메뉴 건너뛰기




Volumn 7, Issue 7, 2012, Pages

Downregulation of miR-205 modulates cell susceptibility to oxidative and endoplasmic reticulum stresses in renal tubular cells

Author keywords

[No Author keywords available]

Indexed keywords

MICRORNA 205; PROCOLLAGEN PROLINE 2 OXOGLUTARATE 4 DIOXYGENASE; REACTIVE OXYGEN METABOLITE;

EID: 84864452770     PISSN: None     EISSN: 19326203     Source Type: Journal    
DOI: 10.1371/journal.pone.0041462     Document Type: Article
Times cited : (106)

References (50)
  • 1
    • 33644614520 scopus 로고    scopus 로고
    • HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia
    • Kim JW, Tchernyshyov I, Semenza GL, Dang CV, ((2006)) HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab 3:: 177--185.
    • (2006) Cell Metab , vol.3 , pp. 177-185
    • Kim, J.W.1    Tchernyshyov, I.2    Semenza, G.L.3    Dang, C.V.4
  • 2
    • 33644622570 scopus 로고    scopus 로고
    • HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption
    • Papandreou I, Cairns RA, Fontana L, Lim AL, Denko NC, ((2006)) HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption. Cell Metab 3:: 187--197.
    • (2006) Cell Metab , vol.3 , pp. 187-197
    • Papandreou, I.1    Cairns, R.A.2    Fontana, L.3    Lim, A.L.4    Denko, N.C.5
  • 3
    • 33645452371 scopus 로고    scopus 로고
    • Chronic hypoxia and tubulointerstitial injury: a final common pathway to end-stage renal failure
    • Nangaku M, ((2006)) Chronic hypoxia and tubulointerstitial injury: a final common pathway to end-stage renal failure. J Am Soc Nephrol 17:: 17--25.
    • (2006) J Am Soc Nephrol , vol.17 , pp. 17-25
    • Nangaku, M.1
  • 4
    • 78049378469 scopus 로고    scopus 로고
    • The suffocating kidney: tubulointerstitial hypoxia in end-stage renal disease
    • Mimura I, Nangaku M, ((2010)) The suffocating kidney: tubulointerstitial hypoxia in end-stage renal disease. Nat Rev Nephrol 6:: 667--678.
    • (2010) Nat Rev Nephrol , vol.6 , pp. 667-678
    • Mimura, I.1    Nangaku, M.2
  • 5
    • 77949730282 scopus 로고    scopus 로고
    • Endoplasmic reticulum stress as a progression factor for kidney injury
    • Inagi R, ((2010)) Endoplasmic reticulum stress as a progression factor for kidney injury. Curr Opin Pharmacol 10:: 156--165.
    • (2010) Curr Opin Pharmacol , vol.10 , pp. 156-165
    • Inagi, R.1
  • 7
    • 79955752164 scopus 로고    scopus 로고
    • The endoplasmic reticulum stress response and diabetic kidney disease
    • Cunard R, Sharma K, ((2011)) The endoplasmic reticulum stress response and diabetic kidney disease. Am J Physiol Renal Physiol 300:: F1054--1061.
    • (2011) Am J Physiol Renal Physiol , vol.300
    • Cunard, R.1    Sharma, K.2
  • 8
    • 74449085963 scopus 로고    scopus 로고
    • Endoplasmic reticulum stress in proteinuric kidney disease
    • Cybulsky AV, ((2010)) Endoplasmic reticulum stress in proteinuric kidney disease. Kidney Int 77:: 187--193.
    • (2010) Kidney Int , vol.77 , pp. 187-193
    • Cybulsky, A.V.1
  • 9
    • 77956453961 scopus 로고    scopus 로고
    • Indoxyl sulfate inhibits proliferation of human proximal tubular cells via endoplasmic reticulum stress
    • Kawakami T, Inagi R, Wada T, Tanaka T, Fujita T, et al. ((2010)) Indoxyl sulfate inhibits proliferation of human proximal tubular cells via endoplasmic reticulum stress. Am J Physiol Renal Physiol 299:: F568--576.
