed  Google Scholar 

  18. Robinson CM, Shirey KA, Carlin JM . Synergistic transcriptional activation of indoleamine dioxygenase by IFN-gamma and tumor necrosis factor-alpha. J Interferon Cytokine Res 2003; 23: 413–421.

    Article  CAS  PubMed  Google Scholar 

  19. Robinson CM, Hale PT, Carlin JM . NF-kappa B activation contributes to indoleamine dioxygenase transcriptional synergy induced by IFN-gamma and tumor necrosis factor-alpha. Cytokine 2006; 35: 53–61.

    Article  CAS  PubMed  Google Scholar 

  20. Pemberton LA, Kerr SJ, Smythe G, Brew BJ . Quinolinic acid production by macrophages stimulated with IFN-gamma, TNF-alpha, and IFN-alpha. J Interferon Cytokine Res 1997; 17: 589–595.

    Article  CAS  PubMed  Google Scholar 

  21. Fujigaki H, Saito K, Fujigaki S, Takemura M, Sudo K, Ishiguro H et al. The signal transducer and activator of transcription 1alpha and interferon regulatory factor 1 are not essential for the induction of indoleamine 2,3-dioxygenase by lipopolysaccharide: involvement of p38 mitogen-activated protein kinase and nuclear factor-kappaB pathways, and synergistic effect of several proinflammatory cytokines. J Biochem 2006; 139: 655–662.

    Article  CAS  PubMed  Google Scholar 

  22. Mellor AL, Munn D, Chandler P, Keskin D, Johnson T, Marshall B et al. Tryptophan catabolism and T cell responses. Adv Exp Med Biol 2003; 527: 27–35.

    Article  CAS  PubMed  Google Scholar 

  23. Owens MJ, Nemeroff CB . Role of serotonin in the pathophysiology of depression: focus on the serotonin transporter. Clin Chem 1994; 40: 288–295.

    CAS  PubMed  Google Scholar 

  24. Flores BH, Musselman DL, DeBattista C, Garlow SJ, Schatzberg AF, Nemeroff CB . Biology of mood disorders. In: Schatzberg AF, Nemeroff CB (eds). Textbook of Psychopharmacology, 3rd edn. America Psychiatric Publishing, Inc.: Washington, DC, 2004, pp 717–763.

    Google Scholar 

  25. O’Connor JC, Lawson MA, Andre C, Moreau M, Lestage J, Castanon N et al. Lipopolysaccharide-induced depressive-like behavior is mediated by indoleamine 2,3-dioxygenase activation in mice. Mol Psychiatry 2009; 14: 511–522.

    Article  PubMed  Google Scholar 

  26. O’Connor JC, Lawson MA, Andre C, Briley EM, Szegedi SS, Lestage J et al. Induction of IDO by bacille Calmette-Guerin is responsible for development of murine depressive-like behavior. J Immunol 2009; 182: 3202–3212.

    Article  PubMed  Google Scholar 

  27. Maes M, Bonaccorso S, Marino V, Puzella A, Pasquini M, Biondi M et al. Treatment with interferon-alpha (IFN alpha) of hepatitis C patients induces lower serum dipeptidyl peptidase IV activity, which is related to IFN alpha-induced depressive and anxiety symptoms and immune activation. Mol Psychiatry 2001; 6: 475–480.

    Article  CAS  PubMed  Google Scholar 

  28. Capuron L, Ravaud A, Neveu PJ, Miller AH, Maes M, Dantzer R . Association between decreased serum tryptophan concentrations and depressive symptoms in cancer patients undergoing cytokine therapy. Mol Psychiatry 2002; 7: 468–473.

    Article  CAS  PubMed  Google Scholar 

  29. Capuron L, Neurauter G, Musselman DL, Lawson DH, Nemeroff CB, Fuchs D et al. Interferon-alpha-induced changes in tryptophan metabolism. Relationship to depression and paroxetine treatment. Biol Psychiatry 2003; 54: 906–914.

    Article  CAS  PubMed  Google Scholar 

  30. Wichers MC, Koek GH, Robaeys G, Verkerk R, Scharpe S, Maes M . IDO and interferon-alpha-induced depressive symptoms: a shift in hypothesis from tryptophan depletion to neurotoxicity. Mol Psychiatry 2005; 10: 538–544.

