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Volumn 30, Issue 6, 2009, Pages 1197-1202

Protective effect of S14G-humanin against beta-amyloid induced LTP inhibition in mouse hippocampal slices

Author keywords

[No Author keywords available]

Indexed keywords

AMYLOID BETA PROTEIN[25-35]; HUMANIN; S14G HUMANIN; UNCLASSIFIED DRUG;

EID: 67349199177     PISSN: 01969781     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.peptides.2009.02.017     Document Type: Article
Times cited : (22)

References (44)
  • 1
    • 54849164100 scopus 로고    scopus 로고
    • A rescue factor for Alzheimer's diseases: discovery, activity, structure, and mechanism
    • Arakawa T., Kita Y., and Niikura T. A rescue factor for Alzheimer's diseases: discovery, activity, structure, and mechanism. Curr Med Chem 15 (2008) 2086-2098
    • (2008) Curr Med Chem , vol.15 , pp. 2086-2098
    • Arakawa, T.1    Kita, Y.2    Niikura, T.3
  • 4
    • 0034069795 scopus 로고    scopus 로고
    • Impairment of hippocampal long-term potentiation by Alzheimer amyloid β-peptides
    • Chen Q.S., Kagan B.L., Hirakura Y., and Xie C.W. Impairment of hippocampal long-term potentiation by Alzheimer amyloid β-peptides. J Neurosci Res 60 (2000) 65-72
    • (2000) J Neurosci Res , vol.60 , pp. 65-72
    • Chen, Q.S.1    Kagan, B.L.2    Hirakura, Y.3    Xie, C.W.4
  • 5
    • 0036354603 scopus 로고    scopus 로고
    • Alzheimer amyloid beta-peptide inhibits the late phase of long-term potentiation through calcineurin-dependent mechanisms in the hippocampal dentate gyrus
    • Chen Q.S., Wei W.Z., Shimahara T., and Xie C.W. Alzheimer amyloid beta-peptide inhibits the late phase of long-term potentiation through calcineurin-dependent mechanisms in the hippocampal dentate gyrus. Neurobiol Learn Mem 77 (2002) 354-371
    • (2002) Neurobiol Learn Mem , vol.77 , pp. 354-371
    • Chen, Q.S.1    Wei, W.Z.2    Shimahara, T.3    Xie, C.W.4
  • 6
    • 0345276572 scopus 로고    scopus 로고
    • Synaptic slaughter in Alzheimer's disease
    • Coleman P.D., and Yao P.J. Synaptic slaughter in Alzheimer's disease. Neurobiol Aging 24 (2003) 1023-1027
    • (2003) Neurobiol Aging , vol.24 , pp. 1023-1027
    • Coleman, P.D.1    Yao, P.J.2
  • 7
    • 0037603598 scopus 로고    scopus 로고
    • A beta 25-35-induced depression of long-term potentiation in area CA1 in vivo and in vitro is attenuated by verapamil
    • Freir D.B., Costello D.A., and Herron C.E. A beta 25-35-induced depression of long-term potentiation in area CA1 in vivo and in vitro is attenuated by verapamil. J Neurophysiol 89 (2003) 3061-3069
    • (2003) J Neurophysiol , vol.89 , pp. 3061-3069
    • Freir, D.B.1    Costello, D.A.2    Herron, C.E.3
  • 8
    • 0035128734 scopus 로고    scopus 로고
    • Blockade of long-term potentiation by beta-amyloid peptides in the CA1 region of the rat hippocampus in vivo
    • Freir D.B., Holscher C., and Herron C.E. Blockade of long-term potentiation by beta-amyloid peptides in the CA1 region of the rat hippocampus in vivo. J Neurophysiol 85 (2001) 708-713
    • (2001) J Neurophysiol , vol.85 , pp. 708-713
    • Freir, D.B.1    Holscher, C.2    Herron, C.E.3
  • 9
    • 0025899041 scopus 로고
    • Amyloid deposition as the central event in the aetiology of Alzheimer's disease
    • Hardy J., and Allsop D. Amyloid deposition as the central event in the aetiology of Alzheimer's disease. Trends Pharmacol Sci 12 (1991) 383-388
