Ageing and Aneuploidy in Oocytes

  • U. Eichenlaub-Ritter
Part of the Ernst Schering Research Foundation Workshop book series (SCHERING FOUND, volume 41)


Correlations between maternal age and Down syndrome have been known already for over half a century (Penrose 1933; Bond and Chandley 1983). Still, the reasons for the dramatic increase in risks for a trisomic conceptus, spontaneous abortion associated with a chromosomally unbalanced embryo and the significantly reduced developmental potential of oocytes and embryos in aged women are unclear. Demographic analysis shows that there still is a trend for delaying childbearing to advanced maternal ages in many industrialized countries. Accordingly, it has been estimated that 25% of conceptions will involve women of 35 years or older in the Netherlands in 2005–2009 (te Velde and Pearson 2002). Many couples attending the infertility clinics are of advanced age. Therefore, it is important to investigate the origin of the maternal age-related decline in fertility associated with aneuploidy in oocytes in order to predict individual risks and, possibly, improve treatment. This contribution reviews briefly the current status of research on the incidence and the origin of aneuploidy in aged oocytes in humans and some experimental animals The observations suggest that prenatal events in oogenesis and recombination patterns influence susceptibility of chromosomes to errors in segregation, but that the depletion of the follicle pool, hormonal homeostasis, the oocyte-specific fragility of cohesion between homologues and permissive cell-cycle regulation at maturation may be important in the reduced quality of aged oocytes, which affects critically the fidelity of chromosome segregation and developmental potential.


Down Syndrome Sister Chromatid Polar Body Mouse Oocyte Human Oocyte 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Angell RR (1991) Predivision in human oocytes at meiosis I, a mechanism for trisomy formation in man. Hum Genet 86: 383–387PubMedCrossRefGoogle Scholar
  2. Angell R (1997) First-meiotic-division nondisjunction in human oocytes. Am J Hum Genet 61: 23–32PubMedCrossRefGoogle Scholar
  3. Battaglia DE, Goodwin P, Klein NA, et al (1996) Influence of maternal age on meiotic spindle assembly in oocytes from naturally cycling women. Mol Hum Reprod 11: 2217–2222CrossRefGoogle Scholar
  4. Benadiva CA, Kligman I, Munné S (1996) Aneuploidy 16 in human embryos increases significantly with maternal age. Fertil Steril 666: 248–255Google Scholar
  5. Benzaken B, Martin-Pont B, Bergere M, et al (1998) Chromosome 21 detection in human oocyte fluorescence in situ hybridization possible effect of maternal age. J Ass Reprod Genet 15: 105–110CrossRefGoogle Scholar
  6. Bhal PS, Pugh ND, Gregory L, et al (2001) Perifollicular vascularity as a potential variable affecting outcome in stimulated intrauterine insemination treatment cycles: a study using transvaginal power Doppler. Hum Reprod 16: 1682–1689PubMedCrossRefGoogle Scholar
  7. Bond DJ, Chandley AC (1983) Aneuploidy. Oxford monographs on medical genetics No. 11. Oxford University Press, OxfordGoogle Scholar
  8. Brook JD, Gosden RG, Chandley AC (1984) Maternal age and aneuploid embryos: evidence from the mouse that biological and not chronological age is the important influence. Hum Genet 6: 41–45CrossRefGoogle Scholar
  9. Brown AS, Feingold E, Broman KW, et al (2000) Genome-wide variation in recombination in female meiosis: a risk factor for non-disjunction of chromosome 21. Hum Mol Genet 9: 515–523PubMedCrossRefGoogle Scholar
