메뉴 건너뛰기




Volumn 19, Issue 5, 1999, Pages 1267-1275

Lovastatin decreases the receptor-mediated degradation of acetylated and oxidized LDLs in human blood monocytes during the early stage of differentiation into macrophages

Author keywords

3 hydroxy 3 methylglutaryl coenzyme A reductase inhibitor; Acetylated LDL; CD36; LDL receptor; Monocyte; Oxidized LDL; Scavenger receptor

Indexed keywords

CHOLESTEROL; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; LOW DENSITY LIPOPROTEIN; LOW DENSITY LIPOPROTEIN RECEPTOR; MEVINOLIN; SCAVENGER RECEPTOR;

EID: 0032941385     PISSN: 10795642     EISSN: None     Source Type: Journal    
DOI: 10.1161/01.ATV.19.5.1267     Document Type: Article
Times cited : (52)

References (53)
  • 1
    • 0027241856 scopus 로고
    • The pathogenesis of atherosclerosis: A perspective for the 1990's
    • Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990's. Nature. 1993;362:801-806.
    • (1993) Nature , vol.362 , pp. 801-806
    • Ross, R.1
  • 2
    • 0020972414 scopus 로고
    • Lipoprotein metabolism in the macrophage: Implications for cholesterol deposition in atherosclerosis
    • Brown MS, Goldstein JS. Lipoprotein metabolism in the macrophage: implications for cholesterol deposition in atherosclerosis. Annu. Rev Biochem. 1983;52:223-261.
    • (1983) Annu. Rev Biochem. , vol.52 , pp. 223-261
    • Brown, M.S.1    Goldstein, J.S.2
  • 3
    • 0027412455 scopus 로고
    • Molecular flypaper, host defence and atherosclerosis: Structure, binding properties, and functions of macrophage scavenger receptors
    • Krieger M. Molecular flypaper, host defence and atherosclerosis: structure, binding properties, and functions of macrophage scavenger receptors. J Biol Chem. 1993;268:4569-4572.
    • (1993) J Biol Chem. , vol.268 , pp. 4569-4572
    • Krieger, M.1
  • 4
    • 0028175555 scopus 로고
    • Differential expression of scavenger receptor isoforms during monocyte-macrophage differentiation and foam cell formation
    • Geng Y, Kodama T, Hansson GK. Differential expression of scavenger receptor isoforms during monocyte-macrophage differentiation and foam cell formation. Arterioscler Thromb. 1994;14:798-806.
    • (1994) Arterioscler Thromb. , vol.14 , pp. 798-806
    • Geng, Y.1    Kodama, T.2    Hansson, G.K.3
  • 6
    • 0028963942 scopus 로고
    • Oxidized LDL binds to CD36 on human monocyte-derived macrophages and transfected cell lines: Evidence implicating the lipid moiety of the lipoprotein as the binding site
    • Nicholson AC, Frieda S, Pearce A, Silverstein RL. Oxidized LDL binds to CD36 on human monocyte-derived macrophages and transfected cell lines: evidence implicating the lipid moiety of the lipoprotein as the binding site. Arterioscler Thromb Vasc Biol. 1995;15:269-275.
    • (1995) Arterioscler Thromb Vasc Biol. , vol.15 , pp. 269-275
    • Nicholson, A.C.1    Frieda, S.2    Pearce, A.3    Silverstein, R.L.4
  • 7
    • 0030799043 scopus 로고    scopus 로고
    • Low density lipoprotein and its pathobiological significance
    • Steinberg D. Low density lipoprotein and its pathobiological significance. J Biol Chem. 1997;272:20963-20966.
    • (1997) J Biol Chem. , vol.272 , pp. 20963-20966
    • Steinberg, D.1
  • 8
    • 0030895048 scopus 로고    scopus 로고
    • A role for macrophage scavenger receptors in atherosclerosis and susceptibility to infection
    • Suzuki H, Kurihara Y, Takeya M, et al. A role for macrophage scavenger receptors in atherosclerosis and susceptibility to infection. Nature. 1997; 386:292-296.