    • (1991) Trends Pharmacol Sci , vol.12 , pp. 383-388
    • Hardy, J.1    Allsop, D.2
  • 10
    • 0037135111 scopus 로고    scopus 로고
    • The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics
    • Hardy J., and Selkoe D.J. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 297 (2002) 353-356
    • (2002) Science , vol.297 , pp. 353-356
    • Hardy, J.1    Selkoe, D.J.2
  • 11
    • 0033570337 scopus 로고    scopus 로고
    • Protofibrillar intermediates of amyloid beta-protein induce acute electrophysiological changes and progressive neurotoxicity in cortical neurons
    • Hartley D.M., Walsh D.M., Ye C.P., Diehl T., Vasquez S., Vassilev P.M., et al. Protofibrillar intermediates of amyloid beta-protein induce acute electrophysiological changes and progressive neurotoxicity in cortical neurons. J Neurosci 19 (1999) 8876-8884
    • (1999) J Neurosci , vol.19 , pp. 8876-8884
    • Hartley, D.M.1    Walsh, D.M.2    Ye, C.P.3    Diehl, T.4    Vasquez, S.5    Vassilev, P.M.6
  • 12
    • 0034805623 scopus 로고    scopus 로고
    • Mechanisms of neuroprotection by a novel rescue factor humanin from Swedish mutant amyloid precursor protein
    • Hashimoto Y., Ito Y., Niikura T., Shao Z., Hata M., Oyama F., et al. Mechanisms of neuroprotection by a novel rescue factor humanin from Swedish mutant amyloid precursor protein. Biochem Biophys Res Commun 283 (2001) 460-468
    • (2001) Biochem Biophys Res Commun , vol.283 , pp. 460-468
    • Hashimoto, Y.1    Ito, Y.2    Niikura, T.3    Shao, Z.4    Hata, M.5    Oyama, F.6
  • 13
    • 4243333514 scopus 로고    scopus 로고
    • A rescue factor abolishing neuronal cell death by a wide spectrum of familial Alzheimer's disease genes and Abeta
    • Hashimoto Y., Niikura T., Tajima H., Yasukawa T., Sudo H., Ito Y., et al. A rescue factor abolishing neuronal cell death by a wide spectrum of familial Alzheimer's disease genes and Abeta. Proc Natl Acad Sci USA 98 (2001) 6336-6341
    • (2001) Proc Natl Acad Sci USA , vol.98 , pp. 6336-6341
    • Hashimoto, Y.1    Niikura, T.2    Tajima, H.3    Yasukawa, T.4    Sudo, H.5    Ito, Y.6
  • 14
    • 0032754051 scopus 로고    scopus 로고
    • Impairments of long-term potentiation in hippocampal slices of beta-amyloid-infused rats
    • Itoh A., Akaike T., Sokabe M., Nitta A., Iida R., Olariu A., et al. Impairments of long-term potentiation in hippocampal slices of beta-amyloid-infused rats. Eur J Pharmacol 382 (1999) 167-175
    • (1999) Eur J Pharmacol , vol.382 , pp. 167-175
    • Itoh, A.1    Akaike, T.2    Sokabe, M.3    Nitta, A.4    Iida, R.5    Olariu, A.6
  • 15
    • 25844477102 scopus 로고    scopus 로고
    • Current concepts in therapeutic strategies targeting cognitive decline and disease modification in Alzheimer's disease
    • Jacobsen J.S., Reinhart P., and Pangalos M.N. Current concepts in therapeutic strategies targeting cognitive decline and disease modification in Alzheimer's disease. NeuroRx 2 (2005) 612-626
    • (2005) NeuroRx , vol.2 , pp. 612-626
    • Jacobsen, J.S.1    Reinhart, P.2    Pangalos, M.N.3
  • 16
    • 0029794770 scopus 로고    scopus 로고
    • A requirement of local protein synthesis in neurotrophin-induced hippocampal synaptic plasticity
    • Kang H., and Schuman E.R. A requirement of local protein synthesis in neurotrophin-induced hippocampal synaptic plasticity. Science 273 (1996) 1042-1046