    Article  CAS  PubMed  Google Scholar 

  31. Bonaccorso S, Marino V, Puzella A, Pasquini M, Biondi M, Artini M et al. Increased depressive ratings in patients with hepatitis C receiving interferon-alpha-based immunotherapy are related to interferon-alpha-induced changes in the serotonergic system. J Clin Psychopharmacol 2002; 22: 86–90.

    Article  CAS  PubMed  Google Scholar 

  32. Schroecksnadel K, Fiegl M, Prassl K, Winkler C, Denz HA, Fuchs D . Diminished quality of life in patients with cancer correlates with tryptophan degradation. J Cancer Res Clin Oncol 2007; 133: 477–485.

    Article  CAS  PubMed  Google Scholar 

  33. Fuchs D, Moller AA, Reibnegger G, Stockle E, Werner ER, Wachter H . Decreased serum tryptophan in patients with HIV-1 infection correlates with increased serum neopterin and with neurologic/psychiatric symptoms. J Acquir Immune Defic Syndr 1990; 3: 873–876.

    CAS  PubMed  Google Scholar 

  34. Vecsei L, Beal MF . Influence of kynurenine treatment on open-field activity, elevated plus-maze, avoidance behaviors and seizures in rats. Pharmacol Biochem Behav 1990; 37: 71–76.

    Article  CAS  PubMed  Google Scholar 

  35. Widner B, Laich A, Sperner-Unterweger B, Ledochowski M, Fuchs D . Neopterin production, tryptophan degradation, and mental depression—what is the link? Brain Behav Immun 2002; 16: 590–595.

    Article  CAS  PubMed  Google Scholar 

  36. Muller N, Schwarz MJ . The immune-mediated alteration of serotonin and glutamate: towards an integrated view of depression. Mol Psychiatry 2007; 12: 988–1000.

    Article  CAS  PubMed  Google Scholar 

  37. Schwarcz R, Pellicciari R . Manipulation of brain kynurenines: glial targets, neuronal effects, and clinical opportunities. J Pharmacol Exp Ther 2002; 303: 1–10.

    Article  CAS  PubMed  Google Scholar 

  38. Saito K, Crowley JS, Markey SP, Heyes MP . A mechanism for increased quinolinic acid formation following acute systemic immune stimulation. J Biol Chem 1993; 268: 15496–15503.

    CAS  PubMed  Google Scholar 

  39. Guillemin GJ, Smythe G, Takikawa O, Brew BJ . Expression of indoleamine 2,3-dioxygenase and production of quinolinic acid by human microglia, astrocytes, and neurons. Glia 2005; 49: 15–23.

    Article  PubMed  Google Scholar 

  40. Guillemin GJ, Smith DG, Smythe GA, Armati PJ, Brew BJ . Expression of the kynurenine pathway enzymes in human microglia and macrophages. Adv Exp Med Biol 2003; 527: 105–112.

    Article  CAS  PubMed  Google Scholar 

  41. Rios C, Santamaria A . Quinolinic acid is a potent lipid peroxidant in rat brain homogenates. Neurochem Res 1991; 16: 1139–1143.

    Article  CAS  PubMed  Google Scholar 

  42. Guillemin GJ, Wang L, Brew BJ . Quinolinic acid selectively induces apoptosis of human astrocytes: potential role in AIDS dementia complex. J Neuroinflammation 2005; 2: 16.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Guillemin GJ, Brew BJ, Noonan CE, Takikawa O, Cullen KM . Indoleamine 2,3 dioxygenase and quinolinic acid immunoreactivity in Alzheimer's disease hippocampus. Neuropathol Appl Neurobiol 2005; 31: 395–404.

    Article  CAS  PubMed  Google Scholar 

  44. Guillemin GJ, Meininger V, Brew BJ . Implications for the kynurenine pathway and quinolinic acid in amyotrophic lateral sclerosis. Neurodegener Dis 2005; 2: 166–176.

    Article  CAS  PubMed  Google Scholar 

  45. Guidetti P, Schwarcz R . 3-Hydroxykynurenine and quinolinate: pathogenic synergism in early grade Huntington's disease? Adv Exp Med Biol 2003; 527: 137–145.