    • (1997) Nature , vol.386 , pp. 292-296
    • Suzuki, H.1    Kurihara, Y.2    Takeya, M.3
  • 9
    • 0029877694 scopus 로고    scopus 로고
    • Increased expression of scavenger receptor type 1 gene in human peripheral blood from hyperlipidemic patients determined by quantitative additive RT-PCR
    • Villanova JG, Lucena JLD, Arcas NF, Engel AR. Increased expression of scavenger receptor type 1 gene in human peripheral blood from hyperlipidemic patients determined by quantitative additive RT-PCR. Biochim Biophys Acta. 1996;1300:135-141.
    • (1996) Biochim Biophys Acta , vol.1300 , pp. 135-141
    • Villanova, J.G.1    Lucena, J.L.D.2    Arcas, N.F.3    Engel, A.R.4
  • 11
    • 0000306390 scopus 로고    scopus 로고
    • Statins do more than lower cholesterol
    • Vaughan, CJ, Murphy MB, Buckley BM. Statins do more than lower cholesterol. Lancet. 1996;348:1079-1082.
    • (1996) Lancet , vol.348 , pp. 1079-1082
    • Murphy, M.B.1    Buckley, B.M.2
  • 12
    • 0028080736 scopus 로고
    • Pravastatin inhibits cellular cholesterol synthesis and increases low density lipoprotein activity in macrophages: In vitro and in vivo studies
    • Keidar S, Aviram M, Maor I, Oiknine J, Brook G. Pravastatin inhibits cellular cholesterol synthesis and increases low density lipoprotein activity in macrophages: in vitro and in vivo studies. Br J Clin Pharmacol. 1994;38:513-519.
    • (1994) Br J Clin Pharmacol. , vol.38 , pp. 513-519
    • Keidar, S.1    Aviram, M.2    Maor, I.3    Oiknine, J.4    Brook, G.5
  • 13
    • 0025333455 scopus 로고
    • Effects of lovastatin therapy on LDL receptor activity in circulating monocytes and on structure and composition of plasma lipoproteins
    • Raveh D, Israeli A, Arnon R, Eisenberg S. Effects of lovastatin therapy on LDL receptor activity in circulating monocytes and on structure and composition of plasma lipoproteins. Atherosclerosis. 1990;82:19-26.
    • (1990) Atherosclerosis , vol.82 , pp. 19-26
    • Raveh, D.1    Israeli, A.2    Arnon, R.3    Eisenberg, S.4
  • 14
    • 0024847925 scopus 로고
    • Lovastatin treatment inhibits sterol synthesis and induced HMG-CoA reductase activity in mononuclear monocytes of normal subjects
    • Stone BG, Evans CD, Prigge WF, Daune WC, Gebhard RL. Lovastatin treatment inhibits sterol synthesis and induced HMG-CoA reductase activity in mononuclear monocytes of normal subjects. J Lipid Res. 1989;30:1943-1952.
    • (1989) J Lipid Res. , vol.30 , pp. 1943-1952
    • Stone, B.G.1    Evans, C.D.2    Prigge, W.F.3    Daune, W.C.4    Gebhard, R.L.5
  • 15
    • 0026082759 scopus 로고
    • Vastatins inhibit cholesterol ester accumulation in human monocyte-derived macrophages
    • Kempen HJM, Vermeer M, deWit E, Havekes LM. Vastatins inhibit cholesterol ester accumulation in human monocyte-derived macrophages. Arterioscler Thromb. 1991;11:146-153.
    • (1991) Arterioscler Thromb. , vol.11 , pp. 146-153
    • Kempen, H.J.M.1    Vermeer, M.2    Dewit, E.3    Havekes, L.M.4
  • 16
    • 0029116986 scopus 로고
    • HMG-CoA reductase inhibitors reduce acetyl LDL endocytosis in mouse peritoneal macrophages
    • Bernini F, Scurati N, Bonfadini G, Fumagalli R. HMG-CoA reductase inhibitors reduce acetyl LDL endocytosis in mouse peritoneal macrophages. Arterioscler Thromb Vasc Biol 1995;15:1352-1358.
    • (1995) Arterioscler Thromb Vasc Biol , vol.15 , pp. 1352-1358
    • Bernini, F.1    Scurati, N.2    Bonfadini, G.3    Fumagalli, R.4
  • 17
    • 0030592542 scopus 로고    scopus 로고
    • Lovastatin inhibits gene expression of type-I scavenger receptor in THP-1 human macrophages
    • Umetani N, Kanayama Y, Okamura M, Negoro N, Takeda T. Lovastatin inhibits gene expression of type-I scavenger receptor in THP-1 human macrophages. Biochim Biophys Acta. 1996;1303:199-206.