    • (1996) Science , vol.273 , pp. 1042-1046
    • Kang, H.1    Schuman, E.R.2
  • 17
    • 0242668337 scopus 로고    scopus 로고
    • Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis
    • Kayed R., Head E., Thompson J.L., McIntire T.M., Milton S.C., Cotman C.W., et al. Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis. Science 300 (2003) 486-489
    • (2003) Science , vol.300 , pp. 486-489
    • Kayed, R.1    Head, E.2    Thompson, J.L.3    McIntire, T.M.4    Milton, S.C.5    Cotman, C.W.6
  • 18
    • 6944252056 scopus 로고    scopus 로고
    • Effect of humanin analogues on experimentally induced impairment of spatial memory in rats
    • Krejcova G., Patocka J., and Slaninova J. Effect of humanin analogues on experimentally induced impairment of spatial memory in rats. J Pept Sci 10 (2004) 636-639
    • (2004) J Pept Sci , vol.10 , pp. 636-639
    • Krejcova, G.1    Patocka, J.2    Slaninova, J.3
  • 19
    • 54149087626 scopus 로고    scopus 로고
    • The multiple T-maze in vivo testing of the neuroprotective effect of humanin analogues
    • Kunesová G., Hlavácek J., Patocka J., Evangelou A., Zikos C., Benaki D., et al. The multiple T-maze in vivo testing of the neuroprotective effect of humanin analogues. Peptides 29 (2008) 1982-1987
    • (2008) Peptides , vol.29 , pp. 1982-1987
    • Kunesová, G.1    Hlavácek, J.2    Patocka, J.3    Evangelou, A.4    Zikos, C.5    Benaki, D.6
  • 20
    • 45049087835 scopus 로고    scopus 로고
    • A transgenic rat that develops Alzheimer's disease-like amyloid pathology, deficits in synaptic plasticity and cognitive impairment
    • Liu L., Orozco I.J., Planel E., Wen Y., Bretteville A., Krishnamurthy P., et al. A transgenic rat that develops Alzheimer's disease-like amyloid pathology, deficits in synaptic plasticity and cognitive impairment. Neurobiol Dis 31 (2008) 46-57
    • (2008) Neurobiol Dis , vol.31 , pp. 46-57
    • Liu, L.1    Orozco, I.J.2    Planel, E.3    Wen, Y.4    Bretteville, A.5    Krishnamurthy, P.6
  • 21
    • 0037101970 scopus 로고    scopus 로고
    • Function and regulation of CREB family transcription factors in the nervous system
    • Lonze B.E., and Ginty D.D. Function and regulation of CREB family transcription factors in the nervous system. Neuron 35 (2002) 605-623
    • (2002) Neuron , vol.35 , pp. 605-623
    • Lonze, B.E.1    Ginty, D.D.2
  • 22
    • 0033493229 scopus 로고    scopus 로고
    • Nitric oxide signaling contributes to late-phase LTP and CREB phosphorylation in the Hippocampus
    • Lu Y., Kandel E.R., and Hawkins R.D. Nitric oxide signaling contributes to late-phase LTP and CREB phosphorylation in the Hippocampus. J Neurosci 19 (1999) 10250-10261
    • (1999) J Neurosci , vol.19 , pp. 10250-10261
    • Lu, Y.1    Kandel, E.R.2    Hawkins, R.D.3
  • 23
    • 0035678839 scopus 로고    scopus 로고
    • [Gly(14)]-Humanin improved the learning and memory impairment induced by scopolamine in vivo
    • Mamiya T., and Ukai M. [Gly(14)]-Humanin improved the learning and memory impairment induced by scopolamine in vivo. Br J Pharmacol 134 (2001) 1597-1599
    • (2001) Br J Pharmacol , vol.134 , pp. 1597-1599
    • Mamiya, T.1    Ukai, M.2
  • 24
    • 56349147722 scopus 로고    scopus 로고
    • S14G-humanin ameliorates Abeta25-35-induced behavioral deficits by reducing neuroinflammatory responses and apoptosis in mice
