Rho

Summary

Gene Symbol: Rho
Description: rhodopsin
Alias: rhodopsin, Rhodopsin (retinitis pigmentosa 4, autosomal dominant)
Species: rat
Products:     Rho

Top Publications

  1. Dryja T, McGee T, Hahn L, Cowley G, Olsson J, Reichel E, et al. Mutations within the rhodopsin gene in patients with autosomal dominant retinitis pigmentosa. N Engl J Med. 1990;323:1302-7 pubmed
    ..The rod photoreceptors are responsible for night vision and use rhodopsin as the photosensitive pigment...
  2. Lei B, Yao G, Zhang K, Hofeldt K, Chang B. Study of rod- and cone-driven oscillatory potentials in mice. Invest Ophthalmol Vis Sci. 2006;47:2732-8 pubmed
    ..obtained in three mouse models: wild-type C57BL/6J mouse, cone photoreceptor function loss 1 (cpfl1) mouse, and rhodopsin knockout (rho-/-) mouse. A Butterworth filter was used to extract OPs from ERG signals...
  3. Kosmaoglou M, Kanuga N, Aguilà M, Garriga P, Cheetham M. A dual role for EDEM1 in the processing of rod opsin. J Cell Sci. 2009;122:4465-72 pubmed publisher
  4. Azam M, Khan M, Gal A, Hussain A, Shah S, Khan M, et al. A homozygous p.Glu150Lys mutation in the opsin gene of two Pakistani families with autosomal recessive retinitis pigmentosa. Mol Vis. 2009;15:2526-34 pubmed
    ..In two families, RP21 and RP53, homozygosity mapping suggested RHO, the gene encoding rhodopsin, as a candidate disease gene on chromosome 3q21...
  5. Kaur J, Mencl S, Sahaboglu A, Farinelli P, van Veen T, Zrenner E, et al. Calpain and PARP activation during photoreceptor cell death in P23H and S334ter rhodopsin mutant rats. PLoS ONE. 2011;6:e22181 pubmed publisher
    ..Many human cases are caused by mutations in the rhodopsin gene...
  6. Shinde V, Sizova O, Lin J, Lavail M, Gorbatyuk M. ER stress in retinal degeneration in S334ter Rho rats. PLoS ONE. 2012;7:e33266 pubmed publisher
    The S334ter rhodopsin (Rho) rat (line 4) bears the rhodopsin gene with an early termination codon at residue 334 that is a model for several such mutations found in human patients with autosomal dominant retinitis pigmentosa (ADRP)...
  7. Westfall J, Hoyt C, Liu Q, Hsiao Y, Pierce E, Page McCaw P, et al. Retinal degeneration and failure of photoreceptor outer segment formation in mice with targeted deletion of the Joubert syndrome gene, Ahi1. J Neurosci. 2010;30:8759-68 pubmed publisher
    ..The retinal degeneration observed in Ahi1(-/-) mice recapitulates aspects of the retinal phenotype observed in patients with JBTS and suggests the importance of Ahi1 in photoreceptor function. ..
  8. Szabó K, Szabó A, Enzsoly A, Szel A, Lukats A. Immunocytochemical analysis of misplaced rhodopsin-positive cells in the developing rodent retina. Cell Tissue Res. 2014;356:49-63 pubmed publisher
    During the first postnatal weeks of the developing rodent retina, rhodopsin can be detected in a number of neuron-like cells in the inner retina...
  9. Mussolino C, Sanges D, Marrocco E, Bonetti C, Di Vicino U, Marigo V, et al. Zinc-finger-based transcriptional repression of rhodopsin in a model of dominant retinitis pigmentosa. EMBO Mol Med. 2011;3:118-28 pubmed publisher
    ..Here, we generated a series of transcriptional repressors to silence human rhodopsin (hRHO), the gene most abundantly expressed in retinal photoreceptors...

More Information

Publications64

  1. Pinilla I, Lund R, Sauve Y. Enhanced cone dysfunction in rats homozygous for the P23H rhodopsin mutation. Neurosci Lett. 2005;382:16-21 pubmed
    ..P23H transgenic rat is a model of autosomal dominant retinitis pigmentosa, in which a mutation in the rhodopsin gene leads to a rapid loss of rods and a more protracted loss of cones...