    • (1996) Biochim Biophys Acta , vol.1303 , pp. 199-206
    • Umetani, N.1    Kanayama, Y.2    Okamura, M.3    Negoro, N.4    Takeda, T.5
  • 18
    • 0027738796 scopus 로고
    • Requirement for mevalonate in acetylated LDL induction of cholesterol esterification in macrophages
    • Bernini F, Didoni G, Bonfadini G, Bellosta S, Fumagalli R. Requirement for mevalonate in acetylated LDL induction of cholesterol esterification in macrophages. Atherosclerosis. 1993;104:19-26.
    • (1993) Atherosclerosis , vol.104 , pp. 19-26
    • Bernini, F.1    Didoni, G.2    Bonfadini, G.3    Bellosta, S.4    Fumagalli, R.5
  • 19
    • 0030576663 scopus 로고    scopus 로고
    • Lovastatin reduces the expression of the combined adhesion and scavenger receptor CD36 in human monocytic cells
    • Pietsch A, Erl W, Lorenz RL. Lovastatin reduces the expression of the combined adhesion and scavenger receptor CD36 in human monocytic cells Biochem Pharmacol. 1996;52:433-439.
    • (1996) Biochem Pharmacol. , vol.52 , pp. 433-439
    • Pietsch, A.1    Erl, W.2    Lorenz, R.L.3
  • 20
    • 0019730393 scopus 로고
    • Factors regulating the activities of the low density lipoprotein receptor and the scavenger receptor on human monocyte-macrophages
    • Fogelman AM, Haberland ME, Seager J, Hokom M, Edwards PA. Factors regulating the activities of the low density lipoprotein receptor and the scavenger receptor on human monocyte-macrophages. J Lipid Res. 1981; 22:1131-1141.
    • (1981) J Lipid Res. , vol.22 , pp. 1131-1141
    • Fogelman, A.M.1    Haberland, M.E.2    Seager, J.3    Hokom, M.4    Edwards, P.A.5
  • 21
    • 0030030886 scopus 로고    scopus 로고
    • Synthesis, processing and intracellular transport of CD36 during monocytic differentiation
    • Alessio M, De Monte L, Scirea A, Gruarin P, Tandon NN, Sitia R. Synthesis, processing and intracellular transport of CD36 during monocytic differentiation. J Biol Chem. 1996;271:1770-1775.
    • (1996) J Biol Chem. , vol.271 , pp. 1770-1775
    • Alessio, M.1    De Monte, L.2    Scirea, A.3    Gruarin, P.4    Tandon, N.N.5    Sitia, R.6
  • 22
    • 0024560643 scopus 로고
    • Human monocyte inflammatory mediator gene expression is selectively regulated by adherence substrates
    • Eierman DF, Johnson CE, Haskill SJ. Human monocyte inflammatory mediator gene expression is selectively regulated by adherence substrates. J Immunol. 1989;142:1970-1976.
    • (1989) J Immunol. , vol.142 , pp. 1970-1976
    • Eierman, D.F.1    Johnson, C.E.2    Haskill, S.J.3
  • 23
    • 0005849853 scopus 로고
    • Degradation of cationized LDL and regulation of cholesterol metabolism in homozygous familial hypercholesterolemia fibroblasts
    • Basu SK, Goldstein JL, Anderson RG, Brown MS. Degradation of cationized LDL and regulation of cholesterol metabolism in homozygous familial hypercholesterolemia fibroblasts. Proc Natl Acad Sci U S A. 1976;73:3178-3182.
    • (1976) Proc Natl Acad Sci U S A , vol.73 , pp. 3178-3182
    • Basu, S.K.1    Goldstein, J.L.2    Anderson, R.G.3    Brown, M.S.4
  • 24
    • 0015518106 scopus 로고
    • The metabolism of very low density lipoprotein proteins. I: Preliminary in vitro and in vivo observations
    • Bilheimer D, Eisenberg S, Levy R. The metabolism of very low density lipoprotein proteins. I: Preliminary in vitro and in vivo observations. Biochem Biophys Acta. 1972; 260:212-221.
