Thrb

Summary

Gene Symbol: Thrb
Description: thyroid hormone receptor beta
Alias: C-erba-beta, ERBA2, Nr1a2, RATT3REC, T3rec, TRbeta, thyroid hormone receptor beta, TRbeta2Delta, c-erbA-2, nuclear receptor subfamily 1 group A member 2, thyroid hormone receptor beta 3, thyroid hormone receptor beta2delta, thyroid hormone receptor, beta (avian erythroblastic leukemia viral (v-erb-a) oncogene homolog 2)
Species: rat
Products:     Thrb

Top Publications

  1. Hörlein A, Näär A, Heinzel T, Torchia J, Gloss B, Kurokawa R, et al. Ligand-independent repression by the thyroid hormone receptor mediated by a nuclear receptor co-repressor. Nature. 1995;377:397-404 pubmed
  2. Ali I, Lidereau R, Callahan R. Presence of two members of c-erbA receptor gene family (c-erbA beta and c-erbA2) in smallest region of somatic homozygosity on chromosome 3p21-p25 in human breast carcinoma. J Natl Cancer Inst. 1989;81:1815-20 pubmed
    ..This region includes at least two members of the c-erbA steroid/thyroid hormone receptor family (c-erbA beta and c-erbA2) that may be of special relevance to breast cancer...
  3. Murray M, Zilz N, McCreary N, MacDonald M, Towle H. Isolation and characterization of rat cDNA clones for two distinct thyroid hormone receptors. J Biol Chem. 1988;263:12770-7 pubmed
    ..Based on this correlation, we suggest that rc-erbA-beta may encode the "classical" nuclear thyroid hormone receptor, whereas rc-erbA-alpha may encode an isoreceptor species with differing functional properties. ..
  4. Qi C, Chang J, Zhu Y, Yeldandi A, Rao S, Zhu Y. Identification of protein arginine methyltransferase 2 as a coactivator for estrogen receptor alpha. J Biol Chem. 2002;277:28624-30 pubmed
    ..PRMT2 also binds to ERbeta, PR, TRbeta, RARalpha, PPARgamma, and RXRalpha in a ligand-independent manner...
  5. Gassanov N, Er F, Michels G, Zagidullin N, Brandt M, Hoppe U. Divergent regulation of cardiac KCND3 potassium channel expression by the thyroid hormone receptors alpha1 and beta1. J Physiol. 2009;587:1319-29 pubmed publisher
    ..Thus, I(to) is modulated by diverse T3-dependent regulation of underlying gene transcription. TRalpha1 and TRbeta1 exhibit distinct effects on KCND3 transactivation with TRalpha1 enhancing and TRbeta1 suppressing KCND3 transcription. ..
  6. Hodin R, Lazar M, Wintman B, Darling D, Koenig R, Larsen P, et al. Identification of a thyroid hormone receptor that is pituitary-specific. Science. 1989;244:76-9 pubmed
    ..The presence of a pituitary-specific form of the thyroid hormone receptor that may be selectively regulated by thyroid hormone could be important for the differential regulation of gene expression by T3 in the pituitary gland. ..
  7. Freitas F, Capelo L, O Shea P, Jorgetti V, Moriscot A, Scanlan T, et al. The thyroid hormone receptor beta-specific agonist GC-1 selectively affects the bone development of hypothyroid rats. J Bone Miner Res. 2005;20:294-304 pubmed
    We investigated the effects of GC-1, a TRbeta-selective thyromimetic, on bone development of hypothyroid rats...
  8. Compe E, Malerba M, Soler L, Marescaux J, Borrelli E, Egly J. Neurological defects in trichothiodystrophy reveal a coactivator function of TFIIH. Nat Neurosci. 2007;10:1414-22 pubmed
    ..The discovery of an unexpected stabilizing function for TFIIH deepens our understanding of the pathogenesis and neurological manifestations observed in TTD individuals. ..
  9. Zandieh Doulabi B, Platvoet Ter Schiphorst M, Kalsbeek A, Fliers E, Bakker O, Wiersinga W. Diurnal variation in rat liver thyroid hormone receptor (TR)-alpha messenger ribonucleic acid (mRNA) is dependent on the biological clock in the suprachiasmatic nucleus, whereas diurnal variation of TR beta 1 mRNA is modified by food intake. Endocrinology. 2004;145:1284-9 pubmed
    ..The findings may have physiological relevance for diurnal variation of T(3)-dependent gene expression, which is supported by a diurnal variation in the expression of the 5'-deiodinase gene. ..

