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Volumn 29, Issue 1, 2016, Pages 10-23

Calf Lung Surfactant Recovers Surface Functionality after Exposure to Aerosols Containing Polymeric Particles

Author keywords

Aerosol; Infasurf; nanoparticles; surface tension; surfactant inhibition

Indexed keywords

CALFACTANT; DIPALMITOYLPHOSPHATIDYLCHOLINE; POLYSTYRENE;

EID: 84941227837     PISSN: 19412711     EISSN: 19412703     Source Type: Journal    
DOI: 10.1089/jamp.2014.1165     Document Type: Article
Times cited : (22)

References (56)
  • 1
    • 0035206189 scopus 로고    scopus 로고
    • Pulmonary surfactant: Functions, abnormalities and therapeutic options
    • Frerking I, Gunther A, Seeger W, and Pison U: Pulmonary surfactant: Functions, abnormalities and therapeutic options. J Intensive Care Med. 2001;27:1699-1717.
    • (2001) J Intensive Care Med , vol.27 , pp. 1699-1717
    • Frerking, I1    Gunther, A2    Seeger, W3    Pison, U4
  • 2
    • 77955978148 scopus 로고    scopus 로고
    • Pulmonary toxicity of polysorbate-80-coated inhalable nanoparticles in vitro and in vivo evaluation
    • Al-Hallak MHDK, Azarmi S, Sun C, Lai P, Prenner EJ, Roa W, and Lobenberg R: Pulmonary toxicity of polysorbate-80-coated inhalable nanoparticles in vitro and in vivo evaluation. AAPS J. 2010;12:294-299.
    • (2010) AAPS J , vol.12 , pp. 294-299
    • Al-Hallak, MHDK1    Azarmi, S2    Sun, C3    Lai, P4    Prenner, EJ5    Roa, W6    Lobenberg, R7
  • 3
    • 38549150752 scopus 로고    scopus 로고
    • Metal nanoparticle pollutants interfere with pulmonary surfactant function in vitro
    • Bakshi MS, Zhao L, Smith R, Possmayer F, and Petersen NO: Metal nanoparticle pollutants interfere with pulmonary surfactant function in vitro. Biophy J. 2008;94:855-868.
    • (2008) Biophy J , vol.94 , pp. 855-868
    • Bakshi, MS1    Zhao, L2    Smith, R3    Possmayer, F4    Petersen, NO5
  • 4
    • 84867098471 scopus 로고    scopus 로고
    • DPPC-DOPC Langmuir monolayers modified by hydrophilic silica nanoparticles: Phase behaviour, structure and rheology
    • Guzman E, Liggieri L, Santini E, Ferrari M, and Ravera F: DPPC-DOPC Langmuir monolayers modified by hydrophilic silica nanoparticles: Phase behaviour, structure and rheology. Colloids Surf A, Physicochem Eng Asp. 2011: 174-183.
    • (2011) Colloids Surf A, Physicochem Eng Asp , pp. 174-183
    • Guzman, E1    Liggieri, L2    Santini, E3    Ferrari, M4    Ravera, F5
  • 5
    • 80455126016 scopus 로고    scopus 로고
    • Effect of hydrophilic and hydrophobic nanoparticles on the surface pressure response of DPPC monolayers
    • Guzman E, Liggieri L, Santini E, Ferrari M, and Ravera F: Effect of hydrophilic and hydrophobic nanoparticles on the surface pressure response of DPPC monolayers. J Phys Chem C, Nanomater Interfaces. 2011;115:21715-21722.
    • (2011) J Phys Chem C, Nanomater Interfaces , vol.115 , pp. 21715-21722
    • Guzman, E1    Liggieri, L2    Santini, E3    Ferrari, M4    Ravera, F5
  • 6
    • 84873247827 scopus 로고    scopus 로고
    • Mixed DPPC-cholesterol Langmuir monolayers in presence of hydrophilic silica nanoparticles
    • Guzman E, Liggieri L, Santini E, Ferrari M, and Ravera F: Mixed DPPC-cholesterol Langmuir monolayers in presence of hydrophilic silica nanoparticles. Colloids Surf B, Biointerfaces. 2013;105:284-293.
