Gene Symbol: krt4
Description: keratin 4
Alias: cb59, etID20321.6, krt8, wu:fa91a11, wu:fd19e09, wu:fl23c09, zf-K8, keratin 4, cytokeratin, keratin 8
Species: zebrafish
Products:     krt4

Top Publications

  1. Lee R, AshaRani P, Carney T. Basal keratinocytes contribute to all strata of the adult zebrafish epidermis. PLoS ONE. 2014;9:e84858 pubmed publisher
    ..Future use of this promoter will assist genetic analysis of basal keratinocyte biology in zebrafish. ..
  2. Gong Z, Ju B, Wang X, He J, Wan H, Sudha P, et al. Green fluorescent protein expression in germ-line transmitted transgenic zebrafish under a stratified epithelial promoter from keratin8. Dev Dyn. 2002;223:204-15 pubmed
    A zebrafish cDNA encoding a novel keratin protein was characterized and named keratin8, or krt8. krt8 expression was initiated at 4.5 hr postfertilization, immediately after the time of zygotic genome activation...
  3. Li Z, Huang X, Zhan H, Zeng Z, Li C, Spitsbergen J, et al. Inducible and repressable oncogene-addicted hepatocellular carcinoma in Tet-on xmrk transgenic zebrafish. J Hepatol. 2012;56:419-25 pubmed publisher
    ..It provides clear evidence for the requirement of only a single oncogene for HCC initiation and maintenance and is thus a convenient model for further investigation of oncogene addiction and future anti-cancer drug screening. ..
  4. Parinov S, Kondrichin I, Korzh V, Emelyanov A. Tol2 transposon-mediated enhancer trap to identify developmentally regulated zebrafish genes in vivo. Dev Dyn. 2004;231:449-59 pubmed
    ..and displayed various specific EGFP expression patterns in addition to basal expression from the modified keratin 8 promoter...
  5. Kondrychyn I, Garcia Lecea M, Emelyanov A, Parinov S, Korzh V. Genome-wide analysis of Tol2 transposon reintegration in zebrafish. BMC Genomics. 2009;10:418 pubmed publisher
    ..This information will influence the development of various applications involving DNA transposons and Tol2 in particular. ..
  6. Lam P, Harvie E, Huttenlocher A. Heat shock modulates neutrophil motility in zebrafish. PLoS ONE. 2013;8:e84436 pubmed publisher
    ..Our results indicate that routine heat shock can alter neutrophil function in zebrafish. The findings suggest that caution should be taken when employing a heat shock-dependent inducible system to study the innate immune response. ..
  7. Shiau C, Monk K, Joo W, Talbot W. An anti-inflammatory NOD-like receptor is required for microglia development. Cell Rep. 2013;5:1342-52 pubmed publisher
    ..Together, these results demonstrate that NLRC3-like prevents inappropriate macrophage activation, thereby allowing normal microglial development. ..
  8. Chen C, Chu C, Chen T, Lee S, Shen C, Hsiao C. Establishment of a transgenic zebrafish line for superficial skin ablation and functional validation of apoptosis modulators in vivo. PLoS ONE. 2011;6:e20654 pubmed publisher
    ..A transgenic zebrafish line of Tg(krt4:NTR-hKikGR)(cy17) (killer line), which can conditionally trigger apoptosis in superficial skin cells, was first ..
  9. Nowak M, Koster C, Hammerschmidt M. Perp is required for tissue-specific cell survival during zebrafish development. Cell Death Differ. 2005;12:52-64 pubmed
    ..We conclude that, in contrast to its proapoptotic function in stressed cells, Perp plays an antiapoptotic role during normal zebrafish development to regulate tissue-specific cell survival. ..

More Information


  1. Fukazawa C, Santiago C, Park K, Deery W, Gomez de la Torre Canny S, Holterhoff C, et al. poky/chuk/ikk1 is required for differentiation of the zebrafish embryonic epidermis. Dev Biol. 2010;346:272-83 pubmed publisher
  2. Ju B, Spitsbergen J, Eden C, Taylor M, Chen W. Co-activation of hedgehog and AKT pathways promote tumorigenesis in zebrafish. Mol Cancer. 2009;8:40 pubmed publisher
    ..These results suggest that co-activation of the hedgehog and AKT pathways promote tumorigenesis, and that the binary transgenic approach is a useful tool for studying interaction of oncogenes and oncogenic pathways in zebrafish. ..
