Skip to main content
Log in

Formaldehyde stress

  • Reviews
  • Published:
Science China Life Sciences Aims and scope Submit manuscript

Abstract

Formaldehyde, one of the most toxic organic compounds, is produced and processed in human cells. The level of human endogenous formaldehyde is maintained at a low concentration (0.01–0.08 mmol L−1 in blood) under physiological conditions, but the concentration increases during ageing (over 65 years old). Clinical trials have shown that urine formaldehyde concentrations are significantly different between elderly Alzheimer’s patients (n=91) and normal elderly volunteers (n=38) (P<0.001). Abnormally high levels of intrinsic formaldehyde lead to dysfunction in cognition such as learning decline and memory loss. Excess extracellular and intracellular formaldehyde could induce metabolic response and abnormal modifications of cellular proteins such as hydroxymethylation and hyperphosphorylation, protein misfolding, nuclear translocation and even cell death. This cellular response called formaldehyde stress is dependent upon the concentration of formaldehyde. Chronic impairments of the brain resulted from formaldehyde stress could be one of the mechanisms involved in the process of senile dementia during ageing.

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

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Blennow K, de Leon M J, Zetterberg H, et al. Alzheimer’s disease. Lancet, 2006, 368: 387–403 1:CAS:528:DC%2BD28XnsFymsbY%3D, 10.1016/S0140-6736(06)69113-7, 16876668

    Article  PubMed  CAS  Google Scholar 

  2. Hardy J, Allsop D. Amyloid deposition as the central event in the aetiology of Alzheimer’s disease. Trends Pharmacol Sci, 1991, 12: 383–388 1:CAS:528:DyaK3MXmslKktr8%3D, 10.1016/0165-6147(91)90609-V, 1763432

    Article  PubMed  CAS  Google Scholar 

  3. Flament S, Delacourte A, Mann D M. Phosphorylation of Tau proteins: A major event during the process of neurofibrillary degeneration. A comparative study between Alzheimer’s disease and Down’s syndrome. Brain Res, 1990, 516: 15–19 1:CAS:528:DyaK3cXkvFGltrs%3D

    PubMed  CAS  Google Scholar 

  4. Bignall J. APOE gene dose in Alzheimer’s disease. Lancet, 1993, 342: 426 1:STN:280:DyaK3szktFahsw%3D%3D, 10.1016/0140-6736(93)92826-F, 8101911

    Article  PubMed  CAS  Google Scholar 

  5. Anwar R, Moynihan T P, Ardley H, et al. Molecular analysis of the presenilin 1 (S182) gene in “sporadic” cases of Alzheimer’s disease: Identification and characterisation of unusual splice variants. J Neurochem, 1996, 66: 1774–1777 1:CAS:528:DyaK28XhslGhsbc%3D, 10.1046/j.1471-4159.1996.66041774.x, 8627338

    Article  PubMed  CAS  Google Scholar 

  6. Bertoni-Freddari C, Fattoretti P, Paoloni R, et al. Impaired dynamic morphology of cerebellar mitochondria in physiological aging and Alzheimer’s disease. Ann N Y Acad Sci, 1997, 826: 479–482 1:STN:280:DyaK2svntVeisw%3D%3D, 10.1111/j.1749-6632.1997.tb48508.x, 9329728

    Article  PubMed  CAS  Google Scholar 

  7. Kilburn K H, Warshaw R, Thornton J C. Formaldehyde impairs memory, equilibrium, and dexterity in histology technicians: Effects which persist for days after exposure. Arch Environ Health, 1987, 42: 117–120 1:CAS:528:DyaL2sXkvVeisL0%3D, 10.1080/00039896.1987.9935806, 3579365

    Article  PubMed  CAS  Google Scholar 

  8. Kilburn K H. Neurobehavioral impairment and seizures from formaldehyde. Arch Environ Health, 1994, 49: 37–44 1:STN:280:DyaK2c7mtFGqsw%3D%3D, 10.1080/00039896.1994.9934412, 8117145