    • Miao J., Zhang W., Yin R., Liu R., Su C., Lei G., et al. S14G-humanin ameliorates Abeta25-35-induced behavioral deficits by reducing neuroinflammatory responses and apoptosis in mice. Neuropeptides 42 (2008) 557-567
    • (2008) Neuropeptides , vol.42 , pp. 557-567
    • Miao, J.1    Zhang, W.2    Yin, R.3    Liu, R.4    Su, C.5    Lei, G.6
  • 25
    • 34249069455 scopus 로고    scopus 로고
    • Amyloid, memory and neurogenesis
    • Morgan D. Amyloid, memory and neurogenesis. Exp Neurol 205 (2007) 330-335
    • (2007) Exp Neurol , vol.205 , pp. 330-335
    • Morgan, D.1
  • 26
    • 0032728994 scopus 로고    scopus 로고
    • A new planar multielectrode array for extracellular recording: application to hippocampal acute slice
    • Oka H., Shimono K., Ogawa R., Sugihara H., and Taketani M. A new planar multielectrode array for extracellular recording: application to hippocampal acute slice. J Neurosci Methods 93 (1999) 61-67
    • (1999) J Neurosci Methods , vol.93 , pp. 61-67
    • Oka, H.1    Shimono, K.2    Ogawa, R.3    Sugihara, H.4    Taketani, M.5
  • 27
    • 0032945724 scopus 로고    scopus 로고
    • Synaptic transmission and hippocampal long-term potentiation in transgenic mice expressing FAD-linked presenilin 1
    • Parent A., Linden D.J., Sisodia S.S., and Borchelt D.R. Synaptic transmission and hippocampal long-term potentiation in transgenic mice expressing FAD-linked presenilin 1. Neurobiol Dis 6 (1999) 56-62
    • (1999) Neurobiol Dis , vol.6 , pp. 56-62
    • Parent, A.1    Linden, D.J.2    Sisodia, S.S.3    Borchelt, D.R.4
  • 28
    • 0344464937 scopus 로고    scopus 로고
    • GABAB receptor- and metabotropic glutamate receptor-dependent cooperative long-term potentiation of rat hippocampal GABAA synaptic transmission
    • Patenaude C., Chapman C.A., Bertrand S., Congar P., and Lacaille J.C. GABAB receptor- and metabotropic glutamate receptor-dependent cooperative long-term potentiation of rat hippocampal GABAA synaptic transmission. J Physiol 553 (2003) 155-167
    • (2003) J Physiol , vol.553 , pp. 155-167
    • Patenaude, C.1    Chapman, C.A.2    Bertrand, S.3    Congar, P.4    Lacaille, J.C.5
  • 29
    • 22544485048 scopus 로고    scopus 로고
    • Amyloid-beta peptide inhibits activation of the nitric oxide/cGMP/cAMP-responsive element-binding protein pathway during hippocampal synaptic plasticity
    • Puzzo D., Vitolo O., Trinchese F., Jacob J.P., Palmeri A., and Arancio O. Amyloid-beta peptide inhibits activation of the nitric oxide/cGMP/cAMP-responsive element-binding protein pathway during hippocampal synaptic plasticity. J Neurosci 25 (2005) 6887-6897
    • (2005) J Neurosci , vol.25 , pp. 6887-6897
    • Puzzo, D.1    Vitolo, O.2    Trinchese, F.3    Jacob, J.P.4    Palmeri, A.5    Arancio, O.6
  • 30
    • 36749014118 scopus 로고    scopus 로고
    • Synaptic memory mechanisms: Alzheimer's disease amyloid beta-peptide-induced dysfunction
    • Rowan M.J., Klyubin I., Wang Q., Hu N.W., and Anwyl R. Synaptic memory mechanisms: Alzheimer's disease amyloid beta-peptide-induced dysfunction. Biochem Soc Trans 35 (2007) 1219-1223
    • (2007) Biochem Soc Trans , vol.35 , pp. 1219-1223
    • Rowan, M.J.1    Klyubin, I.2    Wang, Q.3    Hu, N.W.4    Anwyl, R.5
  • 31
    • 0037174618 scopus 로고    scopus 로고
    • Alzheimer's disease is a synaptic failure
    • Selkoe D.J. Alzheimer's disease is a synaptic failure. Science 298 (2002) 789-791
    • (2002) Science , vol.298 , pp. 789-791