  3. Sabel J, d Alençon C, O Brien E, Van Otterloo E, Lutz K, Cuykendall T, et al. Maternal Interferon Regulatory Factor 6 is required for the differentiation of primary superficial epithelia in Danio and Xenopus embryos. Dev Biol. 2009;325:249-62 pubmed publisher
    ..These experiments reveal a conserved role for maternally-encoded Irf6 in differentiation of a simple epithelium in X. laevis and D. rerio. This epithelium constitutes a novel model tissue in which to explore the Irf6 regulatory pathway. ..
  4. Emelyanov A, Gao Y, Naqvi N, Parinov S. Trans-kingdom transposition of the maize dissociation element. Genetics. 2006;174:1095-104 pubmed
  5. Imboden M, Goblet C, Korn H, Vriz S. Cytokeratin 8 is a suitable epidermal marker during zebrafish development. C R Acad Sci III. 1997;320:689-700 pubmed
    We have cloned and characterized the zebrafish (Danio rerio) homologous cytokeratin 8 (zf-K8) cDNA. This cytokeratin belongs to the gene family of intermediate filaments and it is a component of the cytoskeleton of epithelial cells...
  6. Krushna Padhi B, Akimenko M, Ekker M. Independent expansion of the keratin gene family in teleostean fish and mammals: an insight from phylogenetic analysis and radiation hybrid mapping of keratin genes in zebrafish. Gene. 2006;368:37-45 pubmed
    ..This contrasts with other members of the keratin gene family, which diverged independently between fish and mammals. ..
  7. Ju B, Xu Y, He J, Liao J, Yan T, Hew C, et al. Faithful expression of green fluorescent protein (GFP) in transgenic zebrafish embryos under control of zebrafish gene promoters. Dev Genet. 1999;25:158-67 pubmed
    ..The first clone encodes a type II cytokeratin (CK), which is specifically expressed in skin epithelia in early embryos and prominently expressed in the adult ..
  8. Hug B, Walter V, Grunwald D. tbx6, a Brachyury-related gene expressed by ventral mesendodermal precursors in the zebrafish embryo. Dev Biol. 1997;183:61-73 pubmed
    ..However, no tail appears to contribute to the maintenance of normal levels of tbx6 transcription and may be required for tbx6 transcription in the developing tail. ..
  9. Potok M, Nix D, Parnell T, Cairns B. Reprogramming the maternal zebrafish genome after fertilization to match the paternal methylation pattern. Cell. 2013;153:759-72 pubmed publisher
    ..Thus, zebrafish achieve a totipotent chromatin state at ZGA through paternal genome competency and maternal genome DNAme reprogramming. ..
  10. Ton Q, Kathryn Iovine M. Semaphorin3d mediates Cx43-dependent phenotypes during fin regeneration. Dev Biol. 2012;366:195-203 pubmed publisher
    ..Furthermore, functional evaluation of putative Sema3d receptors suggests that Cx43-dependent cell proliferation and joint formation utilize independent membrane-bound receptors to mediate downstream cellular phenotypes. ..
  11. Lepage S, Tada M, Bruce A. Zebrafish Dynamin is required for maintenance of enveloping layer integrity and the progression of epiboly. Dev Biol. 2014;385:52-66 pubmed publisher
    ..Furthermore, we show that Dynamin maintains EVL and promotes epiboly progression by antagonizing Rho A activity. ..
  12. Pei W, Noushmehr H, Costa J, Ouspenskaia M, Elkahloun A, Feldman B. An early requirement for maternal FoxH1 during zebrafish gastrulation. Dev Biol. 2007;310:10-22 pubmed
    ..Probing FoxH1 morphant RNA by microarray, we identified a cohort of five keratin genes--cyt1, cyt2, krt4, krt8 and krt18--that are normally transcribed in the embryo's enveloping layer (EVL) and which have significantly ..
  13. Heiden T, Struble C, Rise M, Hessner M, Hutz R, Carvan M. Molecular targets of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) within the zebrafish ovary: insights into TCDD-induced endocrine disruption and reproductive toxicity. Reprod Toxicol. 2008;25:47-57 pubmed
    ..Data presented here provide further insight into the mechanisms by which TCDD disrupts follicular development and reproduction in fish, and can be used to formulate new hypotheses regarding previously documented ovarian toxicity. ..