    • (1972) Biochem Biophys Acta , vol.260 , pp. 212-221
    • Bilheimer, D.1    Eisenberg, S.2    Levy, R.3
  • 25
    • 0018178434 scopus 로고
    • Modification of the lowry procedure to simplify protein determination in membrane and lipoprotein samples
    • Markwell MAK, Haas SM, Bieber LL, Telbert MEA. Modification of the Lowry procedure to simplify protein determination in membrane and lipoprotein samples. Anal Biochem. 1987;87:206-210.
    • (1987) Anal Biochem. , vol.87 , pp. 206-210
    • Markwell, M.A.K.1    Haas, S.M.2    Bieber, L.L.3    Telbert, M.E.A.4
  • 26
    • 0027945160 scopus 로고
    • Arachidonic acid increases c-fos and Erg-1 mRNA in 3T3 fibroblasts by formation of prostaglandin E2 and activation of protein kinase C
    • Danesch U, Weber PC, Sellmayer A. Arachidonic acid increases c-fos and Erg-1 mRNA in 3T3 Fibroblasts by formation of prostaglandin E2 and activation of protein kinase C. J Biol Chem. 1994;269:27258-27263.
    • (1994) J Biol Chem. , vol.269 , pp. 27258-27263
    • Danesch, U.1    Weber, P.C.2    Sellmayer, A.3
  • 28
    • 0021742599 scopus 로고
    • The human LDL receptor: A cysteine-rich protein with multiple Alu sequences in its mRNA
    • Goldstein JL, Russel DW. The human LDL receptor: a cysteine-rich protein with multiple Alu sequences in its mRNA. Cell. 1984;39:27-38.
    • (1984) Cell , vol.39 , pp. 27-38
    • Goldstein, J.L.1    Russel, D.W.2
  • 29
    • 0024395109 scopus 로고
    • CD36 directly mediates cytoadherence of plasmodium falciparum parasitized erythrocytes
    • Oquendo P, Hundt E, Lawier J, Seed B. CD36 directly mediates cytoadherence of plasmodium falciparum parasitized erythrocytes. Cell. 1989; 58:95-101.
    • (1989) Cell , vol.58 , pp. 95-101
    • Oquendo, P.1    Hundt, E.2    Lawier, J.3    Seed, B.4
  • 30
    • 0021759199 scopus 로고
    • Evolutionary conservation in the untranslated regions of actin mRNAs: DNA sequence of a human beta-actin cDNA
    • Ponte P, Ng SY, Engel J, Gunning P, Kedes L. Evolutionary conservation in the untranslated regions of actin mRNAs: DNA sequence of a human beta-actin cDNA. Nucleic Acids Res. 1984;12:1687-1696.
    • (1984) Nucleic Acids Res. , vol.12 , pp. 1687-1696
    • Ponte, P.1    Ng, S.Y.2    Engel, J.3    Gunning, P.4    Kedes, L.5
  • 32
    • 0028060607 scopus 로고
    • Inactivation of lysosomal proteases by oxidized low density lipoprotein is partially responsible for its poor degradation by mouse peritoneal macrophages
    • Hoppe G, O'Neil J, Hoff HF. Inactivation of lysosomal proteases by oxidized low density lipoprotein is partially responsible for its poor degradation by mouse peritoneal macrophages. J Clin Invest. 1994;94: 1506-1512.
    • (1994) J Clin Invest. , vol.94 , pp. 1506-1512
    • Hoppe, G.1    O'Neil, J.2    Hoff, H.F.3
  • 33
    • 15844392529 scopus 로고    scopus 로고
    • Mechanism of uptake of copper-oxidized low-density lipoprotein in macrophages is dependent on its extent of oxidation
    • Lougheed M, Steinbrecher UP. Mechanism of uptake of copper-oxidized low-density lipoprotein in macrophages is dependent on its extent of oxidation. J Biol Chem. 1996;271:11798-11805.
    • (1996) J Biol Chem. , vol.271 , pp. 11798-11805
    • Lougheed, M.1    Steinbrecher, U.P.2
  • 34
    • 0026602073 scopus 로고
    • Oxidation of low density lipoprotein leads to particle aggregation and altered macrophage recognition
    • Hoff HF, Whitaker TE, O'Neil J. Oxidation of low density lipoprotein leads to particle aggregation and altered macrophage recognition. J Biol Chem. 1992;267:602-609.