    • (2013) Colloids Surf B, Biointerfaces , vol.105 , pp. 284-293
    • Guzman, E1    Liggieri, L2    Santini, E3    Ferrari, M4    Ravera, F5
  • 9
    • 84891880852 scopus 로고    scopus 로고
    • Size influences the effect of hydrophobic nanoparticles on lung surfactant model systems
    • Dwivedi MV, Harishchandra RK, Koshkina O, Maskos M, and Galla HJ: Size influences the effect of hydrophobic nanoparticles on lung surfactant model systems. Biophys J. 2014;106:289-298.
    • (2014) Biophys J , vol.106 , pp. 289-298
    • Dwivedi, MV1    Harishchandra, RK2    Koshkina, O3    Maskos, M4    Galla, HJ5
  • 10
    • 80052053351 scopus 로고    scopus 로고
    • Adverse biophysical effects of hydroxyapatite nanoparticles on natural pulmonary surfactant
    • Fan Q, Wang YE, Zhao X, Loo JSC, and Zuo YY: Adverse biophysical effects of hydroxyapatite nanoparticles on natural pulmonary surfactant. ACS Nano. 2011;5: 6410-6416.
    • (2011) ACS Nano , vol.5 , pp. 6410-6416
    • Fan, Q1    Wang, YE2    Zhao, X3    Loo, JSC4    Zuo, YY5
  • 11
    • 84870268185 scopus 로고    scopus 로고
    • Low concentrations of negatively charged sub-micron particles alter the microstructure of DPPC at the air-water interface
    • Farnoud AM, and Fiegel J: Low concentrations of negatively charged sub-micron particles alter the microstructure of DPPC at the air-water interface. Colloids Surf A, Physicochem Eng Asp. 2012;415:320-327.
    • (2012) Colloids Surf A, Physicochem Eng Asp , vol.415 , pp. 320-327
    • Farnoud, AM1    Fiegel, J2
  • 12
    • 84885643345 scopus 로고    scopus 로고
    • Interaction of dipalmitoyl phosphatidylcholine monolayers with a particle-laden subphase
    • Farnoud AM, and Fiegel J: Interaction of dipalmitoyl phosphatidylcholine monolayers with a particle-laden subphase. J Phys Chem B. 2013;117:12124-12134.
    • (2013) J Phys Chem B , vol.117 , pp. 12124-12134
    • Farnoud, AM1    Fiegel, J2
  • 13
    • 84903976066 scopus 로고    scopus 로고
    • Increasing hydrophobicity of nanoparticles intensifies lung surfactant film inhibition and particle retention
    • Valle RP, Huang CL, Loo SCJ, and Zuo YY: Increasing hydrophobicity of nanoparticles intensifies lung surfactant film inhibition and particle retention. ACS Sustainable Chem Eng. 2014;2:1574-1580.
    • (2014) ACS Sustainable Chem Eng , vol.2 , pp. 1574-1580
    • Valle, RP1    Huang, CL2    Loo, SCJ3    Zuo, YY4
  • 14
    • 0030805798 scopus 로고    scopus 로고
    • In vivo determination of surface tension in the horse trachea and in vitro model studies
    • Im Hof V, Gehr P, Gerber V, Lee M, and Schurch S: In vivo determination of surface tension in the horse trachea and in vitro model studies. Respir Physiol Neurobiol. 1997;109: 81-93.
    • (1997) Respir Physiol Neurobiol , vol.109 , pp. 81-93
    • Im Hof, V1    Gehr, P2    Gerber, V3    Lee, M4    Schurch, S5
  • 15
    • 43149104977 scopus 로고    scopus 로고
    • Comparing experimental and simulated pressure-area isotherms for DPPC
    • Duncan SL, and Larson RG: Comparing experimental and simulated pressure-area isotherms for DPPC. Biophys J. 2008;94:2965-2986.
    • (2008) Biophys J , vol.94 , pp. 2965-2986
    • Duncan, SL1    Larson, RG2
  • 16
    • 77951922214 scopus 로고    scopus 로고
    • Nanoparticle interaction with model lung surfactant monolayers
    • Harishchandra RK, Saleem M, and Galla HJ: Nanoparticle interaction with model lung surfactant monolayers. J R Soc Interface. 2010;7:15-26.