    • (2010) Am J Physiol Renal Physiol , vol.299
    • Kawakami, T.1    Inagi, R.2    Wada, T.3    Tanaka, T.4    Fujita, T.5
  • 10
    • 44049098171 scopus 로고    scopus 로고
    • Preconditioning with endoplasmic reticulum stress ameliorates mesangioproliferative glomerulonephritis
    • Inagi R, Kumagai T, Nishi H, Kawakami T, Miyata T, et al. ((2008)) Preconditioning with endoplasmic reticulum stress ameliorates mesangioproliferative glomerulonephritis. J Am Soc Nephrol 19:: 915--922.
    • (2008) J Am Soc Nephrol , vol.19 , pp. 915-922
    • Inagi, R.1    Kumagai, T.2    Nishi, H.3    Kawakami, T.4    Miyata, T.5
  • 11
    • 33749532327 scopus 로고    scopus 로고
    • Albumin induces endoplasmic reticulum stress and apoptosis in renal proximal tubular cells
    • Ohse T, Inagi R, Tanaka T, Ota T, Miyata T, et al. ((2006)) Albumin induces endoplasmic reticulum stress and apoptosis in renal proximal tubular cells. Kidney Int 70:: 1447--1455.
    • (2006) Kidney Int , vol.70 , pp. 1447-1455
    • Ohse, T.1    Inagi, R.2    Tanaka, T.3    Ota, T.4    Miyata, T.5
  • 12
    • 63349088070 scopus 로고    scopus 로고
    • Endoplasmic reticulum stress in the kidney as a novel mediator of kidney injury
    • Inagi R, ((2009)) Endoplasmic reticulum stress in the kidney as a novel mediator of kidney injury. Nephron Exp Nephrol 112:: e1--9.
    • (2009) Nephron Exp Nephrol , vol.112
    • Inagi, R.1
  • 13
    • 9444268084 scopus 로고    scopus 로고
    • ORP150/HSP12A protects renal tubular epithelium from ischemia-induced cell death
    • Bando Y, Tsukamoto Y, Katayama T, Ozawa K, Kitao Y, et al. ((2004)) ORP150/HSP12A protects renal tubular epithelium from ischemia-induced cell death. FASEB J 18:: 1401--1403.
    • (2004) FASEB J , vol.18 , pp. 1401-1403
    • Bando, Y.1    Tsukamoto, Y.2    Katayama, T.3    Ozawa, K.4    Kitao, Y.5
  • 14
    • 0141925706 scopus 로고    scopus 로고
    • Oxidative damage to the endoplasmic reticulum is implicated in ischemic neuronal cell death
    • Hayashi T, Saito A, Okuno S, Ferrand-Drake M, Dodd RL, et al. ((2003)) Oxidative damage to the endoplasmic reticulum is implicated in ischemic neuronal cell death. J Cereb Blood Flow Metab 23:: 1117--1128.
    • (2003) J Cereb Blood Flow Metab , vol.23 , pp. 1117-1128
    • Hayashi, T.1    Saito, A.2    Okuno, S.3    Ferrand-Drake, M.4    Dodd, R.L.5
  • 15
    • 41149169845 scopus 로고    scopus 로고
    • Involvement of selective reactive oxygen species upstream of proapoptotic branches of unfolded protein response
    • Yokouchi M, Hiramatsu N, Hayakawa K, Okamura M, Du S, et al. ((2008)) Involvement of selective reactive oxygen species upstream of proapoptotic branches of unfolded protein response. J Biol Chem 283:: 4252--4260.
    • (2008) J Biol Chem , vol.283 , pp. 4252-4260
    • Yokouchi, M.1    Hiramatsu, N.2    Hayakawa, K.3    Okamura, M.4    Du, S.5
  • 16
    • 38349169664 scopus 로고    scopus 로고
    • Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight?
    • Filipowicz W, Bhattacharyya SN, Sonenberg N, ((2008)) Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight? Nat Rev Genet 9:: 102--114.
    • (2008) Nat Rev Genet , vol.9 , pp. 102-114
    • Filipowicz, W.1    Bhattacharyya, S.N.2    Sonenberg, N.3
  • 17
    • 0347444723 scopus 로고    scopus 로고
    • MicroRNAs: genomics, biogenesis, mechanism, and function
    • Bartel DP, ((2004)) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116:: 281--297.