    Article  PubMed  CAS  Google Scholar 

  9. Perna R B, Bordini E J, Deinzer-Lifrak M. A case of claimed persistent neuropsychological sequelae of chronic formaldehyde exposure: Clinical, psychometric, and functional findings. Arch Clin Neuropsychol, 2001, 16: 33–44 1:STN:280:DC%2BD3srhtlertw%3D%3D, 14590191

    Article  PubMed  CAS  Google Scholar 

  10. Miller J A. Formaldehyde stress response in Methylobacterium extorquens AM1. Ph.D. Thesis. Washington, USA: University of Washington, 2009. 10

    Google Scholar 

  11. Joseph M M, Norman W. The rapid activation of tyrosine hydroxylase by the subcutaneous injection of formaldehyde. Life Sci, 1981, 29: 2025–2029 10.1016/0024-3205(81)90435-5

    Article  Google Scholar 

  12. Bottiglionie, Sturani P L. Formaldehyde stress and experimental tuber culosis. II. Modifications of ground substance of the connective tissue in the skin, in the specific granuloma and in the kidneys. Arch Patol Clin Med, 1955, 32: 210–219

    Google Scholar 

  13. Pinto J P, Gladstone G R, Yung Y L. Photochemical production of formaldehyde in earth’s primitive atmosphere. Science, 1980, 210: 183–185 1:CAS:528:DyaL3cXmtFKqtLk%3D, 10.1126/science.210.4466.183, 17741284

    Article  PubMed  CAS  Google Scholar 

  14. Andres N, Lizcano J M, Rodriguez M J, et al. Tissue activity and cellular localization of human semicarbazide-sensitive amine oxidase. J Histochem Cytochem, 2001, 49: 209–217 1:CAS:528:DC%2BD3MXpsFGhtw%3D%3D, 11156689

    Article  PubMed  CAS  Google Scholar 

  15. Bell-Parikh L C, Guengerich F P. Kinetics of cytochrome P450 2E1-catalyzed oxidation of ethanol to acetic acid via acetaldehyde. J Biol Chem, 1999, 274: 23833–23840 1:CAS:528:DyaK1MXlsVOnsb0%3D, 10.1074/jbc.274.34.23833, 10446146

    Article  PubMed  CAS  Google Scholar 

  16. Binkova B, Sram R J. Lipid-peroxidation in biological-membranes. Chemicke Listy, 1989, 83: 1065–1084 1:CAS:528:DyaK3cXislSj

    CAS  Google Scholar 

  17. Iborra F J, Renau-Piqueras J, Portoles M, et al. Immunocytochemical and biochemical demonstration of formaldhyde dehydrogenase (class III alcohol dehydrogenase) in the nucleus. J Histochem Cytochem, 1992, 40: 1865–1878 1:CAS:528:DyaK3sXnslKhug%3D%3D, 1453005

    Article  PubMed  CAS  Google Scholar 

  18. Jelski W, Chrostek L, Szmitkowski M, et al. Activity of class I, II, III, and IV alcohol dehydrogenase isoenzymes in human gastric mucosa. Dig Dis Sci, 2002, 47: 1554–1557 1:CAS:528:DC%2BD38XkvVajs7w%3D, 10.1023/A:1015871219922, 12141816

    Article  PubMed  CAS  Google Scholar 

  19. Jelski W, Sani T A, Szmitkowski M. Class III alcohol dehydrogenase and its role in the human body. Postepy Hig Med Dosw (Online), 2006, 60: 406–409

    Google Scholar 

  20. Lambert C E, Shank R C. Role of formaldehyde hydrazone and catalase in hydrazine-induced methylation of DNA guanine. Carcinogenesis, 1988, 9: 65–70 1:CAS:528:DyaL1cXktVaiu7o%3D, 10.1093/carcin/9.1.65, 3335049

    Article  PubMed  CAS  Google Scholar 

  21. Binzak B A, Wevers R A, Moolenaar S H, et al. Cloning of dimethylglycine dehydrogenase and a new human inborn error of metabolism, dimethylglycine dehydrogenase deficiency. Am J Hum Genet, 2001, 68: 839–847 1:CAS:528:DC%2BD3MXkvFarsrs%3D, 10.1086/319520, 11231903