  10. Brunet S, Maria AS, Guillaud P, et al (1999) Kinetochore fibers are not involved in the formation of the first meiotic spindle in mouse oocytes, but control the exit from the first meiotic M phase. J Cell Biol 146: 1–12PubMedCrossRefGoogle Scholar
  11. Buonomo SB, Clyne RK, Fuchs J et al (2000) Disjunction of homologous chromosomes in meiosis I depends on proteolytic cleavage of the meiotic cohesin Rec8 by separin. Cell 103: 387–398PubMedCrossRefGoogle Scholar
  12. Bugge M, Collins A, Peterson M, et al (1998) Non-disjunction of chromosome 18. Hum Mol Genet 7: 661–669PubMedCrossRefGoogle Scholar
  13. Caligara C, Navarro J, Vargas G et al (2001) The effect of repeated controlled ovarian stimulation in donors. Hum Reprod 16: 2320–2323PubMedCrossRefGoogle Scholar
  14. Carabatsos MJ, Sellitto C, Goodenough DA, et al (2000) Oocyte-granulosa cell heterologous gap junctions are required for the coordination of nuclear and cytoplasmic meiotic competence. Dev Biol 226: 167–179PubMedCrossRefGoogle Scholar
  15. Clyde JM, Gosden RG, Rutherford AJ, et al (2001) Demonstration of a mechanism of aneuploidy in human oocytes using Multifluor fluorescence in situ hybridization. Fertil Steril 76: 837–840PubMedCrossRefGoogle Scholar
  16. Coulam CB, Goodman C, Rinehart JS (1999) Colour Doppler indices of follicular blood flow as predictors of pregnancy after in-vitro fertilization and embryo transfer. Hum Reprod 14: 1979–1982PubMedCrossRefGoogle Scholar
  17. Crowley PH, Gulati DK, Hayden TL, et al (1979) A chiasma-hormonal hypothesis relating Down’s syndrome and maternal age. Nature 280: 417–418PubMedCrossRefGoogle Scholar
  18. Dailey T, Dale B, Cohen J, et al (1996) Association between nondisjunction and maternal age in meiosis-II human oocytes. Am J Hum Genet 59: 176–184PubMedGoogle Scholar
  19. De La Fuente R, Eppig JJ (2001) Transcriptional activity of the mouse oocyte genome: companion granulosa cells modulate transcription and chromatin remodeling. Dev Biol 229: 224–236CrossRefGoogle Scholar
  20. Delhanty JD, Harper JC, Ao A, et al (1997) Multicolour FISH detects frequent chromosomal mosaicism and chaotic division in normal preimplantation embryos from fertile patients. Hum Genet 99: 755–760PubMedCrossRefGoogle Scholar
  21. Eichenlaub-Ritter U (1996) Parental age-related aneuploidy in human germ cells and offspring: a story of past and present. Environ Mol Mutagen 28: 211–236PubMedCrossRefGoogle Scholar
  22. Eichenlaub-Ritter U (1998) Genetics of oocyte ageing. Maturitas 30: 143–169PubMedCrossRefGoogle Scholar
  23. Eichenlaub-Ritter U (2000) The determinants of non-disjunction and their possible relationship with oocyte ageing. In: te Velde ER, Pearson PL, Broekmans FJ (eds) Studies in profertility series 9: female reproductive aging. Parthenon, New York, pp 149–184Google Scholar
  24. Eichenlaub-Ritter U, Boll I (1989) Nocodazole sensitivity, age-related aneuploidy, and alterations in the cell cycle during maturation of mouse oocytes. Cytogenet Cell Genet 52: 170–176PubMedCrossRefGoogle Scholar
  25. Eichenlaub-Ritter U, Peschke M (2002) Expression in in vivo and in vitro growing and maturing oocytes: focus on regulation of expression at the translational level. Hum Reprod Update (in press)Google Scholar
  26. Eichenlaub-Ritter U, Chandley AC, Gosden RG (1988) The CBA mouse as a model for age-related aneuploidy in man: studies of oocyte maturation, spindle formation and chromosome alignment during meiosis. Chromosoma 96: 220–226PubMedCrossRefGoogle Scholar
  27. Fabricant JD, Schneider E (1978) Studies on the genetic and immunologic components of the maternal age effect. Dev Biol 66: 41–45CrossRefGoogle Scholar
  28. Faddy MJ (2000) Follicle dynamics during ovarian ageing. Mol Cell Endocrinol 163: 43–48PubMedCrossRefGoogle Scholar