    • Selkoe, D.J.1
  • 32
    • 0035433962 scopus 로고    scopus 로고
    • Alzheimer's disease and Abeta toxicity: from top to bottom
    • Small D.H., Mok S.S., and Bornstein J.C. Alzheimer's disease and Abeta toxicity: from top to bottom. Nat Rev Neurosci 2 (2001) 595-598
    • (2001) Nat Rev Neurosci , vol.2 , pp. 595-598
    • Small, D.H.1    Mok, S.S.2    Bornstein, J.C.3
  • 33
    • 20144387217 scopus 로고    scopus 로고
    • A humanin derivative, S14G-HN, prevents amyloid-beta-induced memory impairment in mice
    • Tajima H., Kawasumi M., Chiba T., Yamada M., Yamashita K., Nawa M., et al. A humanin derivative, S14G-HN, prevents amyloid-beta-induced memory impairment in mice. J Neurosci Res 79 (2005) 714-723
    • (2005) J Neurosci Res , vol.79 , pp. 714-723
    • Tajima, H.1    Kawasumi, M.2    Chiba, T.3    Yamada, M.4    Yamashita, K.5    Nawa, M.6
  • 34
    • 34547824397 scopus 로고    scopus 로고
    • EGb 761 enhances adult hippocampal neurogenesis and phosphorylation of CREB in transgenic mouse model of Alzheimer's disease
    • Tchantchou F., Xu Y., Wu Y., Christen Y., and Luo Y. EGb 761 enhances adult hippocampal neurogenesis and phosphorylation of CREB in transgenic mouse model of Alzheimer's disease. FASEB J 21 (2007) 2400-2408
    • (2007) FASEB J , vol.21 , pp. 2400-2408
    • Tchantchou, F.1    Xu, Y.2    Wu, Y.3    Christen, Y.4    Luo, Y.5
  • 35
    • 0035907325 scopus 로고    scopus 로고
    • Beta-amyloid-(1-42) impairs activity-dependent cAMP-response element-binding protein signaling in neurons at concentrations in which cell survival is not compromised
    • Tong L., Thornton P.L., Balazs R., and Cotman C.W. Beta-amyloid-(1-42) impairs activity-dependent cAMP-response element-binding protein signaling in neurons at concentrations in which cell survival is not compromised. J Biol Chem 276 (2001) 17301-17306
    • (2001) J Biol Chem , vol.276 , pp. 17301-17306
    • Tong, L.1    Thornton, P.L.2    Balazs, R.3    Cotman, C.W.4
  • 36
    • 2542584749 scopus 로고    scopus 로고
    • Progressive age-related development of Alzheimer-like pathology in APP/PS1 mice
    • Trinchese F., Liu S., Battaglia F., Walter S., Mathews P.M., and Arancio O. Progressive age-related development of Alzheimer-like pathology in APP/PS1 mice. Ann Neurol 55 (2004) 801-814
    • (2004) Ann Neurol , vol.55 , pp. 801-814
    • Trinchese, F.1    Liu, S.2    Battaglia, F.3    Walter, S.4    Mathews, P.M.5    Arancio, O.6
  • 37
    • 57749117451 scopus 로고    scopus 로고
    • Protection against beta-amyloid induced abnormal synaptic function and cell death by Ginkgolide
    • Vitolo O., Gong B., Cao Z., Ishii H., Jaracz S., Nakanishi K., et al. Protection against beta-amyloid induced abnormal synaptic function and cell death by Ginkgolide. J Neurobiol Aging 30 (2009) 257-265
    • (2009) J Neurobiol Aging , vol.30 , pp. 257-265
    • Vitolo, O.1    Gong, B.2    Cao, Z.3    Ishii, H.4    Jaracz, S.5    Nakanishi, K.6
  • 38
    • 0036792096 scopus 로고    scopus 로고
    • Amyloid peptide inhibition of the PKA/CREB pathway and long-term potentiation: reversibility by drugs that enhance cAMP signalling
    • Vitolo O.V., Sant'Angelo A., Costanzo V., Battaglia F., Arancio O., and Shelanski M. Amyloid peptide inhibition of the PKA/CREB pathway and long-term potentiation: reversibility by drugs that enhance cAMP signalling. Proc Natl Acad Sci USA 99 (2002) 13217-13221