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  22. Hibi M, Sonoki T, Mori H. Functional coupling between vanillate-O-demethylase and formaldehyde detoxification pathway. Fems Microbiol Lett, 2005, 253: 237–242 1:CAS:528:DC%2BD2MXht1Gns7zE, 10.1016/j.femsle.2005.09.036, 16242864

    Article  PubMed  CAS  Google Scholar 

  23. Shi Y, Lan F, Matson C, et al. Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell, 2004, 119: 941–953 1:CAS:528:DC%2BD2MXltlSitg%3D%3D, 10.1016/j.cell.2004.12.012, 15620353

    Article  PubMed  CAS  Google Scholar 

  24. Stover P J, Chen L H, Suh J R, et al. Molecular cloning, characterization, and regulation of the human mitochondrial serine hydroxymethyltransferase gene. J Biol Chem, 1997, 272: 1842–1848 1:CAS:528:DyaK2sXls1ymtg%3D%3D, 10.1074/jbc.272.3.1842, 8999870

    Article  PubMed  CAS  Google Scholar 

  25. Teng S, Beard K, Pourahmad J, et al. The formaldehyde metabolic detoxification enzyme systems and molecular cytotoxic mechanism in isolated rat hepatocytes. Chem Biol Interact, 2001, 130–132: 285–296 10.1016/S0009-2797(00)00272-6, 11306052

    Article  PubMed  Google Scholar 

  26. Li F X, Lu J, Xu Y J, et al. Formaldehyde-mediated chronic damage may be related to sporadic neurodegeneration. Prog Biochem Biophys, 2008, 35: 393–400

    Google Scholar 

  27. Nie C L, Wei Y, Chen X Y, et al. Formaldehyde at low concentration induces protein Tau into globular amyloid-like aggregates in vitro and in vivo. PLoS ONE, 2007, 2: e629 10.1371/journal.pone.0000629, 17637844

    Article  PubMed  PubMed Central  Google Scholar 

  28. Nie C L, Zhang W, Zhang D, et al. Changes in conformation of human neuronal tau during denaturation in formaldehyde solution. Protein Pept Lett, 2005, 12: 75–78 1:CAS:528:DC%2BD2MXjvVOrsg%3D%3D, 10.2174/0929866053405931, 15638805

    Article  PubMed  CAS  Google Scholar 

  29. Nie C L, Wang X S, Liu Y, et al. Amyloid-like aggregates of neuronal tau induced by formaldehyde promote apoptosis of neuronal cells. BMC Neurosci, 2007, 8: 9 10.1186/1471-2202-8-9, 17241479

    Article  PubMed  PubMed Central  Google Scholar 

  30. Naqvi S H, Wang W S, Miao J Y, et al. Pore-like aggregates of Tau protein induced by formaldehyde (in press). Prog Biochem Biophys, 2010, 37: 1195–1203

    Article  CAS  Google Scholar 

  31. Klaassen C D. Casarett and Doull’s Toxicology: The Basic Science of Poisons. 6th ed. Beijing: People’s Medical Publishing House, 2002. 894–895

    Google Scholar 

  32. Sheng Z L, Qu M H, He H J, et al. Localization of Tau protein in SH-SY5Y, HeLa and HEK293 cells. Prog Biochem Biophys, 2008, 35: 1364–1370 1:CAS:528:DC%2BD1MXhsVWkurw%3D

    CAS  Google Scholar 

  33. Chen K, Maley J, Yu P H. Potential inplications of endogenous aldehydes in beta-amyloid misfolding, oligomerization and fibrillogenesis. J Neurochem, 2006, 99: 1413–1424 1:CAS:528:DC%2BD28XhtlCntrnM, 10.1111/j.1471-4159.2006.04181.x, 17074066

    Article  PubMed  CAS  Google Scholar 

  34. Mori K. Cellular response to endoplasmic reticulum stress mediated by unfolded protein response pathway. Tanpakushitsu Kakusan Koso, 1999, 44: 2442–2448 1:CAS:528:DyaK1MXnt1ensr8%3D, 10586697

    PubMed  CAS  Google Scholar 

  35. Tong Z Q, Zhang J L, Luo W H, et al. Urine formaldehyde level is inversely correlated to mini mental state examination scores in senile dementia. Neurobiol Aging, 2011, 32: 31–34 1:CAS:528:DC%2BC3cXhsVGrtL7O, 10.1016/j.neurobiolaging.2009.07.013, 19879019