  29. Freeman SB, Yang Q, Allran K (2000) Women with a reduced ovarian complement may have an increased risk for a child with Down syndrome. Am J Hum Genet 66: 1680–1683PubMedCrossRefGoogle Scholar
  30. Fritz B, Hallermann C, Olert J, et al (2001) Cytogenetic analyses of culture failures by comparative genomic hybridisation ( CGH)-Re-evaluation of chromosome aberration rates in early spontaneous abortions. Eur J Hum Genet 9: 539–547PubMedCrossRefGoogle Scholar
  31. Fulka J Jr, Jung T, Moor RM (1992) The fall of biological maturation promoting factor (MPF) and histone H1 kinase activity during anaphase and telophase in mouse oocytes. Mol Reprod Dev 32: 378–382PubMedCrossRefGoogle Scholar
  32. Gardner RD, Burke DJ (2000) The spindle checkpoint: two transitions, two pathways. Trends Cell Biol 10: 154–218PubMedCrossRefGoogle Scholar
  33. Gaulden ME (1992) Maternal age-effect: the enigma of Down syndrome and other trisomie conditions. Mutation Res 296: 69–88PubMedCrossRefGoogle Scholar
  34. Gianaroli L, Magli MC, Ferraretti AP, et al (1999) Preimplantation diagnosis for aneuploidies in patients undergoing in vitro fertilization with a poor prognosis: identification of the categories for which it should be proposed. Fertil Steril 72: 837–844PubMedCrossRefGoogle Scholar
  35. Gosden RG (1973) Chromosome anomalies of preimplantation mouse embryos in relation to maternal age. J Reprod Fertil 35: 351–354PubMedCrossRefGoogle Scholar
  36. Gras L, McBain J, Trounson A, et al (1992) The incidence of chromosomal aneuploidy in stimulated and unstimulated [natural] uninseminated human oocytes. Hum Reprod 7: 1396–1401PubMedGoogle Scholar
  37. Harrison RH, Kuo HC, Scriven PN (2000) Lack of cell cycle checkpoints in human cleavage stage embryos revealed by a clonal pattern of chromosomal mosaicism analysed by sequential multicolour FISH. Zygote 8: 217–224PubMedCrossRefGoogle Scholar
  38. Hassold TJ (1998) Nondisjunction in the human male. Curr Topics Dev Biol 37: 383–406CrossRefGoogle Scholar
  39. Hassold T, Hunt P (2001) To err (meiotically) is human: the genesis of human aneuploidy. Nat Rev Genet 2: 280–291PubMedCrossRefGoogle Scholar
  40. Hassold TJ, Sherman SL, Pettay D, et al (1991) XY chromosome nondisjunction in man is associated with diminished recombination in the pseudoautosomal region. Am J Hum Genet 49: 253–260PubMedGoogle Scholar
  41. Hassold TJ, Merrill M, Adkins K, et al (1995) Recombination and maternal age-related non-disjunction: molecular studies of trisomy 16. Am J Hum Genet 57: 867–874PubMedGoogle Scholar
  42. Hassold T, Sherman S, Hunt P (2000) Counting cross-overs: characterizing meiotic recombination in mammals. Hum Mol Genet 9: 2409–2419PubMedCrossRefGoogle Scholar
  43. Henderson SA, Edwards RG (1968) Chiasma frequency and maternal age in mammals. Nature 217: 22–28CrossRefGoogle Scholar
  44. Hodges CA, LeMaire-Adkins R, Hunt PA (2001) Coordinating the segregation of sister chromatids during the first meiotic division: evidence for sexual dimorphism. J Cell Sci 114: 2417–2426PubMedGoogle Scholar
  45. Iwarsson E, Lundqvist M, Inzunza J, et al (1999) A high degree of aneuploidy in frozen-thawed human preimplantation embryos. Hum Genet 104: 376–382PubMedCrossRefGoogle Scholar
  46. Jamieson ME, Coutts JR, Connor JM (1994) The chromosome constitution of human preimplantation embryos fertilized in vitro. Mol Hum Reprod 9: 709–715Google Scholar
  47. Keefe DL, Niven-Fairchild T, Powell S, et al (1995) Mitochondrial deoxyribonucleic acid deletions in oocytes and reproductive aging in women. Fertil Steril 64: 577–583PubMedGoogle Scholar