    • (2004) Cell , vol.116 , pp. 281-297
    • Bartel, D.P.1
  • 18
    • 0141843656 scopus 로고    scopus 로고
    • The nuclear RNase III Drosha initiates microRNA processing
    • Lee Y, Ahn C, Han J, Choi H, Kim J, et al. ((2003)) The nuclear RNase III Drosha initiates microRNA processing. Nature 425:: 415--419.
    • (2003) Nature , vol.425 , pp. 415-419
    • Lee, Y.1    Ahn, C.2    Han, J.3    Choi, H.4    Kim, J.5
  • 19
    • 79955593914 scopus 로고    scopus 로고
    • MicroRNAs as mediators and therapeutic targets in chronic kidney disease
    • Lorenzen JM, Haller H, Thum T, ((2011)) MicroRNAs as mediators and therapeutic targets in chronic kidney disease. Nat Rev Nephrol 7:: 286--294.
    • (2011) Nat Rev Nephrol , vol.7 , pp. 286-294
    • Lorenzen, J.M.1    Haller, H.2    Thum, T.3
  • 20
    • 82555179130 scopus 로고    scopus 로고
    • PHD1 interacts with ATF4 and negatively regulates its transcriptional activity without prolyl hydroxylation
    • Hiwatashi Y, Kanno K, Takasaki C, Goryo K, Sato T, et al. ((2011)) PHD1 interacts with ATF4 and negatively regulates its transcriptional activity without prolyl hydroxylation. Exp Cell Res.
    • (2011) Exp Cell Res
    • Hiwatashi, Y.1    Kanno, K.2    Takasaki, C.3    Goryo, K.4    Sato, T.5
  • 21
    • 0028010818 scopus 로고
    • HK-2: an immortalized proximal tubule epithelial cell line from normal adult human kidney
    • Ryan MJ, Johnson G, Kirk J, Fuerstenberg SM, Zager RA, et al. ((1994)) HK-2: an immortalized proximal tubule epithelial cell line from normal adult human kidney. Kidney Int 45:: 48--57.
    • (1994) Kidney Int , vol.45 , pp. 48-57
    • Ryan, M.J.1    Johnson, G.2    Kirk, J.3    Fuerstenberg, S.M.4    Zager, R.A.5
  • 22
    • 0038412774 scopus 로고    scopus 로고
    • Testing for differentially expressed genes with microarray data
    • Tsai CA, Chen YJ, Chen JJ, ((2003)) Testing for differentially expressed genes with microarray data. Nucleic Acids Res 31:: e52.
    • (2003) Nucleic Acids Res , vol.31
    • Tsai, C.A.1    Chen, Y.J.2    Chen, J.J.3
  • 24
    • 70349168446 scopus 로고    scopus 로고
    • Hypoxia-inducible mir-210 regulates normoxic gene expression involved in tumor initiation
    • Huang X, Ding L, Bennewith KL, Tong RT, Welford SM, et al. ((2009)) Hypoxia-inducible mir-210 regulates normoxic gene expression involved in tumor initiation. Mol Cell 35:: 856--867.
    • (2009) Mol Cell , vol.35 , pp. 856-867
    • Huang, X.1    Ding, L.2    Bennewith, K.L.3    Tong, R.T.4    Welford, S.M.5
  • 25
    • 80053259947 scopus 로고    scopus 로고
    • microRNA-210 is Upregulated in Hypoxic Cardiomyocytes through Akt- and p53-dependent Pathways and Exerts Cytoprotective Effects
    • Mutharasan RK, Nagpal V, Ichikawa Y, Ardehali H, ((2011)) microRNA-210 is Upregulated in Hypoxic Cardiomyocytes through Akt- and p53-dependent Pathways and Exerts Cytoprotective Effects. Am J Physiol Heart Circ Physiol.