    • (1992) J Biol Chem. , vol.267 , pp. 602-609
    • Hoff, H.F.1    Whitaker, T.E.2    O'Neil, J.3
  • 35
    • 0019973550 scopus 로고
    • In vitro differentiation of human monocytes: Differences in monocyte phenotypes induced by cultivation on glass and collagen
    • Kaplan G, Gaudemack G. In vitro differentiation of human monocytes: differences in monocyte phenotypes induced by cultivation on glass and collagen. J Exp Med. 1982;156:1101-1114.
    • (1982) J Exp Med. , vol.156 , pp. 1101-1114
    • Kaplan, G.1    Gaudemack, G.2
  • 36
    • 0025120211 scopus 로고
    • Regulation of the mevalonate pathway
    • Goldstein JL, Brown MS. Regulation of the mevalonate pathway. Nature. 1990;343:425-430.
    • (1990) Nature , vol.343 , pp. 425-430
    • Goldstein, J.L.1    Brown, M.S.2
  • 37
    • 0025826965 scopus 로고
    • Lesion-derived low density lipoprotein and oxidized low density lipoprotein share a lability for aggregation, leading to enhanced macrophage degradation
    • Hoff HF, O'Neil J. Lesion-derived low density lipoprotein and oxidized low density lipoprotein share a lability for aggregation, leading to enhanced macrophage degradation. Arterioscler Thromb. 1991;11: 1209-1222.
    • (1991) Arterioscler Thromb. , vol.11 , pp. 1209-1222
    • Hoff, H.F.1    O'Neil, J.2
  • 38
    • 0026592207 scopus 로고
    • A macrophage Fc receptor for IgG is also a receptor for oxidized low density lipoprotein
    • Stanton LW, White RT, Bryant CM, Protter AA, Endemann G. A macrophage Fc receptor for IgG is also a receptor for oxidized low density lipoprotein. J Biol Chem. 1992;31:22446-22451.
    • (1992) J Biol Chem. , vol.31 , pp. 22446-22451
    • Stanton, L.W.1    White, R.T.2    Bryant, C.M.3    Protter, A.A.4    Endemann, G.5
  • 39
    • 0027956806 scopus 로고
    • Expression cloning of SR-BI, a CD36-related class B scavenger receptor
    • Acton SL, Scherer PE, Lodish HF, Krieger M. Expression cloning of SR-BI, a CD36-related class B scavenger receptor. J Biol Chem. 1994; 269:21003-21009.
    • (1994) J Biol Chem. , vol.269 , pp. 21003-21009
    • Acton, S.L.1    Scherer, P.E.2    Lodish, H.F.3    Krieger, M.4
  • 40
    • 0028841044 scopus 로고
    • The 94-to 97-kDa mouse macrophage membrane protein that recognizes oxidized low density lipoprotein and phosphatidylserine-rich liposomes is identical to macrosialin, the mouse homologue of human CD68
    • Ramprasad MP, Fischer W, Witztum JL, Sambrano GR, Quehenberger O, Steinberg D. The 94-to 97-kDa mouse macrophage membrane protein that recognizes oxidized low density lipoprotein and phosphatidylserine-rich liposomes is identical to macrosialin, the mouse homologue of human CD68. Proc Natl Acad Sci U S A. 1995;92:9580-9587.
    • (1995) Proc Natl Acad Sci U S A , vol.92 , pp. 9580-9587
    • Ramprasad, M.P.1    Fischer, W.2    Witztum, J.L.3    Sambrano, G.R.4    Quehenberger, O.5    Steinberg, D.6
  • 42
    • 0030007111 scopus 로고    scopus 로고
    • Structural and functional characterization of the human CD36 gene promoter
    • Armesilla AL, Calvo D, Vega MA. Structural and functional characterization of the human CD36 gene promoter. J Biol Chem. 1996;271: 7781-7787.
    • (1996) J Biol Chem. , vol.271 , pp. 7781-7787
    • Armesilla, A.L.1    Calvo, D.2    Vega, M.A.3
  • 43
    • 0027492038 scopus 로고
    • Simvastatin inhibits the oxidation of low-density-lipoproteins by activated human monocyte-derived macrophages
    • Giroux LM, Davignon J, Naruszewicz M. Simvastatin inhibits the oxidation of low-density-lipoproteins by activated human monocyte-derived macrophages. Biochim Biophys Acta. 1993;1165:335-338.