    • (2010) J R Soc Interface , vol.7 , pp. 15-26
    • Harishchandra, RK1    Saleem, M2    Galla, HJ3
  • 17
    • 33748986733 scopus 로고    scopus 로고
    • Effect of particle emissions from biofuel combustion on surface activity of model and therapeutic pulmonary surfactants
    • Kanishtha T, Banerjee R, and Venkataraman C: Effect of particle emissions from biofuel combustion on surface activity of model and therapeutic pulmonary surfactants. Environ Toxicol Pharmacol. 2006;22:325-333.
    • (2006) Environ Toxicol Pharmacol , vol.22 , pp. 325-333
    • Kanishtha, T1    Banerjee, R2    Venkataraman, C3
  • 18
    • 77955447204 scopus 로고    scopus 로고
    • Real-time imaging of interactions between dipalmitoylphosphatidylcholine monolayers and gelatin based nanoparticles using Brewster angle microscopy
    • Lai P, Nathoo S, Ku T, Gill S, Azarmi S, Roa W, Lobenberg R, and Prenner EJ: Real-time imaging of interactions between dipalmitoylphosphatidylcholine monolayers and gelatin based nanoparticles using Brewster angle microscopy. J Biomed Nanotechnol. 2010;6:145-152.
    • (2010) J Biomed Nanotechnol , vol.6 , pp. 145-152
    • Lai, P1    Nathoo, S2    Ku, T3    Gill, S4    Azarmi, S5    Roa, W6    Lobenberg, R7    Prenner, EJ8
  • 19
    • 0034527992 scopus 로고    scopus 로고
    • Influence of insoluble aerosol deposits on the surface activity of the pulmonary surfactant: A possible mechanism of alveolar clearance retardation?
    • Sosnowski TR, Gradon L, and Podgorski A: Influence of insoluble aerosol deposits on the surface activity of the pulmonary surfactant: A possible mechanism of alveolar clearance retardation? Aerosol Sci Tech. 2000;32:52-60.
    • (2000) Aerosol Sci Tech , vol.32 , pp. 52-60
    • Sosnowski, TR1    Gradon, L2    Podgorski, A3
  • 20
    • 42649114134 scopus 로고    scopus 로고
    • Biophysical investigation of nanoparticle interactions with lung surfactant model systems
    • Stuart D, Lobenberg R, Ku T, Azarmi S, Ely L, Roa W, and Prenner EJ: Biophysical investigation of nanoparticle interactions with lung surfactant model systems. J Biomed Nanotechnol. 2006;2:245-252.
    • (2006) J Biomed Nanotechnol , vol.2 , pp. 245-252
    • Stuart, D1    Lobenberg, R2    Ku, T3    Azarmi, S4    Ely, L5    Roa, W6    Prenner, EJ7
  • 21
    • 84888148644 scopus 로고    scopus 로고
    • Biophysical inhibition of synthetic vs. naturally-derived pulmonary surfactant preparations by polymeric nanoparticles
    • Beck-Broichsitter M, Ruppert C, Schmehl T, Gunther A, and Seeger W: Biophysical inhibition of synthetic vs. naturally-derived pulmonary surfactant preparations by polymeric nanoparticles. Biochim Biophys Acta. 2014;1838: 474-481.
    • (2014) Biochim Biophys Acta , vol.1838 , pp. 474-481
    • Beck-Broichsitter, M1    Ruppert, C2    Schmehl, T3    Gunther, A4    Seeger, W5
  • 22
    • 77956304534 scopus 로고    scopus 로고
    • Macrophages recognize size and shape of their targets
    • Doshi N, and Mitragotri S: Macrophages recognize size and shape of their targets. PLoS One. 2010;5:e10051.
    • (2010) PLoS One , vol.5 , pp. e10051
    • Doshi, N1    Mitragotri, S2
  • 23
    • 46749119051 scopus 로고    scopus 로고
    • Role of particle size in phagocytosis of polymeric microspheres
    • Champion JA, Walker A, and Mitragotri S: Role of particle size in phagocytosis of polymeric microspheres. Pharmaceut Res. 2008;25:1815-1821.
    • (2008) Pharmaceut Res , vol.25 , pp. 1815-1821
    • Champion, JA1    Walker, A2    Mitragotri, S3
  • 26
    • 0023239485 scopus 로고
    • Relations among alveolar surface tension, surface area, volume, and recoil pressure
    • Bachofen H, Schurch S, Urbinelli M, and Weibel E: Relations among alveolar surface tension, surface area, volume, and recoil pressure. J Appl Physiol. 1987;62:1878-1887.