  14. Freisinger C, Huttenlocher A. Live imaging and gene expression analysis in zebrafish identifies a link between neutrophils and epithelial to mesenchymal transition. PLoS ONE. 2014;9:e112183 pubmed publisher
    ..Taken together, these findings implicate both autocrine and paracrine signaling through Cxcr2 in the regulation of inflammation and gene expression in transformed epithelial cells. ..
  15. Sims K, Eble D, Iovine M. Connexin43 regulates joint location in zebrafish fins. Dev Biol. 2009;327:410-8 pubmed publisher
    ..One possibility is that communication between the Cx43-positive mesenchyme and the overlying ZNS5-positive cells regulates joint location, and upregulation of Cx43 in joint-forming cells contributes to joint morphogenesis. ..
  16. Roberts J, Miguel Escalada I, Slovik K, Walsh K, Hadzhiev Y, Sanges R, et al. Targeted transgene integration overcomes variability of position effects in zebrafish. Development. 2014;141:715-24 pubmed publisher
  17. Lisse T, Middleton L, Pellegrini A, Martin P, Spaulding E, Lopes O, et al. Paclitaxel-induced epithelial damage and ectopic MMP-13 expression promotes neurotoxicity in zebrafish. Proc Natl Acad Sci U S A. 2016;113:E2189-98 pubmed publisher
    ..Thus, our studies provide evidence that the epidermis plays a critical role in this condition, and we provide a previously unidentified candidate for therapeutic interventions. ..
  18. Mishima Y, Tomari Y. Codon Usage and 3' UTR Length Determine Maternal mRNA Stability in Zebrafish. Mol Cell. 2016;61:874-85 pubmed publisher
    ..Our study thus highlights the codon-mediated mRNA decay as a conserved regulatory mechanism in eukaryotes. ..
  19. Richardson R, Metzger M, Knyphausen P, Ramezani T, Slanchev K, Kraus C, et al. Re-epithelialization of cutaneous wounds in adult zebrafish combines mechanisms of wound closure in embryonic and adult mammals. Development. 2016;143:2077-88 pubmed publisher
  20. Doğanlı C, Beck H, Ribera A, Oxvig C, Lykke Hartmann K. ?3Na+/K+-ATPase deficiency causes brain ventricle dilation and abrupt embryonic motility in zebrafish. J Biol Chem. 2013;288:8862-74 pubmed publisher
    ..Our data thus strongly support the role of ?3Na(+)/K(+)-ATPase in zebrafish motility and brain development, associating for the first time the ?3Na(+)/K(+)-ATPase deficiency with brain ventricle dilation. ..
  21. Wan H, He J, Ju B, Yan T, Lam T, Gong Z. Generation of two-color transgenic zebrafish using the green and red fluorescent protein reporter genes gfp and rfp. Mar Biotechnol (NY). 2002;4:146-54 pubmed
    ..One promoter (CK), derived from a cytokeratin gene, is active specifically in skin epithelia in embryos, and the other promoter (MLC) from a muscle-specific ..
  22. Brend T, Holley S. Expression of the oscillating gene her1 is directly regulated by Hairy/Enhancer of Split, T-box, and Suppressor of Hairless proteins in the zebrafish segmentation clock. Dev Dyn. 2009;238:2745-59 pubmed publisher
    ..These data provide the foundation for a precise description of the regulatory grammar that defines oscillating gene expression in the zebrafish segmentation clock...
  23. Schwend T, Loucks E, Snyder D, Ahlgren S. Requirement of Npc1 and availability of cholesterol for early embryonic cell movements in zebrafish. J Lipid Res. 2011;52:1328-44 pubmed publisher
    ..Collectively, these studies show that npc1 is required early for proper cell movement and cholesterol localization and later for cell survival. ..
  24. Hatzold J, Beleggia F, Herzig H, Altmuller J, Nurnberg P, Bloch W, et al. Tumor suppression in basal keratinocytes via dual non-cell-autonomous functions of a Na,K-ATPase beta subunit. elife. 2016;5: pubmed publisher
    ..Our results identify hypotonic stress as a (previously unrecognized) contributor to tumor development and establish a novel paradigm of tumor suppression. ..