  48. Kline J, Kinney A, Levin B, et al (2000) Trisomic pregnancy and earlier age at menopause. Am J Hum Genet 67: 395–404PubMedCrossRefGoogle Scholar
  49. Koehler KE, Hawley RS, Sherman S, et al (1996) Recombination and nondisjunction in humans and flies. Hum Mol Genet 5: 1495–1504PubMedGoogle Scholar
  50. Lamb NE, Freeman SB, Savage-Austin A, et al (1996) Susceptible chiasmate configurations of chromosome 21 predispose to non-disjunction in both maternal meiosis I and meiosis II. Nat Genet 14: 400–405PubMedCrossRefGoogle Scholar
  51. Lamb NE, Feingold E, Savage A, et al (1997) Characterization of susceptible chiasma configurations that increase the risk for maternal nondisjunction of chromosome 21. Hum Mol Genet 6: 1391–1399PubMedCrossRefGoogle Scholar
  52. Ledan E, Polanski Z, Tenet ME (2001) Meiotic maturation of the mouse oocyte requires an equilibrium between cyclin B synthesis and degradation. Dev Biol 232: 400–413PubMedCrossRefGoogle Scholar
  53. Lee JY, Orr-Weaver TL (2001) The molecular basis of sister-chromatid cohesion. Annu Rev Cell Dev Biol 17: 753–777PubMedCrossRefGoogle Scholar
  54. LeMaire-Adkins E, Radke K, Hunt PA (1997) Lack of checkpoint control at the metaphase-anaphase transition: a mechanism of meiotic non-disjunction in mammalian females. J Cell Biol 139: 1611–1619PubMedCrossRefGoogle Scholar
  55. LeMaire-Adkins R, Hunt PA (2000) Nonrandom segregation of the mouse univalent X chromosome: evidence of spindle-mediated meiotic drive. Genetics 156: 775–783PubMedGoogle Scholar
  56. Libby BJ, De La Fuente R, O’Brien MJ, et al (2002) The mouse meiotic mutation mei 1 disrupts chromosome synapsis with sexually dimorphic consequences for meiotic progression. Dev Biol 242: 174–187PubMedCrossRefGoogle Scholar
  57. Lu Q, Dunn RL, Angeles R, et al (2002) Regulation of spindle formation by active mitogen-activated protein kinase and protein phosphatase 2 a during mouse oocyte meiosis. Biol Reprod 66: 29–37PubMedCrossRefGoogle Scholar
  58. MacDonald M, Hassold TJ, Harvey J (1994) The origin of 47,XXY and 47,XXX aneuploidy: heterogeneous mechanisms and role of aberrant recombination. Hum Mol Genet 3: 1365–1371PubMedCrossRefGoogle Scholar
  59. Mahmood R, Brierley CH, Faed MJ, et al (2000) Mechanisms of maternal aneuploidy: FISH analysis of oocytes and polar bodies in patients undergoing assisted conception. Hum Genet 106: 620–626PubMedCrossRefGoogle Scholar
  60. Mailhes JB, Young D, London SN (1998) Postovulatory ageing of mouse oocytes in vivo and premature centromere separation and aneuploidy. Biol Re-prod 58: 1206–1210CrossRefGoogle Scholar
  61. Marquez C, Cohen J, Munné S (1998) Chromosome identification in human oocytes and polar bodies by spectral karyotyping. Cytogenet Cell Genet 81: 254–258PubMedCrossRefGoogle Scholar
  62. Marquez C, Sandalinas M, Bahçe M, et al (2000) Chromosome abnormalities in 1255 cleavage-stage human embryos. Reprod Biomed Online 1: 17–27PubMedCrossRefGoogle Scholar
  63. Martini E, Flaherty SP, Swann NJ (2000) FISH analysis of six chromosomes in unfertilized human oocytes after polar body removal. J Assist Reprod Genet 17: 276–283PubMedCrossRefGoogle Scholar
  64. Mitra J, Schultz RM (1996) Regulation of the acquisition of meiotic competence in the mouse: changes in the subcellular localization of cdc2, cyclin B1, cdc25 C and weel, and in the concentration of these proteins and their transcripts. J Cell Sci 109: 2407–2415PubMedGoogle Scholar
  65. Muller-Hocker J, Schafer S, Weis S, et al (1996) Morphological-cytochemical and molecular genetic analyses of mitochondria in isolated human oocytes in the reproductive age. Mol Hum Reprod 2: 951–958PubMedCrossRefGoogle Scholar