  2. Chuang J, Hsu Y, Sung C. Ultrastructural visualization of trans-ciliary rhodopsin cargoes in mammalian rods. Cilia. 2015;4:4 pubmed publisher
    ..In the vertebrate photoreceptor, rhodopsin is synthesized and transported from the inner segment to the disc membranes of the outer segment (OS), which is ..
  3. Lei B. Rod-driven OFF pathway responses in the distal retina: dark-adapted flicker electroretinogram in mouse. PLoS ONE. 2012;7:e43856 pubmed publisher
    ..dark-adapted flicker ERGs were obtained in wild-type mice (C57BL/6), in mice with pure rod (cpfl1) or pure cone (rho(-/-)) function, and in nob1 mice which have a selective ON-pathway defect...
  4. Rivera De La Parra D, Cabral Macias J, Matias Florentino M, Rodriguez Ruiz G, Robredo V, Zenteno J. Rhodopsin p.N78I dominant mutation causing sectorial retinitis pigmentosa in a pedigree with intrafamilial clinical heterogeneity. Gene. 2013;519:173-6 pubmed publisher
    ..Molecular analysis included direct nucleotide sequencing of the rhodopsin gene (RHO), at chromosome 3q21-q24, in DNA from a total of 4 affected sibs...
  5. Yu X, Chung M, Morabito M, Barnstable C. Shared nuclear protein binding sites in the upstream region of the rat opsin gene. Biochem Biophys Res Commun. 1993;191:76-82 pubmed
    ..The protein(s) were also present at adult levels at birth, suggesting that they may represent differentiation products expressed in the proliferating retinal epithelium. ..
  6. Barnstable C, Morabito M. Isolation and coding sequence of the rat rod opsin gene. J Mol Neurosci. 1994;5:207-9 pubmed
  7. Daiger S, Sullivan L, Bowne S. Genes and mutations causing retinitis pigmentosa. Clin Genet. 2013;84:132-41 pubmed publisher
    ..In this review, we summarize the current approaches to gene discovery and mutation detection for RP, and indicate pitfalls and unsolved problems. Similar considerations apply to other forms of inherited retinal disease. ..
  8. Wahlin K, Adler R, Zack D, Campochiaro P. Neurotrophic signaling in normal and degenerating rodent retinas. Exp Eye Res. 2001;73:693-701 pubmed
    ..These data add to the mounting evidence suggesting that neurotrophic factors act indirectly through Müller cells to promote photoreceptor survival. ..
  9. Ekema G, Zheng W, Lu L. Interaction of GABA receptor/channel rho(1) and gamma(2) subunit. Invest Ophthalmol Vis Sci. 2002;43:2326-33 pubmed
    ..occur between gamma-aminobutyric acid (GABA)(A) receptor/channels gamma(2) subunit and the retina-specific GABA(C) rho(1) subunit...
  10. Zhao Y, Hong D, Pawlyk B, Yue G, Adamian M, Grynberg M, et al. The retinitis pigmentosa GTPase regulator (RPGR)- interacting protein: subserving RPGR function and participating in disk morphogenesis. Proc Natl Acad Sci U S A. 2003;100:3965-70 pubmed
    ..A defect in RPGRIP encompasses loss of both functions, hence the more severe clinical manifestation as LCA. ..
  11. Soliman H, Craig G, Nagareddy P, Yuen V, Lin G, Kumar U, et al. Role of inducible nitric oxide synthase in induction of RhoA expression in hearts from diabetic rats. Cardiovasc Res. 2008;79:322-30 pubmed publisher
    ..laboratory demonstrated that increased expression of the small GTP-binding protein RhoA and activation of the RhoA/rho kinase (ROCK) pathway play an important role in the contractile dysfunction associated with diabetic cardiomyopathy ..
  12. Maubaret C, Kosmaoglou M, Low S, Chakarova C, Bidot S, Thauvin Robinet C, et al. Functional characterization of a novel c.614-622del rhodopsin mutation in a French pedigree with retinitis pigmentosa. Mol Vis. 2012;18:581-7 pubmed
    ..individuals from three-generations were available for linkage analysis using microsatellite markers flanking the rhodopsin (RHO) gene...