    • (1987) J Appl Physiol , vol.62 , pp. 1878-1887
    • Bachofen, H1    Schurch, S2    Urbinelli, M3    Weibel, E4
  • 27
    • 0016255269 scopus 로고
    • Static and dynamic properties of excised cat lung in relation to temperature
    • Horie T, Ardila R, and Hildebrandt J: Static and dynamic properties of excised cat lung in relation to temperature. J Appl Physiol. 1974;36:317-322.
    • (1974) J Appl Physiol , vol.36 , pp. 317-322
    • Horie, T1    Ardila, R2    Hildebrandt, J3
  • 28
    • 0022413653 scopus 로고
    • Alveolar surface tensions in excised rabbit lungs: Effect of temperature
    • Schurch S, Bachofen H, and Weibel ER: Alveolar surface tensions in excised rabbit lungs: Effect of temperature. Respir Physiol Neurobiol. 1985;62:31-45.
    • (1985) Respir Physiol Neurobiol , vol.62 , pp. 31-45
    • Schurch, S1    Bachofen, H2    Weibel, ER3
  • 29
    • 0022549667 scopus 로고
    • Surface forces in lungs. I. Alveolar surface tension-lung volume relationships
    • Smith JC, and Stamenovic D: Surface forces in lungs. I. Alveolar surface tension-lung volume relationships. J Appl Physiol. 1986;60:1341-1350.
    • (1986) J Appl Physiol , vol.60 , pp. 1341-1350
    • Smith, JC1    Stamenovic, D2
  • 31
    • 0027536933 scopus 로고
    • Determination of particle concentration in latexes by turbidimetry
    • Irache J, Durrer C, Ponchel G, and Duchene D: Determination of particle concentration in latexes by turbidimetry. Int J Pharm. 1993;90:9-12.
    • (1993) Int J Pharm , vol.90 , pp. 9-12
    • Irache, J1    Durrer, C2    Ponchel, G3    Duchene, D4
  • 33
    • 43949085700 scopus 로고    scopus 로고
    • Collapse mechanisms of Langmuir monolayers
    • Lee KYC: Collapse mechanisms of Langmuir monolayers. Annu Rev Phys Chem. 2008;59:771-791.
    • (2008) Annu Rev Phys Chem , vol.59 , pp. 771-791
    • Lee, KYC1
  • 34
    • 27944446971 scopus 로고    scopus 로고
    • Interfacial properties of pulmonary surfactant layers
    • Wustneck R: Interfacial properties of pulmonary surfactant layers. Adv Colloid Interface Sci. 2005;117:33-58.
    • (2005) Adv Colloid Interface Sci , vol.117 , pp. 33-58
    • Wustneck, R1
  • 35
    • 17644445466 scopus 로고    scopus 로고
    • Comparison of Infasurf (calf lung surfactant extract) to Survanta (Beractant) in the treatment and prevention of respiratory distress syndrome
    • Bloom BT, Kattwinkel J, Hall RT, Delmore PM, Egan EA, Trout JR, Malloy MH, Brown DR, Holzman IR, and Coghill CH: Comparison of Infasurf (calf lung surfactant extract) to Survanta (Beractant) in the treatment and prevention of respiratory distress syndrome. Pediatrics. 1997;100:31-38.
    • (1997) Pediatrics , vol.100 , pp. 31-38
    • Bloom, BT1    Kattwinkel, J2    Hall, RT3    Delmore, PM4    Egan, EA5    Trout, JR6    Malloy, MH7    Brown, DR8    Holzman, IR9    Coghill, CH10
  • 36
    • 83455162516 scopus 로고    scopus 로고
    • Biophysical interaction between corticosteroids and natural surfactant preparation: Implications for pulmonary drug delivery using surfactant as a carrier
    • Wang YE, Zhang H, Fan Q, Neal CR, and Zuo YY: Biophysical interaction between corticosteroids and natural surfactant preparation: Implications for pulmonary drug delivery using surfactant as a carrier. Soft Matter. 2012; 8:504-511.