  66. Munné S, Cohen J (1998) Chromosome abnormalities in human embryos. Hum Reprod Update 4: 842–855PubMedCrossRefGoogle Scholar
  67. Nakaoka Y, Okamoto E, Miharu N. et al (1998) Chromosome analysis in human oocytes remaining unfertilized after in-vitro insemination: effect of maternal age and fertilization rate. Hum Reprod 13: 419–424PubMedCrossRefGoogle Scholar
  68. Nasmyth K (2001) Disseminating the genome: joining, resolving, and separating sister chromatids during mitosis and meiosis. Annu Rev Genet 35: 673–745PubMedCrossRefGoogle Scholar
  69. Nicklas RB, Waters JC, Salmon ED, et al (2001) Checkpoint signals in grasshopper meiosis are sensitive to microtubule attachment, but tension is still essential. J Cell Sci 114: 4173–4183PubMedGoogle Scholar
  70. Parisi S, McKay MJ, Molnar M, et al (1999) Recap, a meiotic recombination and sister chromatid cohesion phosphoprotein of the Rad2lp family is conserved from fission yeast to humans. Mol Cell Biol 19: 3515–3528PubMedGoogle Scholar
  71. Penrose LS (1933) The relative effects of paternal and maternal age in mongolism. J Genet 27: 219–224CrossRefGoogle Scholar
  72. Plachot M (2001) Chromosomal abnormalities in oocytes. Mol Cell Endocrinol 183 (Suppl 1): S59–S63PubMedCrossRefGoogle Scholar
  73. Polani PE, Crolla JA (1981) A test of the production line hypothesis of mammalian oogenesis. Hum Genet 88: 64–70CrossRefGoogle Scholar
  74. Rieder CL, Schultz A, Cole R, et al (1994) Anaphase onset in vertebrate somatic cells is controlled by a checkpoint that monitors sister kinetochore attachment to the spindle. J Cell Biol 127: 1301–1310PubMedCrossRefGoogle Scholar
  75. Robinson WP, Kuchinka, B., Bernasconi F, et al (1998) Maternal meiosis I non-disjunction of chromosome 15: dependence of the maternal age effect on level of recombination. Hum Mol Genet 7: 1011–1019PubMedCrossRefGoogle Scholar
  76. Roeder GS, Bailis JM (2000) The pachytene checkpoint. Trends Genet 16: 395–403PubMedCrossRefGoogle Scholar
  77. Sakurada K, Ishikawa H, Endo A (1996) Cytogenetic effects of advanced maternal age and delayed fertilization on first-cleavage mouse embryos. Cytogenet Cell Genet 72: 46–49PubMedCrossRefGoogle Scholar
  78. Schon EA, Kim SH, Ferreira JC, et al (2000) Chromosomal non-disjunction in human oocytes: is there a mitochondrial connection? Hum Reprod 15 (Suppl 2): 160–172PubMedCrossRefGoogle Scholar
  79. Sears DD, Hegemann JH, Hieter P (1992) Meiotic recombination and segregation of human-derived artificial chromosomes in Saccharomyces cerevisiae. Proc Natl Acad Sci USA 89: 5296–5300PubMedCrossRefGoogle Scholar
  80. Shonn MA, McCarroll R, Murray AW (2000) Requirement of the spindle checkpoint for proper chromosome segregation in budding yeast meiosis. Science 289: 300–303PubMedCrossRefGoogle Scholar
  81. Soewarto D, Schmiady H, Eichenlaub-Ritter U (1995) Consequences of non-extrusion of the first polar body and control of the sequential segregation of homologues and chromatids in mammalian oocytes. Hum Reprod 10: 2350–2360PubMedGoogle Scholar
  82. Steuerwald N, Cohen J, Herrera RJ, et al (2001) Association between spindle assembly checkpoint expression and maternal age in human oocytes. Mol Hum Reprod 7: 49–55PubMedCrossRefGoogle Scholar
  83. Sudakin V, Chan GK, Yen TJ (2001) Checkpoint inhibition of the APC/C in HeLa cells is mediated by a complex of BUBR1, BUB3, CDC20, and MAD2. J Cell Biol 154: 925–936PubMedCrossRefGoogle Scholar
  84. Sugawara S, Mikamo K (1983) Absence of correlation between univalent formation and meiotic nondisjunction in aged female Chinese hamsters. Cytogenet Cell Genet 35: 34–40PubMedCrossRefGoogle Scholar