  13. Chen C, Burns M, Spencer M, Niemi G, Chen J, Hurley J, et al. Abnormal photoresponses and light-induced apoptosis in rods lacking rhodopsin kinase. Proc Natl Acad Sci U S A. 1999;96:3718-22 pubmed
    Phosphorylation is thought to be an essential first step in the prompt deactivation of photoexcited rhodopsin. In vitro, the phosphorylation can be catalyzed either by rhodopsin kinase (RK) or by protein kinase C (PKC)...
  14. Sun X, Haley J, Bulgakov O, Cai X, McGinnis J, Li T. Tubby is required for trafficking G protein-coupled receptors to neuronal cilia. Cilia. 2012;1:21 pubmed publisher
    ..We used immunofluoresence labeling to examine the subcellular localization of rhodopsin, somatostatin receptor 3 (SSTR3) and melanin concentrating hormone receptor 1 (MCHR1), all of which are G ..
  15. Won J, Shi L, Hicks W, Wang J, Naggert J, Nishina P. Translational vision research models program. Adv Exp Med Biol. 2012;723:391-7 pubmed publisher
    ..The new alleles described herein will be a useful resource to further examine the role of the affected molecules and the effects of their disruption within the retina. ..
  16. Genové G, Mollick T, Johansson K. Photoreceptor degeneration, structural remodeling and glial activation: a morphological study on a genetic mouse model for pericyte deficiency. Neuroscience. 2014;279:269-84 pubmed publisher
  17. St Jules R, Smith S, O Brien P. The localization and timing of post-translational modifications of rat rhodopsin. Exp Eye Res. 1990;51:427-34 pubmed
    ..At selected intervals, subcellular fractions were prepared on linear sucrose gradients and rhodopsin was extracted and purified by affinity chromatography and gel electrophoresis...
  18. Tai A, Chuang J, Bode C, Wolfrum U, Sung C. Rhodopsin's carboxy-terminal cytoplasmic tail acts as a membrane receptor for cytoplasmic dynein by binding to the dynein light chain Tctex-1. Cell. 1999;97:877-87 pubmed
    ..Here we demonstrate that dynein translocates rhodopsin-bearing vesicles along microtubules...
  19. Murray S, Jazayeri A, Matthes M, Yasumura D, Yang H, Peralta R, et al. Allele-Specific Inhibition of Rhodopsin With an Antisense Oligonucleotide Slows Photoreceptor Cell Degeneration. Invest Ophthalmol Vis Sci. 2015;56:6362-75 pubmed publisher
    To preserve photoreceptor cell structure and function in a rodent model of retinitis pigmentosa with P23H rhodopsin by selective inhibition of the mutant rhodopsin allele using a second generation antisense oligonucleotide (ASO)...
  20. Gorbatyuk M, Justilien V, Liu J, Hauswirth W, Lewin A. Preservation of photoreceptor morphology and function in P23H rats using an allele independent ribozyme. Exp Eye Res. 2007;84:44-52 pubmed
    ..ribozyme for the treatment of autosomal dominant retinitis pigmentosa (ADRP) associated with mutations in the rhodopsin (RHO) gene, a ribozyme targeting dog, mouse, human but not rat rhodopsin (RHO) mRNA was designed and tested in ..
  21. Katti C, Dalal J, Dose A, Burnside B, Battelle B. Cloning and distribution of myosin 3B in the mouse retina: differential distribution in cone outer segments. Exp Eye Res. 2009;89:224-37 pubmed publisher
    ..Myo3B may have diverse roles in retinal neurons. In photoreceptor inner segments Myo3B is positioned appropriately to prevent photoreceptor loss of function caused by Myo3A defects. ..
  22. Zhang Y, Seo S, Bhattarai S, Bugge K, Searby C, Zhang Q, et al. BBS mutations modify phenotypic expression of CEP290-related ciliopathies. Hum Mol Genet. 2014;23:40-51 pubmed publisher
    ..Our data indicate that genetic interactions between BBSome components and CEP290 could underlie the variable expression and overlapping phenotypes of ciliopathies caused by CEP290 mutations. ..
  23. Schoenenberger P, Grunditz A, Rose T, Oertner T. Optimizing the spatial resolution of Channelrhodopsin-2 activation. Brain Cell Biol. 2008;36:119-27 pubmed publisher
  24. St Jules R, Wallingford J, Smith S, O Brien P. Addition of the chromophore to rat rhodopsin is an early post-translational event. Exp Eye Res. 1989;48:653-65 pubmed
    ..Subcellular fractions were prepared on linear sucrose gradients and rhodopsin was extracted with detergent and purified by chromatography on ConA-Sepharose...