    • (2011) Am J Physiol Heart Circ Physiol
    • Mutharasan, R.K.1    Nagpal, V.2    Ichikawa, Y.3    Ardehali, H.4
  • 26
    • 77955170881 scopus 로고    scopus 로고
    • Hypoxia-regulated microRNA-210 modulates mitochondrial function and decreases ISCU and COX10 expression
    • Chen Z, Li Y, Zhang H, Huang P, Luthra R, ((2010)) Hypoxia-regulated microRNA-210 modulates mitochondrial function and decreases ISCU and COX10 expression. Oncogene 29:: 4362--4368.
    • (2010) Oncogene , vol.29 , pp. 4362-4368
    • Chen, Z.1    Li, Y.2    Zhang, H.3    Huang, P.4    Luthra, R.5
  • 27
    • 77649270362 scopus 로고    scopus 로고
    • High glucose down-regulates miR-29a to increase collagen IV production in HK-2 cells
    • Du B, Ma LM, Huang MB, Zhou H, Huang HL, et al. ((2010)) High glucose down-regulates miR-29a to increase collagen IV production in HK-2 cells. FEBS Lett 584:: 811--816.
    • (2010) FEBS Lett , vol.584 , pp. 811-816
    • Du, B.1    Ma, L.M.2    Huang, M.B.3    Zhou, H.4    Huang, H.L.5
  • 28
    • 72449164871 scopus 로고    scopus 로고
    • Intrarenal expression of miRNAs in patients with hypertensive nephrosclerosis
    • Wang G, Kwan BC, Lai FM, Choi PC, Chow KM, et al. ((2010)) Intrarenal expression of miRNAs in patients with hypertensive nephrosclerosis. Am J Hypertens 23:: 78--84.
    • (2010) Am J Hypertens , vol.23 , pp. 78-84
    • Wang, G.1    Kwan, B.C.2    Lai, F.M.3    Choi, P.C.4    Chow, K.M.5
  • 30
    • 33644667584 scopus 로고    scopus 로고
    • Susceptibility to diabetic nephropathy is related to dicarbonyl and oxidative stress
    • Beisswenger PJ, Drummond KS, Nelson RG, Howell SK, Szwergold BS, et al. ((2005)) Susceptibility to diabetic nephropathy is related to dicarbonyl and oxidative stress. Diabetes 54:: 3274--3281.
    • (2005) Diabetes , vol.54 , pp. 3274-3281
    • Beisswenger, P.J.1    Drummond, K.S.2    Nelson, R.G.3    Howell, S.K.4    Szwergold, B.S.5
  • 31
    • 70349478990 scopus 로고    scopus 로고
    • MicroRNA-210 controls mitochondrial metabolism during hypoxia by repressing the iron-sulfur cluster assembly proteins ISCU1/2
    • Chan SY, Zhang YY, Hemann C, Mahoney CE, Zweier JL, et al. ((2009)) MicroRNA-210 controls mitochondrial metabolism during hypoxia by repressing the iron-sulfur cluster assembly proteins ISCU1/2. Cell Metab 10:: 273--284.
    • (2009) Cell Metab , vol.10 , pp. 273-284
    • Chan, S.Y.1    Zhang, Y.Y.2    Hemann, C.3    Mahoney, C.E.4    Zweier, J.L.5
  • 32
  • 33
    • 85011942157 scopus 로고    scopus 로고
    • The ups and downs of miR-205: identifying the roles of miR-205 in mammary gland development and breast cancer
    • Greene SB, Herschkowitz JI, Rosen JM, ((2010)) The ups and downs of miR-205: identifying the roles of miR-205 in mammary gland development and breast cancer. RNA Biol 7:: 300--304.
    • (2010) RNA Biol , vol.7 , pp. 300-304
    • Greene, S.B.1    Herschkowitz, J.I.2    Rosen, J.M.3
  • 34
    • 76649099166 scopus 로고    scopus 로고
    • A putative role for microRNA-205 in mammary epithelial cell progenitors
    • Greene SB, Gunaratne PH, Hammond SM, Rosen JM, ((2010)) A putative role for microRNA-205 in mammary epithelial cell progenitors. J Cell Sci 123:: 606--618.