  25. Gündel U, Kalkhof S, Zitzkat D, von Bergen M, Altenburger R, Küster E. Concentration-response concept in ecotoxicoproteomics: effects of different phenanthrene concentrations to the zebrafish (Danio rerio) embryo proteome. Ecotoxicol Environ Saf. 2012;76:11-22 pubmed publisher
    ..Using this experimental design based on testing of several exposure concentrations and less replicates might provide a step forward in getting increased output from toxicoproteomics studies. ..
  26. Yin C, Evason K, Maher J, Stainier D. The basic helix-loop-helix transcription factor, heart and neural crest derivatives expressed transcript 2, marks hepatic stellate cells in zebrafish: analysis of stellate cell entry into the developing liver. Hepatology. 2012;56:1958-70 pubmed publisher
    ..The Tg(hand2:EGFP) line represents a unique tool for in vivo analysis and molecular dissection of HSC behavior. ..
  27. Havis E, Anselme I, Schneider Maunoury S. Whole embryo chromatin immunoprecipitation protocol for the in vivo study of zebrafish development. Biotechniques. 2006;40:34, 36, 38 passim pubmed
  28. Hall C, Boyle R, Sun X, Wicker S, Misa J, Krissansen G, et al. Epidermal cells help coordinate leukocyte migration during inflammation through fatty acid-fuelled matrix metalloproteinase production. Nat Commun. 2014;5:3880 pubmed publisher
    ..Targeting of this metabolic-immunologic interface within keratinocytes may prove useful in treating inflammatory dermatoses. ..
  29. Chatterjee S, Min L, Karuturi R, Lufkin T. The role of post-transcriptional RNA processing and plasmid vector sequences on transient transgene expression in zebrafish. Transgenic Res. 2010;19:299-304 pubmed publisher
    ..In this model, the 2.3 kb promoter taken from the 5' upstream region of the transcription initiation site of keratin 4 (krt4) was used to drive the enhanced green fluorescence protein (EGFP) reporter gene in a transgenic vector...
  30. Li E, Truong D, Hallett S, Mukherjee K, Schutte B, Liao E. Rapid functional analysis of computationally complex rare human IRF6 gene variants using a novel zebrafish model. PLoS Genet. 2017;13:e1007009 pubmed publisher
    ..Furthermore, it unlocked the possibility for characterizing yet undiscovered human IRF6 missense gene variants from orofacial cleft patients, and illustrated a generalizable functional genomics paradigm in personalized medicine. ..
  31. Mesquita S, van Drooge B, Oliveira E, Grimalt J, Barata C, Vieira N, et al. Differential embryotoxicity of the organic pollutants in rural and urban air particles. Environ Pollut. 2015;206:535-42 pubmed publisher
    ..The observed effects can be directly related to air pollution-related human disorders, suggesting different potential adverse outcomes for human populations exposed to air pollution from specific sources. ..
  32. Shimizu T, Yabe T, Muraoka O, Yonemura S, Aramaki S, Hatta K, et al. E-cadherin is required for gastrulation cell movements in zebrafish. Mech Dev. 2005;122:747-63 pubmed
    ..These data suggest that E-cadherin-mediated cell adhesion between the DC and EVL plays a role in the epiboly movement in zebrafish. ..
  33. Tsujimura T, Chinen A, Kawamura S. Identification of a locus control region for quadruplicated green-sensitive opsin genes in zebrafish. Proc Natl Acad Sci U S A. 2007;104:12813-8 pubmed
    ..5-kb region conferred the SDC-specific expression for promoters of a non-SDC (UV opsin) and a nonretinal (keratin 8) gene. Changing the location of the 0...
  34. Li Z, Zheng W, Wang Z, Zeng Z, Zhan H, Li C, et al. A transgenic zebrafish liver tumor model with inducible Myc expression reveals conserved Myc signatures with mammalian liver tumors. Dis Model Mech. 2013;6:414-23 pubmed publisher
    ..Thus, our zebrafish model demonstrated the conserved role of Myc in promoting hepatocarcinogenesis in all vertebrate species. ..