  25. Gilliam J, Chang J, Sandoval I, Zhang Y, Li T, Pittler S, et al. Three-dimensional architecture of the rod sensory cilium and its disruption in retinal neurodegeneration. Cell. 2012;151:1029-41 pubmed publisher
    ..The structures of the outer segment membranes support a model for disk morphogenesis in which basal disks are enveloped by the plasma membrane. ..
  26. Campbell M, Humphries M, Kennan A, Kenna P, Humphries P, Brankin B. Aberrant retinal tight junction and adherens junction protein expression in an animal model of autosomal dominant Retinitis pigmentosa: the Rho(-/-) mouse. Exp Eye Res. 2006;83:484-92 pubmed
    ..model of autosomal dominant Retinitis pigmentosa (adRP) with retinopathy induced by targeted disruption of the rhodopsin gene Rho(-/-), we have analysed the levels of expression of a range of tight and adherens junction associated ..
  27. Pinto L, Vitaterna M, Shimomura K, Siepka S, McDearmon E, Fenner D, et al. Generation, characterization, and molecular cloning of the Noerg-1 mutation of rhodopsin in the mouse. Vis Neurosci. 2005;22:619-29 pubmed
    ..A non-recombinant region from 112.8 Mb to 115.1 Mb was identified, encompassing the rhodopsin (Rho) coding region...
  28. Palanivel R, Ganguly R, Turdi S, Xu A, Sweeney G. Adiponectin stimulates Rho-mediated actin cytoskeleton remodeling and glucose uptake via APPL1 in primary cardiomyocytes. Metabolism. 2014;63:1363-73 pubmed publisher
    ..Both fAd and gAd increased RhoA activity, phosphorylation of the Rho/ROCK signaling target cofilin and actin polymerization to form filamentous actin as determined by rhodamine-..
  29. Lee E, Flannery J. Transport of truncated rhodopsin and its effects on rod function and degeneration. Invest Ophthalmol Vis Sci. 2007;48:2868-76 pubmed
    Most transgenic animal models of retinal degeneration caused by rhodopsin mutations express the rhodopsin transgene on a wild-type (WT) genetic background...
  30. Milla E, Heon E, Grounauer P, Piguet B, Ducrey N, Stone E, et al. Rhodopsin C110Y mutation causes a type 2 autosomal dominant retinitis pigmentosa. Ophthalmic Genet. 1998;19:131-9 pubmed
    The RHO C110Y mutation has been recently reported to cause a phenotypically unspecified form of autosomal dominant retinitis pigmentosa (adRP)...
  31. Wright A, Chakarova C, Abd El Aziz M, Bhattacharya S. Photoreceptor degeneration: genetic and mechanistic dissection of a complex trait. Nat Rev Genet. 2010;11:273-84 pubmed publisher
    ..Although genetic and mechanistic diversity creates challenges for therapy, some approaches--particularly gene-replacement therapy--are showing considerable promise. ..
  32. Mao H, James T, Schwein A, Shabashvili A, Hauswirth W, Gorbatyuk M, et al. AAV delivery of wild-type rhodopsin preserves retinal function in a mouse model of autosomal dominant retinitis pigmentosa. Hum Gene Ther. 2011;22:567-75 pubmed publisher
    ..Earlier, a study on mice carrying mutated rhodopsin transgenes on either RHO?+?/?+? or RHO?+?/- backgrounds suggested that the amount of wild-type rhodopsin ..
  33. Kennan A, Aherne A, Palfi A, Humphries M, McKee A, Stitt A, et al. Identification of an IMPDH1 mutation in autosomal dominant retinitis pigmentosa (RP10) revealed following comparative microarray analysis of transcripts derived from retinas of wild-type and Rho(-/-) mice. Hum Mol Genet. 2002;11:547-57 pubmed
    ..of approximately 6000 genes in the retinas of wild-type mice with those carrying a targeted disruption of the rhodopsin gene was undertaken by microarray analysis...
  34. Franke R, Konig B, Sakmar T, Khorana H, Hofmann K. Rhodopsin mutants that bind but fail to activate transducin. Science. 1990;250:123-5 pubmed
    b>Rhodopsin is a member of a family of receptors that contain seven transmembrane helices and are coupled to G proteins...