    Article  CAS  PubMed  Google Scholar 

  46. Heyes MP, Saito K, Crowley JS, Davis LE, Demitrack MA, Der M et al. Quinolinic acid and kynurenine pathway metabolism in inflammatory and non-inflammatory neurological disease. Brain 1992; 115 (Pt 5): 1249–1273.

    Article  PubMed  Google Scholar 

  47. McNally L, Bhagwagar Z, Hannestad J . Inflammation, glutamate, and glia in depression: a literature review. CNS Spectr 2008; 13: 501–510.

    Article  PubMed  Google Scholar 

  48. Capuron L, Miller AH . Cytokines and psychopathology: lessons from interferon-alpha. Biol Psychiatry 2004; 56: 819–824.

    Article  CAS  PubMed  Google Scholar 

  49. Raison CL, Borisov AS, Broadwell SD, Capuron L, Woolwine BJ, Jacobson IM et al. Depression during pegylated interferon-alpha plus ribavirin therapy: prevalence and prediction. J Clin Psychiatry 2005; 66: 41–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. First MB, Spitzer RL, Gibbon M, Williams JB . Structured Clinical Interview for DSM-IV. American Psychiatric Press: Washington, DC, 1997.

    Google Scholar 

  51. Folstein MF, Robins LN, Helzer JE . The mini-mental state examination. Arch Gen Psychiatry 1983; 40: 812.

    Article  CAS  PubMed  Google Scholar 

  52. Majer M, Welberg LA, Capuron L, Pagnoni G, Raison CL, Miller AH . IFN-alpha-induced motor slowing is associated with increased depression and fatigue in patients with chronic hepatitis C. Brain Behav Immun 2008; 22: 870–880.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Raison CL, Borisov AS, Woolwine BJ, Massung B, Vogt G, Miller AH . Interferon-alpha effects on diurnal hypothalamic-pituitary-adrenal axis activity: relationship with proinflammatory cytokines and behavior. Mol Psychiatry (in press).

  54. Montgomery SA, Asberg M . A new depression scale designed to be sensitive to change. Br J Psychiatry 1979; 134: 382–389.

    CAS  PubMed  Google Scholar 

  55. Cohen JD . Statistical Power Analysis for the Behavioral Sciences, 2nd edn. Lawrence Erlbaum Associates: Hillsdale, NJ, 1988.

    Google Scholar 

  56. Fukui S, Schwarcz R, Rapoport SI, Takada Y, Smith QR . Blood-brain barrier transport of kynurenines: implications for brain synthesis and metabolism. J Neurochem 1991; 56: 2007–2017.

    Article  CAS  PubMed  Google Scholar 

  57. Borland LM, Michael AC . Voltammetric study of the control of striatal dopamine release by glutamate. J Neurochem 2004; 91: 220–229.

    Article  CAS  PubMed  Google Scholar 

  58. Wu HQ, Rassoulpour A, Schwarcz R . Kynurenic acid leads, dopamine follows: a new case of volume transmission in the brain? J Neural Transm 2007; 114: 33–41.

    Article  PubMed  Google Scholar 

  59. Shuto H, Kataoka Y, Horikawa T, Fujihara N, Oishi R . Repeated interferon-alpha administration inhibits dopaminergic neural activity in the mouse brain. Brain Res 1997; 747: 348–351.

    Article  CAS  PubMed  Google Scholar 

  60. Heyes MP, Saito K, Major EO, Milstien S, Markey SP, Vickers JH . A mechanism of quinolinic acid formation by brain in inflammatory neurological disease. Attenuation of synthesis from L-tryptophan by 6-chlorotryptophan and 4-chloro-3-hydroxyanthranilate. Brain 1993; 116 (Pt 6): 1425–1450.

    Article  PubMed  Google Scholar 

  61. Guillemin GJ, Croitoru-Lamoury J, Dormont D, Armati PJ, Brew BJ . Quinolinic acid upregulates chemokine production and chemokine receptor expression in astrocytes. Glia 2003; 41: 371–381.

    Article  PubMed  Google Scholar 

  62. Weiss JM, Downie SA, Lyman WD, Berman JW . Astrocyte-derived monocyte-chemoattractant protein-1 directs the transmigration of leukocytes across a model of the human blood-brain barrier. J Immunol 1998; 161: 6896–6903.