  35. Paul T, Rovnak J, Quackenbush S, WHITLOCK K, Zhan H, Gong Z, et al. Transgenic expression of walleye dermal sarcoma virus rv-cyclin (orfA) in zebrafish does not result in tissue proliferation. Mar Biotechnol (NY). 2011;13:142-50 pubmed publisher
    ..These data indicate that rv-cyclin is not independently sufficient for tumor induction in zebrafish...
  36. Liu H, Leslie E, Jia Z, Smith T, Eshete M, Butali A, et al. Irf6 directly regulates Klf17 in zebrafish periderm and Klf4 in murine oral epithelium, and dominant-negative KLF4 variants are present in patients with cleft lip and palate. Hum Mol Genet. 2016;25:766-76 pubmed publisher
    ..These results indicate that rare NSCL/P risk variants can be found in members of the gene regulatory network governing periderm differentiation. ..
  37. Teh C, Chudakov D, Poon K, Mamedov I, Sek J, Shidlovsky K, et al. Optogenetic in vivo cell manipulation in KillerRed-expressing zebrafish transgenics. BMC Dev Biol. 2010;10:110 pubmed publisher
    ..Hence, the zebrafish transgenics expressing mem-KR in a tissue-specific manner are useful tools for studying the biological effects of ROS. ..
  38. Shiau C, Kaufman Z, Meireles A, Talbot W. Differential requirement for irf8 in formation of embryonic and adult macrophages in zebrafish. PLoS ONE. 2015;10:e0117513 pubmed publisher
    ..Our study defines distinct requirement for irf8 in myelopoiesis before and after transition to the adult hematopoietic system. ..
  39. Banerji R, Eble D, Iovine M, Skibbens R. Esco2 regulates cx43 expression during skeletal regeneration in the zebrafish fin. Dev Dyn. 2016;245:7-21 pubmed publisher
    ..These results conceptually link ODDD to cohesinopathies and provide evidence that ESCO2 may play a transcriptional role critical for human development. ..
  40. Eskova A, Chauvigné F, Maischein H, Ammelburg M, Cerdà J, NUSSLEIN VOLHARD C, et al. Gain-of-function mutations in Aqp3a influence zebrafish pigment pattern formation through the tissue environment. Development. 2017;144:2059-2069 pubmed publisher
    ..These results demonstrate an important effect of the tissue environment on pigment cell behaviour and, thereby, on pattern formation. ..
  41. Fischer B, Metzger M, Richardson R, Knyphausen P, Ramezani T, Franzen R, et al. p53 and TAp63 promote keratinocyte proliferation and differentiation in breeding tubercles of the zebrafish. PLoS Genet. 2014;10:e1004048 pubmed publisher
  42. Schaffeld M, Knappe M, Hunzinger C, Markl J. cDNA sequences of the authentic keratins 8 and 18 in zebrafish. Differentiation. 2003;71:73-82 pubmed
    ..Moreover, several zebrafish type II keratin sequences published by other authors have now been assigned to epidermal keratins, previously identified biochemically. ..
  43. Zeng Z, Liu X, Seebah S, Gong Z. Faithful expression of living color reporter genes in transgenic medaka under two tissue-specific zebrafish promoters. Dev Dyn. 2005;234:387-92 pubmed
    ..In the krt8:rfp transgenic medaka line with the zebrafish epithelial krt8 promoter, red fluorescent protein was specifically ..
  44. Liu X, Li Z, Emelyanov A, Parinov S, Gong Z. Generation of oocyte-specifically expressed cre transgenic zebrafish for female germline excision of loxP-flanked transgene. Dev Dyn. 2008;237:2955-62 pubmed publisher
    ..The transgenic line Tg(zp3:cre; krt8:rfp) also contains a co-integrated rfp transgene under the skin epithelial promoter krt8 to allow selection of cre ..
  45. Leslie E, Liu H, Carlson J, Shaffer J, Feingold E, WEHBY G, et al. A Genome-wide Association Study of Nonsyndromic Cleft Palate Identifies an Etiologic Missense Variant in GRHL3. Am J Hum Genet. 2016;98:744-54 pubmed publisher
    ..This finding advances our understanding of the genetic basis of craniofacial development and might ultimately lead to improvements in recurrence risk prediction, treatment, and prognosis. ..