  35. Pan Z, Lu T, Zhang X, Dai H, Yan W, Bai F, et al. Identification of two mutations of the RHO gene in two Chinese families with retinitis pigmentosa: correlation between genotype and phenotype. Mol Vis. 2012;18:3013-20 pubmed
    ..Secondary structure prediction suggested that the mutant rhodopsin 169P led to significant secondary structure changes between residues 165 and 169, which may interfere with the ..
  36. Choudhury S, Bhootada Y, Gorbatyuk O, Gorbatyuk M. Caspase-7 ablation modulates UPR, reprograms TRAF2-JNK apoptosis and protects T17M rhodopsin mice from severe retinal degeneration. Cell Death Dis. 2013;4:e528 pubmed publisher
    The UPR is activated in the mouse retina expressing misfolded T17M rhodopsin (RHO) during autosomal dominant retinitis pigmentosa (ADRP) progression...
  37. Zou J, Luo L, Shen Z, Chiodo V, Ambati B, Hauswirth W, et al. Whirlin replacement restores the formation of the USH2 protein complex in whirlin knockout photoreceptors. Invest Ophthalmol Vis Sci. 2011;52:2343-51 pubmed publisher
    ..Murine whirlin cDNA driven by the human rhodopsin kinase promoter (hRK) was packaged as an AAV2/5 vector and delivered into the whirlin knockout retina through ..
  38. Kroeger H, Lavail M, Lin J. Endoplasmic reticulum stress in vertebrate mutant rhodopsin models of retinal degeneration. Adv Exp Med Biol. 2014;801:585-92 pubmed publisher
    b>Rhodopsin mutations cause many types of heritable retinitis pigmentosa (RP)...
  39. Uchio Yamada K, Manabe N, Yamaguchi M, Akashi N, Goto Y, Yamamoto Y, et al. Localization of extracellular matrix receptors in ICGN mice, a strain of mice with hereditary nephrotic syndrome. J Vet Med Sci. 2001;63:1171-8 pubmed
  40. Hagstrom S, Watson R, Pauer G, Grossman G. Tulp1 is involved in specific photoreceptor protein transport pathways. Adv Exp Med Biol. 2012;723:783-9 pubmed publisher
  41. Simons D, Boye S, Hauswirth W, Wu S. Gene therapy prevents photoreceptor death and preserves retinal function in a Bardet-Biedl syndrome mouse model. Proc Natl Acad Sci U S A. 2011;108:6276-81 pubmed publisher
    ..Here we report the development of an adeno-associated viral (AAV) vector that rescues rhodopsin mislocalization, maintains nearly normal-appearing rod outer segments, and prevents photoreceptor death in the ..
  42. Mockel A, Obringer C, Hakvoort T, Seeliger M, Lamers W, Stoetzel C, et al. Pharmacological modulation of the retinal unfolded protein response in Bardet-Biedl syndrome reduces apoptosis and preserves light detection ability. J Biol Chem. 2012;287:37483-94 pubmed publisher
  43. Ohguro H, Ohguro I, Mamiya K, Maeda T, Nakazawa M. Prolonged survival of the phosphorylated form of rhodopsin during dark adaptation of Royal College Surgeons rat. FEBS Lett. 2003;551:128-32 pubmed
    To study rhodopsin (Rho) phosphorylation and dephosphorylation in Royal College of Surgeons (RCS) rat retina, specific antibodies toward major Rho phosphorylation sites in vivo, 334Ser or 338Ser, were prepared by immunization of ..
  44. Malechka V, Moiseyev G, Takahashi Y, Shin Y, Ma J. Impaired Rhodopsin Generation in the Rat Model of Diabetic Retinopathy. Am J Pathol. 2017;187:2222-2231 pubmed publisher
    ..Although Western blot analysis revealed no difference in opsin expression, rhodopsin content was decreased in diabetic retinas, as shown by a difference in absorbance...
  45. Rajala A, Anderson R, Ma J, Lem J, Al Ubaidi M, Rajala R. G-protein-coupled receptor rhodopsin regulates the phosphorylation of retinal insulin receptor. J Biol Chem. 2007;282:9865-73 pubmed
    ..To confirm that light-induced tyrosine phosphorylation of the IR is signaled through bleachable rhodopsin, we examined IR activation in retinas from RPE65(-/-) mice that are deficient in opsin chromophore...