    • (2002) Proc Natl Acad Sci USA , vol.99 , pp. 13217-13221
    • Vitolo, O.V.1    Sant'Angelo, A.2    Costanzo, V.3    Battaglia, F.4    Arancio, O.5    Shelanski, M.6
  • 39
    • 0037041426 scopus 로고    scopus 로고
    • Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo
    • Walsh D.M., Klyubin I., Fadeeva J.V., Cullen W.K., Anwyl R., Wolfe M.S., et al. Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature 416 (2002) 535-539
    • (2002) Nature , vol.416 , pp. 535-539
    • Walsh, D.M.1    Klyubin, I.2    Fadeeva, J.V.3    Cullen, W.K.4    Anwyl, R.5    Wolfe, M.S.6
  • 40
    • 5344277556 scopus 로고    scopus 로고
    • Deciphering the molecular basis of memory failure in Alzheimer's disease
    • Walsh D.M., and Selkoe D.J. Deciphering the molecular basis of memory failure in Alzheimer's disease. Neuron 44 (2004) 181-193
    • (2004) Neuron , vol.44 , pp. 181-193
    • Walsh, D.M.1    Selkoe, D.J.2
  • 41
    • 0037059598 scopus 로고    scopus 로고
    • Soluble oligomers of beta amyloid (1-42) inhibit long-term potentiation but not long-term depression in rat dentate gyrus
    • Wang H.W., Pasternak J.F., Kuo H., Ristic H., Lambert M.P., Chromy B., et al. Soluble oligomers of beta amyloid (1-42) inhibit long-term potentiation but not long-term depression in rat dentate gyrus. Brain Res 924 (2002) 133-140
    • (2002) Brain Res , vol.924 , pp. 133-140
    • Wang, H.W.1    Pasternak, J.F.2    Kuo, H.3    Ristic, H.4    Lambert, M.P.5    Chromy, B.6
  • 42
    • 1842610852 scopus 로고    scopus 로고
    • Block of long-term potentiation by naturally secreted and synthetic amyloid beta-peptide in hippocampal slices is mediated via activation of the kinases c-Jun N-terminal kinase, cyclin-dependent kinase 5, and p38 mitogen-activated protein kinase as well as metabotropic glutamate receptor type 5
    • Wang Q., Walsh D.M., Rowan M.J., Selkoe D.J., and Anwyl R. Block of long-term potentiation by naturally secreted and synthetic amyloid beta-peptide in hippocampal slices is mediated via activation of the kinases c-Jun N-terminal kinase, cyclin-dependent kinase 5, and p38 mitogen-activated protein kinase as well as metabotropic glutamate receptor type 5. J Neurosci 24 (2004) 3370-3378
    • (2004) J Neurosci , vol.24 , pp. 3370-3378
    • Wang, Q.1    Walsh, D.M.2    Rowan, M.J.3    Selkoe, D.J.4    Anwyl, R.5
  • 43
    • 33749020532 scopus 로고    scopus 로고
    • Humanin is a novel neuroprotective agent against stroke
    • Xu X., Chua C.C., Gao J., Hamdy R.C., and Chua B.H. Humanin is a novel neuroprotective agent against stroke. Stroke 37 (2006) 2613-2619
    • (2006) Stroke , vol.37 , pp. 2613-2619
    • Xu, X.1    Chua, C.C.2    Gao, J.3    Hamdy, R.C.4    Chua, B.H.5
  • 44
    • 36148936388 scopus 로고    scopus 로고
    • Restoration of impaired phosphorylation of cyclic AMP response element-binding protein (CREB) by EGb 761 and its constituents in Abeta-expressing neuroblastoma cells
    • Xu Y., Cui C., Pang C., Christen Y., and Luo Y. Restoration of impaired phosphorylation of cyclic AMP response element-binding protein (CREB) by EGb 761 and its constituents in Abeta-expressing neuroblastoma cells. Eur J Neurosci 26 (2007) 2931-2939
    • (2007) Eur J Neurosci , vol.26 , pp. 2931-2939
    • Xu, Y.1    Cui, C.2    Pang, C.3    Christen, Y.4    Luo, Y.5


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