    • (2012) Soft Matter , vol.8 , pp. 504-511
    • Wang, YE1    Zhang, H2    Fan, Q3    Neal, CR4    Zuo, YY5
  • 37
    • 79955875206 scopus 로고    scopus 로고
    • Comparative study of clinical pulmonary surfactants using atomic force microscopy
    • Zhang H, Fan Q, Wang YE, Neal CR, and Zuo YY: Comparative study of clinical pulmonary surfactants using atomic force microscopy. Biochim Biophys Acta. 2011;1808:1832-1842.
    • (2011) Biochim Biophys Acta , vol.1808 , pp. 1832-1842
    • Zhang, H1    Fan, Q2    Wang, YE3    Neal, CR4    Zuo, YY5
  • 38
    • 79959783364 scopus 로고    scopus 로고
    • On the low surface tension of lung surfactant
    • Zhang H,Wang YE, Fan Q, and Zuo YY: On the low surface tension of lung surfactant. Langmuir. 2011;27:8351-8358.
    • (2011) Langmuir , vol.27 , pp. 8351-8358
    • Zhang, H1    Wang, YE2    Fan, Q3    Zuo, YY4
  • 39
    • 84862979827 scopus 로고    scopus 로고
    • Health impact and toxicological effects of nanomaterials in the lung
    • Kendall M, and Holgate S: Health impact and toxicological effects of nanomaterials in the lung. Respirology.17:743-758.
    • Respirology , vol.17 , pp. 743-758
    • Kendall, M1    Holgate, S2
  • 40
    • 70449249103 scopus 로고
    • Surface properties in relation to atelectasis and hyaline membrane disease
    • Avery ME, and Mead J: Surface properties in relation to atelectasis and hyaline membrane disease. Arch Pediatr Adolesc Med. 1959;97:517-523.
    • (1959) Arch Pediatr Adolesc Med , vol.97 , pp. 517-523
    • Avery, ME1    Mead, J2
  • 41
    • 0022228969 scopus 로고
    • Surface property changes from interactions of albumin with natural lung surfactant and extracted lung lipids
    • Holm BA, Notter R, and Finkelstein JN: Surface property changes from interactions of albumin with natural lung surfactant and extracted lung lipids. Chem Phys Lipids. 1985;38:287-298.
    • (1985) Chem Phys Lipids , vol.38 , pp. 287-298
    • Holm, BA1    Notter, R2    Finkelstein, JN3
  • 42
    • 48449102867 scopus 로고    scopus 로고
    • Size dependent interactions of nanoparticles with lung surfactant model systems and the significant impact on surface potential
    • Ku T, Gill S, Lobenberg R, Azarmi S, Roa W, and Prenner EJ: Size dependent interactions of nanoparticles with lung surfactant model systems and the significant impact on surface potential. J Nanosci Nanotechnol. 2008;8:2971-2978.
    • (2008) J Nanosci Nanotechnol , vol.8 , pp. 2971-2978
    • Ku, T1    Gill, S2    Lobenberg, R3    Azarmi, S4    Roa, W5    Prenner, EJ6
  • 43
    • 84870395437 scopus 로고    scopus 로고
    • Local delivery of biodegradable pirfenidone nanoparticles ameliorates bleomycin-induced pulmonary fibrosis in mice
    • Trivedi R, Redente EF, Thakur A, Riches DW, and Kompella UB: Local delivery of biodegradable pirfenidone nanoparticles ameliorates bleomycin-induced pulmonary fibrosis in mice. Nanotechnology. 2012;23:505101.
    • (2012) Nanotechnology , vol.23 , pp. 505101
    • Trivedi, R1    Redente, EF2    Thakur, A3    Riches, DW4    Kompella, UB5
  • 45
    • 0001386952 scopus 로고
    • Regional deposition of particles in the human respiratory tract
    • DHK Lee, HL Falk, SD Murphy, (eds). Section 9: Reactions to Environmental Agents, American Physiology Society, Bethesda, MD
    • Lippmann M: Regional deposition of particles in the human respiratory tract. In: DHK Lee, HL Falk, SD Murphy, (eds). Handbook of Physiology, Section 9: Reactions to Environmental Agents Handbook of Physiology, Section 9: Reactions to Environmental Agents, American Physiology Society, Bethesda, MD; 1977; pp. 213-232.