    • (1993) Biochim Biophys Acta , vol.1165 , pp. 335-338
    • Giroux, L.M.1    Davignon, J.2    Naruszewicz, M.3
  • 45
    • 0030913574 scopus 로고    scopus 로고
    • Regulation of scavenger receptor expression in smooth muscle cells by protein kinase C: A role for oxidative stress
    • Mietus-Snyder M, Friera A, Glass CK, Pitas RE. Regulation of scavenger receptor expression in smooth muscle cells by protein kinase C: a role for oxidative stress. Arterioscler Thromb Vasc Biol. 1997;17:969-978.
    • (1997) Arterioscler Thromb Vasc Biol. , vol.17 , pp. 969-978
    • Mietus-Snyder, M.1    Friera, A.2    Glass, C.K.3    Pitas, R.E.4
  • 46
    • 0030758289 scopus 로고    scopus 로고
    • Native and modified low density lipoproteins increase the functional expression of the macrophage class B scavenger receptor, CD36
    • Han J, Hajjar DP, Febbraio M, Nicholson AC. Native and modified low density lipoproteins increase the functional expression of the macrophage class B scavenger receptor, CD36. J Biol Chem. 1997;272:21654-21659.
    • (1997) J Biol Chem. , vol.272 , pp. 21654-21659
    • Han, J.1    Hajjar, D.P.2    Febbraio, M.3    Nicholson, A.C.4
  • 47
    • 0031807232 scopus 로고    scopus 로고
    • Minimally oxidized low density lipoprotein increases expression of scavenger receptor A, CD36, and macrosialin in resident mouse peritoneal macrophages
    • Yoshida H, Quehenberger O, Kondratenko N, Green S, Steinberg D. Minimally oxidized low density lipoprotein increases expression of scavenger receptor A, CD36, and Macrosialin in resident mouse peritoneal macrophages. Arterioscler Thromb Vasc Biol. 1998;18:794-802.
    • (1998) Arterioscler Thromb Vasc Biol. , vol.18 , pp. 794-802
    • Yoshida, H.1    Quehenberger, O.2    Kondratenko, N.3    Green, S.4    Steinberg, D.5
  • 48
    • 0026567758 scopus 로고
    • Lipopolysaccharide-induced inhibition of scavenger receptor expression in human monocyte-macrophages is mediated through tumor necrosis factor-34
    • van Lenten BJ, Fogelman AM. Lipopolysaccharide-induced inhibition of scavenger receptor expression in human monocyte-macrophages is mediated through tumor necrosis factor-34. J Immunol. 1992;148: 112-116.
    • (1992) J Immunol. , vol.148 , pp. 112-116
    • Van Lenten, B.J.1    Fogelman, A.M.2
  • 49
    • 0030838319 scopus 로고    scopus 로고
    • HMG-CoA reductase inhibitors decrease CD11b expression and CD11b-dependent adhesion of monocytes to endothelium and reduce increased adhesiveness of monocytes isolated from patients with hypercholesterolemia
    • Weber C, Erl W, Weber KSC, Weber PC. HMG-CoA reductase inhibitors decrease CD11b expression and CD11b-dependent adhesion of monocytes to endothelium and reduce increased adhesiveness of monocytes isolated from patients with hypercholesterolemia. J Am Coll Cardiol. 1997;30:1212-1217.
    • (1997) J Am Coll Cardiol. , vol.30 , pp. 1212-1217
    • Weber, C.1    Erl, W.2    Weber, K.S.C.3    Weber, P.C.4
  • 50
    • 0029966298 scopus 로고    scopus 로고
    • Modulation of macrophage scavenger receptor transport by protein phosphorylation
    • Fong LG. Modulation of macrophage scavenger receptor transport by protein phosphorylation. J Lipid Res. 1996;37:574-587.
    • (1996) J Lipid Res. , vol.37 , pp. 574-587
    • Fong, L.G.1


* 이 정보는 Elsevier사의 SCOPUS DB에서 KISTI가 분석하여 추출한 것입니다.