  85. Sun F, Yin H, Eichenlaub-Ritter U (2001) Differential chromosome behaviour in mammalian oocytes exposed to the tranquilizer diazepam in vitro. Mutagenesis 16: 407–417PubMedCrossRefGoogle Scholar
  86. Tarin JJ (1996) Potential effects of age-associated oxidative stress on mammalian oocytes/embryos. Mol Hum Reprod 2: 717–724PubMedCrossRefGoogle Scholar
  87. Tay J, Richter JD (2001) Germ cell differentiation and synaptonemal complex formation are disrupted in CPEB knockout mice. Dev Cell 1: 201–213PubMedCrossRefGoogle Scholar
  88. Velde E, Pearson P (2002) The variability of female reproductive ageing. Hum Reprod Update 8: 141–154CrossRefGoogle Scholar
  89. Toth A, Rabitsch KP, Galova M (2000) Functional genomics identifies monopolin: a kinetochore protein required for segregation of homologs during meiosis I. Cell 103: 1155–1168PubMedCrossRefGoogle Scholar
  90. Blerkom J (2000) Intrafollicular influences on human oocyte developmental competence: perifollicular vascularity, oocyte metabolism and mitochondrial function. Hum Reprod 15 (Suppl 2): 173–188PubMedCrossRefGoogle Scholar
  91. Blerkom J, Davis P (2001) Differential effects of repeated ovarian stimulation on cytoplasmic and spindle organization in metaphase II mouse oocytes matured in vivo and in vitro. Mol Hum Reprod 16: 757–764CrossRefGoogle Scholar
  92. Vaskivuo TE, Anttonen M, Herva R, et al (2001) Survival of human ovarian follicles from fetal to adult life: apoptosis, apoptosis-related proteins, and transcription factor GATA-4.Clin Endocrinol Metab 86: 3421–3429.Google Scholar
  93. Verlhac MH, Kubiak J, Clarke HJ, et al (1994) Microtubule and chromatin behaviour follow MAP kinase activity but not MPF during meiosis in mouse oocytes. Development 120: 1017–1025PubMedGoogle Scholar
  94. Verlinsky Y, Cieslak J, Ivakhnenko V, et al (2001) Chromosomal abnormalities in the first and second polar body. Mol Cell Endocrinol 183 (Suppl 1): S47–S49PubMedCrossRefGoogle Scholar
  95. Volarcik K, Sheean L, Goldfarb J, et al (1998) The meiotic competence of human oocytes is influenced by donor age: evidence that folliculogenesis is compromised in the reproductively aged ovary. Hum Reprod 13: 154–160PubMedCrossRefGoogle Scholar
  96. Warburton D, Kinney A (1996) Chromosomal differences in suceptibility to meiotic aneuploidy. Environ Mol Mutagen 28: 237–247PubMedCrossRefGoogle Scholar
  97. Wells D, Delhanty JD (2000) Comprehensive chromosomal analysis of human preimplantation embryos using whole genome amplification and single cell comparative genomic hybridization. Mol Hum Reprod 6: 1055–1062PubMedCrossRefGoogle Scholar
  98. Wilding M, Dale B, Marino M, et al (2001) Mitochondrial aggregation patterns and activity in human oocytes and preimplantation embryos. Hum Re-prod 16: 909–917CrossRefGoogle Scholar
  99. Wolstenholme J, Angell RR (2000) Maternal age and trisomy — a unifying mechanism of formation. Chromosoma 109: 435–438PubMedCrossRefGoogle Scholar
  100. Woods LM, Hodges CA, Baart E, et al (1999) Chromosomal influence on meiotic spindle assembly: abnormal meiosis I in female Mlhl mutant mice. J Cell Biol 145: 1395–1406PubMedCrossRefGoogle Scholar
  101. Wu J, Zhang L, Wang X (2000) Maturation and apoptosis of human oocytes in vitro are age-related. Fertil Steril 74: 1137–1141PubMedCrossRefGoogle Scholar
  102. Zuccotti M, Boiani M, Garagna S (1998) Analysis of aneuploidy rate in antral and ovulated mouse oocytes during female aging. Mol Reprod Dev 50: 305–331PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2002

Authors and Affiliations

  • U. Eichenlaub-Ritter

There are no affiliations available

Personalised recommendations