    Article  PubMed  CAS  Google Scholar 

  36. Wang W S, HAO Z H, Zhang L, et al. Research on urine formaldehyde concentration in Alzheimer’s disease elderly and normal elderly. Chin J Geriatr Heart Brain Vessel Dis, 2010, 12: 721–722

    Google Scholar 

  37. Erkrath K D, Adebahr G, Kloppel A. Lethal intoxication by formalin during dialysis (author’s transl). Z Rechtsmed, 1981, 87: 233–236 1:STN:280:DyaL38%2Fkt1eisQ%3D%3D, 10.1007/BF00204769, 7293521

    Article  PubMed  CAS  Google Scholar 

  38. Gong Y, Chang L, Viola K L, et al. Alzheimer’s disease-affected brain: Presence of oligomeric A beta ligands (ADDLs) suggests a molecular basis for reversible memory loss. Proc Natl Acad Sci USA, 2003, 100: 10417–10422 1:CAS:528:DC%2BD3sXntFyns78%3D, 10.1073/pnas.1834302100, 12925731

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  39. Roberson E D, Scearce-Levie K, Palop J J, et al. Reducing endogenous tau ameliorates amyloid beta-induced deficits in an Alzheimer’s disease mouse model. Science, 2007, 316: 750–754 1:CAS:528:DC%2BD2sXkvVWrtrw%3D, 10.1126/science.1141736, 17478722

    Article  PubMed  CAS  Google Scholar 

  40. Urosevic N, Martins R N. Infection and Alzheimer’s disease: The APOE epsilon4 connection and lipid metabolism. J Alzheimers Dis, 2008, 13: 421–435 1:CAS:528:DC%2BD1cXlsFGis74%3D, 18487850

    PubMed  CAS  Google Scholar 

  41. Muller M, Cheung K H, Foskett J K. Enhanced ROS generation mediated by Alzheimer’s disease presenilin regulation of InsP3R Ca2+ signaling. Antioxid Redox Signal, 2010, doi:10.1089/ars.2010.3421

  42. Du H, Guo L, Yan S, et al. Early deficits in synaptic mitochondria in an Alzheimer’s disease mouse model. Proc Natl Acad Sci USA, 2010, 107: 18670–18675 1:CAS:528:DC%2BC3cXhtl2lsr7E, 10.1073/pnas.1006586107, 20937894

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  43. Feng Y, Zhang M, Hu M, et al. Disassembly intermediates of RbsD protein remain oligomeric despite the loss of an intact secondary structure. Sci China Ser C-Life Sci, 2009, 52: 997–1002 1:CAS:528:DC%2BD1MXhsVKntrbF, 10.1007/s11427-009-0141-1

    Article  CAS  Google Scholar 

  44. Jiao G H, Liu C W, Zhang T, et al. Lithium carbonate modulation of delayed rectifier potassium channel involves protein kinase C/mitogen-activated protein kinase signaling in hippocampus of rats. Prog Biochem Biophys, 2008, 35: 814–821 1:CAS:528:DC%2BD1cXhtFOntLjL

    CAS  Google Scholar 

  45. Lu J L, Chu J, Yang J, et al. Detection of β-secretase dimerization in living cells using acceptor photobleaching FRET. Prog Biochem Biophys, 2008, 35: 268–273 1:CAS:528:DC%2BD1cXmtlOitbg%3D

    CAS  Google Scholar 

  46. Zhang D L, Liang L Y, Ji T T, et al. Variation of monoamine neurotransmitter in forebrain of presenilin-1/presenilin-2 double knockout mice. Prog Biochem Biophys, 2009, 36: 1436–1441 1:CAS:528:DC%2BC3cXjtFCqu7k%3D, 10.3724/SP.J.1206.2009.00196

    Article  CAS  Google Scholar 

  47. Liu L, Zhang L, Mao X B, et al. Chaperon-mediated single molecular approach toward modulating A beta peptide aggregation. Nano Lett, 2009, 9: 4066–4072 1:CAS:528:DC%2BD1MXht12hsr3P, 10.1021/nl902256b, 19842691