  46. Krens S, Möllmert S, Heisenberg C. Enveloping cell-layer differentiation at the surface of zebrafish germ-layer tissue explants. Proc Natl Acad Sci U S A. 2011;108:E9-10; author reply E11 pubmed publisher
  47. Chen H, Beasley A, Hu Y, Chen X. A Zebrafish Model for Studies on Esophageal Epithelial Biology. PLoS ONE. 2015;10:e0143878 pubmed publisher loss or disorganization of the squamous epithelium, as well as down-regulation of the differentiation markers Krt4 and Krt5...
  48. Ramezani T, Laux D, Bravo I, Tada M, Feng Y. Live imaging of innate immune and preneoplastic cell interactions using an inducible Gal4/UAS expression system in larval zebrafish skin. J Vis Exp. 2015;: pubmed publisher
    ..We also discuss how one might adapt our protocol to achieve temporal and spatial control of ectopic gene expression in any tissue of interest. ..
  49. Rasmussen J, Sack G, Martin S, Sagasti A. Vertebrate epidermal cells are broad-specificity phagocytes that clear sensory axon debris. J Neurosci. 2015;35:559-70 pubmed publisher
    ..Together, these results identify vertebrate epidermal cells as broad-specificity phagocytes that likely contribute to neural repair and wound healing. ..
  50. Peyrard Janvid M, Leslie E, Kousa Y, Smith T, Dunnwald M, Magnusson M, et al. Dominant mutations in GRHL3 cause Van der Woude Syndrome and disrupt oral periderm development. Am J Hum Genet. 2014;94:23-32 pubmed publisher
    ..They supported the hypotheses that both genes are essential for the presence of a functional oral periderm and that failure of this process contributes to VWS. ..
  51. Siddiqui M, Sheikh H, Tran C, Bruce A. The tight junction component Claudin E is required for zebrafish epiboly. Dev Dyn. 2010;239:715-22 pubmed publisher
    ..Our work is the first to demonstrate that Claudins are important for zebrafish epiboly. ..
  52. Dalton L, Kamarashev J, Barinaga Rementeria Ramírez I, White G, Malliri A, Hurlstone A. Constitutive RAC activation is not sufficient to initiate melanocyte neoplasia but accelerates malignant progression. J Invest Dermatol. 2013;133:1572-81 pubmed publisher
    ..Thus, our data suggest that Rac contributes to the progression of melanoma and that Tiam1 may activate Rac in nodular presentations. ..
  53. Roh Johnson M, Shah A, Stonick J, Poudel K, Kargl J, Yang G, et al. Macrophage-Dependent Cytoplasmic Transfer during Melanoma Invasion In Vivo. Dev Cell. 2017;43:549-562.e6 pubmed publisher
    ..Thus, we present a model in which macrophage/tumor cell contact allows for the transfer of cytoplasmic molecules from macrophages to tumor cells corresponding to increased tumor cell motility and dissemination. ..
  54. O Brien G, Rieger S, Wang F, Smolen G, Gonzalez R, Buchanan J, et al. Coordinate development of skin cells and cutaneous sensory axons in zebrafish. J Comp Neurol. 2012;520:816-31 pubmed publisher
  55. Webb A, Driever W, Kimelman D. psoriasis regulates epidermal development in zebrafish. Dev Dyn. 2008;237:1153-64 pubmed publisher
  56. Schaffeld M, Haberkamp M, Braziulis E, Lieb B, Markl J. Type II keratin cDNAs from the rainbow trout: implications for keratin evolution. Differentiation. 2002;70:292-9 pubmed
    ..The tree also indicates that the published zebrafish sequences represent IIe keratins and that the biochemically identified K8 ortholog in zebrafish has not yet been sequenced. ..
  57. Chen C, Lin D, Cheng C, Lin C, Lo Y, Yen C, et al. Cdc6 cooperates with c-Myc to promote genome instability and epithelial to mesenchymal transition EMT in zebrafish. Oncotarget. 2014;5:6300-11 pubmed using tol2 transposon, in which cdc6 and c-myc were co-overexpressed in epidermis driven by a skin-specific krt4 promoter...
  58. Wada H, Ghysen A, Asakawa K, Abe G, Ishitani T, Kawakami K. Wnt/Dkk negative feedback regulates sensory organ size in zebrafish. Curr Biol. 2013;23:1559-65 pubmed publisher
    ..This study establishes Wnt/Dkk as a novel mechanism to determine the final size of an organ. ..