  46. Yin H, Ru H, Yu L, Kang Y, Lin G, Liu C, et al. Targeting of Rho kinase ameliorates impairment of diabetic endothelial function in intrarenal artery. Int J Mol Sci. 2013;14:20282-98 pubmed publisher
    ..Accumulating evidence suggests the protective role of Rho kinase inhibitors in endothelial dysfunction via modulating eNOS activity and NO production...
  47. Dryja T, Berson E, Rao V, Oprian D. Heterozygous missense mutation in the rhodopsin gene as a cause of congenital stationary night blindness. Nat Genet. 1993;4:280-3 pubmed
    A number of mutations in the rhodopsin gene have been shown to cause both dominant and recessive retinitis pigmentosa. Here we describe another phenotype associated with a defect in this gene...
  48. Sasahara T, Okamoto H, Ohkura N, Kobe A, Yayama K. Epidermal growth factor induces Ca(2+) sensitization through Rho-kinase-dependent phosphorylation of myosin phosphatase target subunit 1 in vascular smooth muscle. Eur J Pharmacol. 2015;762:89-95 pubmed publisher
    ..that the protein tyrosine phosphatase inhibitor orthovanadate evoked a vasoconstrictor effect in rat aortas via Rho-kinase-dependent inactivation of myosin light chain phosphatase (MLCP) downstream of epidermal growth factor (EGF) ..
  49. Sancho Pelluz J, Tosi J, Hsu C, Lee F, Wolpert K, Tabacaru M, et al. Mice with a D190N mutation in the gene encoding rhodopsin: a model for human autosomal-dominant retinitis pigmentosa. Mol Med. 2012;18:549-55 pubmed publisher
    b>Rhodopsin is the G protein-coupled receptor in charge of initiating signal transduction in rod photoreceptor cells upon the arrival of the photon...
  50. Radeff J, Nagy Z, Stern P. Rho and Rho kinase are involved in parathyroid hormone-stimulated protein kinase C alpha translocation and IL-6 promoter activity in osteoblastic cells. J Bone Miner Res. 2004;19:1882-91 pubmed
    ..translocation and IL-6 were inhibited by agents that interfere with the activity of small G-proteins of the Rho family and with the downstream kinase Rho kinase...
  51. Huber A, Sander P, Paulsen R. Phosphorylation of the InaD gene product, a photoreceptor membrane protein required for recovery of visual excitation. J Biol Chem. 1996;271:11710-7 pubmed
    ..It is proposed that the rise of the intracellular Ca2+ concentration upon visual excitation initiates the phosphorylation of the InaD protein by eye-PKC and thereby modulates its function in the control of the light response. ..
  52. Sun H. Membrane receptors and transporters involved in the function and transport of vitamin A and its derivatives. Biochim Biophys Acta. 2012;1821:99-112 pubmed publisher
    ..This article is part of a Special Issue entitled Retinoid and Lipid Metabolism...
  53. Dodge J, Fulton A, Parker C, Hansen R, Williams T. Rhodopsin in immature rod outer segments. Invest Ophthalmol Vis Sci. 1996;37:1951-6 pubmed
    To test the hypothesis that rhodopsin concentration is low in immature rat rod outer segments (ROS)...
  54. Hong D, Pawlyk B, Shang J, Sandberg M, Berson E, Li T. A retinitis pigmentosa GTPase regulator (RPGR)-deficient mouse model for X-linked retinitis pigmentosa (RP3). Proc Natl Acad Sci U S A. 2000;97:3649-54 pubmed
    ..ectopic localization of cone opsins in the cell body and synapses and rod photoreceptors have a reduced level of rhodopsin. Subsequently, both cone and rod photoreceptors degenerate...
  55. Morabito M, Yu X, Barnstable C. Characterization of developmentally regulated and retina-specific nuclear protein binding to a site in the upstream region of the rat opsin gene. J Biol Chem. 1991;266:9667-72 pubmed
    ..The unaltered sequence was over 2 orders of magnitude more effective at inhibiting complex formation than either an unrelated DNA sequence or a concensus sequence corresponding to a known CCAAT box binding protein NF1. ..