    Article  PubMed  CAS  Google Scholar 

  48. Zhang Y W, Wangt R S, Liu Q, et al. Presenilin/gamma-secretase-dependent processing of beta-amyloid precursor protein regulates EGF receptor expression. Proc Natl Acad Sci USA, 2007, 104: 10613–10618 1:CAS:528:DC%2BD2sXnt1Oiu7c%3D, 10.1073/pnas.0703903104, 17556541

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  49. Wu W H, Lei P, Liu Q, et al. Sequestration of copper from beta-amyloid promotes selective lysis by cyclen-hybrid cleavage agents. J Biol Chem, 2008, 283: 31657–31664 1:CAS:528:DC%2BD1cXhtlCjsb3F, 10.1074/jbc.M804722200, 18728006

    Article  PubMed  CAS  Google Scholar 

  50. Shi Y G. Assembly and structure of protein phosphatase 2A. Sci China Ser C-Life Sci, 2009, 52: 135–146 1:CAS:528:DC%2BD1MXivVOmsbc%3D, 10.1007/s11427-009-0018-3

    Article  CAS  Google Scholar 

  51. Yang X, Yang Y, Luo Y, et al. Hyperphosphorylation and accumulation of neurofilament proteins in transgenic mice with Alzheimer presenilin 1 mutation. Cell Mol Neurobiol, 2009, 29: 497–501 1:CAS:528:DC%2BD1MXntVGns7k%3D, 10.1007/s10571-008-9341-7, 19137424

    Article  PubMed  CAS  Google Scholar 

  52. Qian W, Shi J, Yin X, et al. PP2A regulates tau phosphorylation directly and also indirectly via activating GSK-3beta. J Alzheimers Dis, 2010, 19: 1221–1229 1:CAS:528:DC%2BC3cXjslamtrY%3D, 20308788

    PubMed  CAS  Google Scholar 

  53. Luo J, Ma J, Yu D Y, et al. Infusion of FK506, a specific inhibitor of calcineurin, induces potent tau hyperphosphorylation in mouse brain. Brain Res Bull, 2008, 76: 464–468 1:CAS:528:DC%2BD1cXmvFersr0%3D, 10.1016/j.brainresbull.2007.12.005, 18534252

    Article  PubMed  CAS  Google Scholar 

  54. Yang J Y, Gu J L, Shi J H, et al. The inhibitory effect of OGT gene expression on the level of tau phosphorylation. Prog Biochem Biophys, 2009, 36: 346–352 1:CAS:528:DC%2BD1MXmtFart7o%3D, 10.3724/SP.J.1206.2008.00326

    Article  CAS  Google Scholar 

  55. Sheng Z L, Liu Y Y, Chen L, et al. Nonenzymatic glycation of α-synuclein and changes in its conformation. Prog Biochem Biophys, 2008, 35: 1202–1208 1:CAS:528:DC%2BD1cXhsFSmsrjI

    CAS  Google Scholar 

  56. Wei Y, Chen L, Chen J, et al. Rapid glycation with D-ribose induces globular amyloid-like aggregations of BSA with high cytotoxicity to SH-SY5Y cells. Bmc Cell Biol, 2009, 10: 10 10.1186/1471-2121-10-10, 19216769

    Article  PubMed  PubMed Central  Google Scholar 

  57. Chen L, Wei Y, Wang X Q, et al. d-Ribosylated Tau forms globular aggregates with high cytotoxicity. Cell Mol Life Sci, 2009, 66: 2559–2571 1:CAS:528:DC%2BD1MXos1egs7c%3D, 10.1007/s00018-009-0058-7, 19517062

    Article  PubMed  CAS  Google Scholar 

  58. Chen L, Wei Y, Wang X Q, et al. Ribosylation rapidly induces alpha-synuclein to form highly cytotoxic molten globules of advanced glycation end products. PLoS ONE, 2010, 5: e9052 10.1371/journal.pone.0009052, 20140223

    Article  PubMed  PubMed Central  Google Scholar 

  59. He R, Wang E D. The important role of three auxiliary factors of mammalian aminoacyl-tRNA synthetase complex in the cellular signaling network. Prog Biochem Biophys, 2009, 36: 398–402 1:CAS:528:DC%2BD1MXntlCgt78%3D