    • (2010) J Cell Sci , vol.123 , pp. 606-618
    • Greene, S.B.1    Gunaratne, P.H.2    Hammond, S.M.3    Rosen, J.M.4
  • 36
    • 77957853315 scopus 로고    scopus 로고
    • MicroRNA-205 promotes keratinocyte migration via the lipid phosphatase SHIP2
    • Yu J, Peng H, Ruan Q, Fatima A, Getsios S, et al. ((2010)) MicroRNA-205 promotes keratinocyte migration via the lipid phosphatase SHIP2. Faseb J 24:: 3950--3959.
    • (2010) Faseb J , vol.24 , pp. 3950-3959
    • Yu, J.1    Peng, H.2    Ruan, Q.3    Fatima, A.4    Getsios, S.5
  • 38
    • 79955764602 scopus 로고    scopus 로고
    • miRNA-205 suppresses melanoma cell proliferation and induces senescence via regulation of E2F1 protein
    • Dar AA, Majid S, de Semir D, Nosrati M, Bezrookove V, et al. ((2011)) miRNA-205 suppresses melanoma cell proliferation and induces senescence via regulation of E2F1 protein. J Biol Chem 286:: 16606--16614.
    • (2011) J Biol Chem , vol.286 , pp. 16606-16614
    • Dar, A.A.1    Majid, S.2    de Semir, D.3    Nosrati, M.4    Bezrookove, V.5
  • 39
    • 65549115615 scopus 로고    scopus 로고
    • miR-205 Exerts tumor-suppressive functions in human prostate through down-regulation of protein kinase Cepsilon
    • Gandellini P, Folini M, Longoni N, Pennati M, Binda M, et al. ((2009)) miR-205 Exerts tumor-suppressive functions in human prostate through down-regulation of protein kinase Cepsilon. Cancer Res 69:: 2287--2295.
    • (2009) Cancer Res , vol.69 , pp. 2287-2295
    • Gandellini, P.1    Folini, M.2    Longoni, N.3    Pennati, M.4    Binda, M.5
  • 40
    • 79953331942 scopus 로고    scopus 로고
    • MicroRNA-205 inhibits Src-mediated oncogenic pathways in renal cancer
    • Majid S, Saini S, Dar AA, Hirata H, Shahryari V, et al. ((2011)) MicroRNA-205 inhibits Src-mediated oncogenic pathways in renal cancer. Cancer Res 71:: 2611--2621.
    • (2011) Cancer Res , vol.71 , pp. 2611-2621
    • Majid, S.1    Saini, S.2    Dar, A.A.3    Hirata, H.4    Shahryari, V.5
  • 42
    • 43049103824 scopus 로고    scopus 로고
    • The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1
    • Gregory PA, Bert AG, Paterson EL, Barry SC, Tsykin A, et al. ((2008)) The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nat Cell Biol 10:: 593--601.
    • (2008) Nat Cell Biol , vol.10 , pp. 593-601
    • Gregory, P.A.1    Bert, A.G.2    Paterson, E.L.3    Barry, S.C.4    Tsykin, A.5
  • 43
    • 79953108471 scopus 로고    scopus 로고
    • MiRNA-205 modulates cellular invasion and migration via regulating zinc finger E-box binding homeobox 2 expression in esophageal squamous cell carcinoma cells
    • Matsushima K, Isomoto H, Yamaguchi N, Inoue N, Machida H, et al. ((2011)) MiRNA-205 modulates cellular invasion and migration via regulating zinc finger E-box binding homeobox 2 expression in esophageal squamous cell carcinoma cells. J Transl Med 9:: 30.
    • (2011) J Transl Med , vol.9 , pp. 30
    • Matsushima, K.1    Isomoto, H.2    Yamaguchi, N.3    Inoue, N.4    Machida, H.5
  • 44
    • 73349086540 scopus 로고    scopus 로고
    • Intrarenal expression of microRNAs in patients with IgA nephropathy
    • Wang G, Kwan BC, Lai FM, Choi PC, Chow KM, et al. ((2010)) Intrarenal expression of microRNAs in patients with IgA nephropathy. Lab Invest 90:: 98--103.