    • (1977) Handbook of Physiology, Section 9: Reactions to Environmental Agents Handbook of Physiology , pp. 213-232
    • Lippmann, M1
  • 46
    • 35348897315 scopus 로고    scopus 로고
    • Fine airborne urban particles (PM 2.5) sequester lung surfactant and amino acids from human lung lavage
    • Kendall M: Fine airborne urban particles (PM 2.5) sequester lung surfactant and amino acids from human lung lavage. Am J Physiol Lung Cell Mol Physiol. 2007;293: 1053-1058.
    • (2007) Am J Physiol Lung Cell Mol Physiol , vol.293 , pp. 1053-1058
    • Kendall, M1
  • 47
    • 71549147854 scopus 로고    scopus 로고
    • Studies of dipalmitoylphosphatidylcholine (DPPC) monolayers embedded with endohedral metallofullerene (Dy@ C82)
    • Wang Z, Li X, and Yang S: Studies of dipalmitoylphosphatidylcholine (DPPC) monolayers embedded with endohedral metallofullerene (Dy@ C82). Langmuir. 2009;25: 12968-12973.
    • (2009) Langmuir , vol.25 , pp. 12968-12973
    • Wang, Z1    Li, X2    Yang, S3
  • 49
    • 0025307779 scopus 로고
    • Surfactant displaces particles toward the epithelium in airways and alveoli
    • Schurch S, Gehr P, Im Hof V, Geiser M, and Green F: Surfactant displaces particles toward the epithelium in airways and alveoli. Respir Physiol Neurobiol. 1990;80:17-32.
    • (1990) Respir Physiol Neurobiol , vol.80 , pp. 17-32
    • Schurch, S1    Gehr, P2    Im Hof, V3    Geiser, M4    Green, F5
  • 50
    • 0027381960 scopus 로고
    • Surfactant and inhaled particles in the conducting airways: Structural, stereological, and biophysical aspects
    • Gehr P, Geiser M, Im Hof V, Schurch S, Waber U, and Baumann M: Surfactant and inhaled particles in the conducting airways: Structural, stereological, and biophysical aspects. Microsc Res Tech. 1993;26:423-436.
    • (1993) Microsc Res Tech , vol.26 , pp. 423-436
    • Gehr, P1    Geiser, M2    Im Hof, V3    Schurch, S4    Waber, U5    Baumann, M6
  • 51
    • 0038064658 scopus 로고    scopus 로고
    • Interfacial properties of surfactant proteins
    • Perez Gil J: Interfacial properties of surfactant proteins. Biochim Biophys Acta. 1998;1408:203.
    • (1998) Biochim Biophys Acta , vol.1408 , pp. 203
    • Perez Gil, J1
  • 52
    • 0019771444 scopus 로고
    • Precursor-product relationship between rabbit type II cell lamellar bodies and alveolar surface-active material: surfactant turnover time
    • Baritussio AG, Magoon MW, Goerke J, and Clements JA: Precursor-product relationship between rabbit type II cell lamellar bodies and alveolar surface-active material: surfactant turnover time. Biochim Biophys Acta. 1981;666: 382-393.
    • (1981) Biochim Biophys Acta , vol.666 , pp. 382-393
    • Baritussio, AG1    Magoon, MW2    Goerke, J3    Clements, JA4
  • 55
    • 84855711037 scopus 로고    scopus 로고
    • Influence of hydrophobic alkylated gold nanoparticles on the phase behavior of monolayers of DPPC and clinical lung surfactant
    • Tatur S, and Badia A: Influence of hydrophobic alkylated gold nanoparticles on the phase behavior of monolayers of DPPC and clinical lung surfactant. Langmuir. 2012;28: 628-639.
    • (2012) Langmuir , vol.28 , pp. 628-639
    • Tatur, S1    Badia, A2
  • 56
    • 1642502969 scopus 로고    scopus 로고
    • Influence of surface chemistry and topography of particles on their immersion into the lung's surface-lining layer
    • Geiser M, Schurch S, and Gehr P: Influence of surface chemistry and topography of particles on their immersion into the lung's surface-lining layer. J Appl Physiol. 2003;94: 1793-1801.
    • (2003) J Appl Physiol , vol.94 , pp. 1793-1801
    • Geiser, M1    Schurch, S2    Gehr, P3


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