    Article  CAS  Google Scholar 

  60. Wang Y, Jia J. Association between promoter polymorphisms in anterior pharynx-defective-1a and sporadic Alzheimer’s disease in the North Chinese Han population. Neurosci Lett, 2009, 455: 101–104 1:CAS:528:DC%2BD1MXktFCksrc%3D, 10.1016/j.neulet.2009.02.015, 19368855

    Article  PubMed  CAS  Google Scholar 

  61. Yang M, Cai F, Pan Q, et al. Transcriptional regulation of the Alzheimer’s disease-related gene Nicastrin. Prog Biochem Biophys, 2009, 36: 994–1002 1:CAS:528:DC%2BD1MXhsFCrtbnP, 10.3724/SP.J.1206.2008.00860

    Article  CAS  Google Scholar 

  62. Zhao B L. Protective effects of green tea polyphenols against Parkinson’s disease. Prog Biochem Biophys, 2008, 35: 735–743 1:CAS:528:DC%2BD1cXhtFOntLvL

    CAS  Google Scholar 

  63. Tian L J, Du Y R, Xiao Y, et al. Mediating roles of the vanilloid receptor TRPV1 in activation of rat primary afferent nociceptive neurons by formaldehyde. Sheng Li Xue Bao, 2009, 61: 404–416 1:CAS:528:DC%2BC3cXjtFeqtrs%3D, 19847360

    PubMed  CAS  Google Scholar 

  64. Li X A, Zhang Y J, Chang M, et al. Dysfunction of proteasome and formation of Lewy body in sporadic Parkinson’s disease. Prog Biochem Biophys, 2008, 35: 502–511 1:CAS:528:DC%2BD1cXos1Sltbo%3D

    CAS  Google Scholar 

  65. Jiang Q, Lin L, Wang T H. A new model for apoptosis research: Yeast. Prog Biochem Biophys, 2008, 35: 361–367

    Google Scholar 

  66. Chen Y. Neuronal synaptic plasticity, learning and memory. Prog Biochem Biophys, 2008, 35: 610–619

    Google Scholar 

  67. Sun Y N, Luo J Y, Rao Z R, et al. GFAP and Fos immunoreactivity in lumbo-sacral spinal cord and medulla oblongata after chronic colonic inflammation in rats. World J Gastroenterol, 2005, 11: 4827–4832 1:CAS:528:DC%2BD2MXhtVOht7jM, 16097052

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  68. Hu J, Li G, Wang H, et al. Prevention of pathological change and cognitive degeneration of Tg2576 mice by inoculating Abeta(1–15) vaccine. Sci China Ser C-Life Sci, 2008, 51: 743–750 1:CAS:528:DC%2BD1cXhtFOisrvK, 10.1007/s11427-008-0094-9

    Article  CAS  Google Scholar 

  69. Yu C, Li G, Zhou L N, et al. Effect of deep brain stimulationon neural activity of subthalamic nucleus in rats. Prog Biochem Biophys, 2009, 36: 1049–1055 10.3724/SP.J.1206.2009.00001

    Article  Google Scholar 

  70. Bai F, Liao W, Watson D R, et al. Mapping the altered patterns of cerebellar resting-state function in longitudinal amnestic mild cognitive impairment patients. J Alzheimers Dis, 2010, doi: 10.3233/JAD-2010-101533

  71. Yu G, Jia J. Is there an association of regulatory region polymorphism in the alpha-1-antichymotrypsin gene with sporadic Alzheimer’s disease in the northern Han-Chinese population? J Clin Neurosci, 2010, 17: 766–769 1:CAS:528:DC%2BC3cXlsFaiuro%3D, 10.1016/j.jocn.2009.10.017, 20378355

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to RongQiao He.

Rights and permissions

Reprints and permissions

About this article

Cite this article

He, R., Lu, J. & Miao, J. Formaldehyde stress. Sci. China Life Sci. 53, 1399–1404 (2010). https://doi.org/10.1007/s11427-010-4112-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11427-010-4112-3

Keywords

Navigation