    • (2010) Lab Invest , vol.90 , pp. 98-103
    • Wang, G.1    Kwan, B.C.2    Lai, F.M.3    Choi, P.C.4    Chow, K.M.5
  • 45
    • 38649143118 scopus 로고    scopus 로고
    • Deficiency or inhibition of oxygen sensor Phd1 induces hypoxia tolerance by reprogramming basal metabolism
    • Aragones J, Schneider M, Van Geyte K, Fraisl P, Dresselaers T, et al. ((2008)) Deficiency or inhibition of oxygen sensor Phd1 induces hypoxia tolerance by reprogramming basal metabolism. Nat Genet 40:: 170--180.
    • (2008) Nat Genet , vol.40 , pp. 170-180
    • Aragones, J.1    Schneider, M.2    Van Geyte, K.3    Fraisl, P.4    Dresselaers, T.5
  • 46
    • 34047228387 scopus 로고    scopus 로고
    • Protective role of hypoxia-inducible factor-2alpha against ischemic damage and oxidative stress in the kidney
    • Kojima I, Tanaka T, Inagi R, Kato H, Yamashita T, et al. ((2007)) Protective role of hypoxia-inducible factor-2alpha against ischemic damage and oxidative stress in the kidney. J Am Soc Nephrol 18:: 1218--1226.
    • (2007) J Am Soc Nephrol , vol.18 , pp. 1218-1226
    • Kojima, I.1    Tanaka, T.2    Inagi, R.3    Kato, H.4    Yamashita, T.5
  • 47
    • 67650481882 scopus 로고    scopus 로고
    • Selective inhibition of hypoxia-inducible factor (HIF) prolyl-hydroxylase 1 mediates neuroprotection against normoxic oxidative death via HIF- and CREB-independent pathways
    • Siddiq A, Aminova LR, Troy CM, Suh K, Messer Z, et al. ((2009)) Selective inhibition of hypoxia-inducible factor (HIF) prolyl-hydroxylase 1 mediates neuroprotection against normoxic oxidative death via HIF- and CREB-independent pathways. Journal of Neuroscience 29:: 8828--8838.
    • (2009) Journal of Neuroscience , vol.29 , pp. 8828-8838
    • Siddiq, A.1    Aminova, L.R.2    Troy, C.M.3    Suh, K.4    Messer, Z.5
  • 48
    • 39349100840 scopus 로고    scopus 로고
    • Targeting of the molecular chaperone oxygen-regulated protein 150 (ORP150) to mitochondria and its induction by cellular stress
    • Arrington DD, Schnellmann RG, ((2008)) Targeting of the molecular chaperone oxygen-regulated protein 150 (ORP150) to mitochondria and its induction by cellular stress. Am J Physiol Cell Physiol 294:: C641--650.
    • (2008) Am J Physiol Cell Physiol , vol.294
    • Arrington, D.D.1    Schnellmann, R.G.2
  • 49
    • 68049116920 scopus 로고    scopus 로고
    • Prolyl hydroxylase inhibition attenuates post-ischemic cardiac injury via induction of endoplasmic reticulum stress genes
    • Natarajan R, Salloum FN, Fisher BJ, Smithson L, Almenara J, et al. ((2009)) Prolyl hydroxylase inhibition attenuates post-ischemic cardiac injury via induction of endoplasmic reticulum stress genes. Vascul Pharmacol 51:: 110--118.
    • (2009) Vascul Pharmacol , vol.51 , pp. 110-118
    • Natarajan, R.1    Salloum, F.N.2    Fisher, B.J.3    Smithson, L.4    Almenara, J.5
  • 50
    • 0035877643 scopus 로고    scopus 로고
    • Identification of activating transcription factor 4 (ATF4) as an Nrf2-interacting protein. Implication for heme oxygenase-1 gene regulation
    • He CH, Gong P, Hu B, Stewart D, Choi ME, et al. ((2001)) Identification of activating transcription factor 4 (ATF4) as an Nrf2-interacting protein. Implication for heme oxygenase-1 gene regulation. J Biol Chem 276:: 20858--20865.
    • (2001) J Biol Chem , vol.276 , pp. 20858-20865
    • He, C.H.1    Gong, P.2    Hu, B.3    Stewart, D.4    Choi, M.E.5


* 이 정보는 Elsevier사의 SCOPUS DB에서 KISTI가 분석하여 추출한 것입니다.