    CAS  PubMed  Google Scholar 

  63. Owe-Young R, Webster NL, Mukhtar M, Pomerantz RJ, Smythe G, Walker D et al. Kynurenine pathway metabolism in human blood-brain-barrier cells: implications for immune tolerance and neurotoxicity. J Neurochem 2008; 105: 1346–1357.

    Article  CAS  PubMed  Google Scholar 

  64. Scrandis DA, Langenberg P, Tonelli LH, Sheikh TM, Manogura AC, Alberico LA et al. Prepartum depressive symptoms correlate positively with C-reactive protein levels and negatively with tryptophan levels: a preliminary report. Int J Child Health Hum Dev 2008; 1: 167–174.

    PubMed  PubMed Central  Google Scholar 

  65. Kohl C, Walch T, Huber R, Kemmler G, Neurauter G, Fuchs D et al. Measurement of tryptophan, kynurenine and neopterin in women with and without postpartum blues. J Affect Disord 2005; 86: 135–142.

    Article  CAS  PubMed  Google Scholar 

  66. Maes M, Verkerk R, Bonaccorso S, Ombelet W, Bosmans E, Scharpe S . Depressive and anxiety symptoms in the early puerperium are related to increased degradation of tryptophan into kynurenine, a phenomenon which is related to immune activation. Life Sci 2002; 71: 1837–1848.

    Article  CAS  PubMed  Google Scholar 

  67. Orlikov AB, Prakhye IB, Ryzov IV . Kynurenine in blood plasma and DST in patients with endogenous anxiety and endogenous depression. Biol Psychiatry 1994; 36: 97–102.

    Article  CAS  PubMed  Google Scholar 

  68. Moller SE, Kirk L, Honore P . Tryptophan tolerance and metabolism in endogenous depression. Psychopharmacology (Berl) 1982; 76: 79–83.

    Article  CAS  Google Scholar 

  69. Wood K, Harwood J, Coppen A . The effect of antidepressant drugs on plasma kynurenine in depressed patients. Psychopharmacology (Berl) 1978; 59: 263–266.

    Article  CAS  Google Scholar 

  70. Myint AM, Kim YK, Verkerk R, Scharpe S, Steinbusch H, Leonard B . Kynurenine pathway in major depression: evidence of impaired neuroprotection. J Affect Disord 2007; 98: 143–151.

    Article  CAS  PubMed  Google Scholar 

  71. Capuron L, Gumnick JF, Musselman DL, Lawson DH, Reemsnyder A, Nemeroff CB et al. Neurobehavioral effects of interferon-alpha in cancer patients: phenomenology and paroxetine responsiveness of symptom dimensions. Neuropsychopharmacology 2002; 26: 643–652.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This study was supported by grants from the National Institutes of Health to CLR (K23 MH064619 and R01 MH070553), RD (R01 MH 71349 and R01 MH 079829), KWK (R01 AG 029573) and AHM (K05 MH069124 and R01 HL073921 and T32 MH020018) as well as the Centers for Disease Control and Prevention. In addition, this study was supported by PHS Grant UL1 RR025008 from the Clinical and Translational Science Award program and PHS Grant M01 RR0039 from the General Clinical Research Center program, National Institutes of Health, National Center for Research Resources. We thank Philip Harvey, PhD, for his assistance with statistical analyses and Suwako Fujigaki for technical assistance with the assay for QUIN.

Author information

Authors and Affiliations

  1. Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA

    C L Raison, B J Woolwine, G Vogt & A H Miller

  2. Integrative Immunology and Behavior Program, University of Illinois Urbana-Champaign, Champaign, IL, USA

    R Dantzer, K W Kelley & M A Lawson

  3. Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA

    J R Spivey

  4. Human Health Sciences, Kyoto University Graduate School of Medicine and Faculty of Medicine, Kyoto, Japan

    K Saito

Authors
  1. C L Raison
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. R Dantzer
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. K W Kelley
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M A Lawson
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. B J Woolwine
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. G Vogt
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. J R Spivey
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. K Saito
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. A H Miller
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to A H Miller.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Raison, C., Dantzer, R., Kelley, K. et al. CSF concentrations of brain tryptophan and kynurenines during immune stimulation with IFN-α: relationship to CNS immune responses and depression. Mol Psychiatry 15, 393–403 (2010). https://doi.org/10.1038/mp.2009.116

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/mp.2009.116

Keywords

This article is cited by

Search

Advanced search

Quick links