More Information

Publications59

  1. Chang C, Wang S, Wu C, Su T, Wang K, Chen H, et al. Microsatellite alterations in exfoliated cervical epithelia deoxyribonucleic acid as a marker for high-grade dysplasia. Am J Obstet Gynecol. 2001;185:108-15 pubmed
    ..histologic outcomes were subjected to tests of loss of heterozygosity on a panel of 5 microsatellites (D3S1110, THRB, D3S1228, D6S291, D3S1289) within the deoxyribonucleic acid of exfoliated cervical epithelia...
  2. Ng L, Lyubarsky A, Nikonov S, Ma M, Srinivas M, Kefas B, et al. Type 3 deiodinase, a thyroid-hormone-inactivating enzyme, controls survival and maturation of cone photoreceptors. J Neurosci. 2010;30:3347-57 pubmed publisher
    ..The results suggest that type 3 deiodinase limits hormonal exposure of the cone to levels that safeguard both cone survival and the patterning of opsins that is required for cone function. ..
  3. Martinez de Mena R, Scanlan T, Obregon M. The T3 receptor beta1 isoform regulates UCP1 and D2 deiodinase in rat brown adipocytes. Endocrinology. 2010;151:5074-83 pubmed publisher
    ..In summary, T3 increases the adrenergic stimulation of UCP1 and D2 expression mostly via the TR?1 isoform, and in brown adipocytes, D2 is protected from degradation by the action of T3 on TR?1. ..
  4. Masuda N, Yasumo H, Furusawa T, Tsukamoto T, Sadano H, Osumi T. Nuclear receptor binding factor-1 (NRBF-1), a protein interacting with a wide spectrum of nuclear hormone receptors. Gene. 1998;221:225-33 pubmed
    ..NRBF-1 has a significant homology to the yeast protein MRF1, a putative transcription factor regulating the expression of mitochondrial respiratory proteins. NRBF-1 might be another type of nuclear receptor co-operator. ..
  5. Matsen M, Thaler J, Wisse B, Guyenet S, Meek T, Ogimoto K, et al. In uncontrolled diabetes, thyroid hormone and sympathetic activators induce thermogenesis without increasing glucose uptake in brown adipose tissue. Am J Physiol Endocrinol Metab. 2013;304:E734-46 pubmed publisher
  6. Williams G. Cloning and characterization of two novel thyroid hormone receptor beta isoforms. Mol Cell Biol. 2000;20:8329-42 pubmed
    Thyroid hormone (T(3)) activates nuclear receptor transcription factors, encoded by the TRalpha (NR1A1) and TRbeta (NR1A2) genes, to regulate target gene expression...
  7. Ko L, Cardona G, Henrion Caude A, Chin W. Identification and characterization of a tissue-specific coactivator, GT198, that interacts with the DNA-binding domains of nuclear receptors. Mol Cell Biol. 2002;22:357-69 pubmed
    ..These data suggest that GT198 is a tissue-specific, kinase-regulated nuclear receptor coactivator that interacts with the DNA-binding domains of nuclear receptors. ..
  8. Kamiya Y, Puzianowska Kuznicka M, McPhie P, Nauman J, Cheng S, Nauman A. Expression of mutant thyroid hormone nuclear receptors is associated with human renal clear cell carcinoma. Carcinogenesis. 2002;23:25-33 pubmed
    ..We have previously found aberrant expression of TRalpha and TRbeta mRNAs in renal clear cell carcinoma (RCCC), suggesting possible involvement of TRs in the carcinogenesis of RCCC...
  9. Hong W, Li J, Wang B, Chen L, Niu W, Yao Z, et al. Epigenetic involvement of Alien/ESET complex in thyroid hormone-mediated repression of E2F1 gene expression and cell proliferation. Biochem Biophys Res Commun. 2011;415:650-5 pubmed publisher
    ..Taken together, our data indicate that ESET is involved in TR?1-mediated transcription repression and provide a molecular basis of thyroid hormone-induced repression of proliferation. ..
  10. De Paul A, Mukdsi J, Pellizas C, Montesinos M, Gutierrez S, Susperreguy S, et al. Thyroid hormone receptor alpha 1-beta 1 expression in epididymal epithelium from euthyroid and hypothyroid rats. Histochem Cell Biol. 2008;129:631-42 pubmed publisher
    ..The differences in expression levels assessed in control and thyroidectomized rats ascertain a specific function of TH on this organ. ..
  11. Tian H, Mahajan M, Wong C, Habeos I, Samuels H. The N-Terminal A/B domain of the thyroid hormone receptor-beta2 isoform influences ligand-dependent recruitment of coactivators to the ligand-binding domain. Mol Endocrinol. 2006;20:2036-51 pubmed
  12. Liu C, Li L, Shi F, Zang X, Liu Y, Sun Y, et al. Effects of hyper- and hypothyroid on expression of thyroid hormone receptor mRNA in rat myocardium. J Endocrinol. 2007;195:429-38 pubmed
    ..Taken together, the abnormal expression of TR subtype mRNA may have a close relationship with the pathogenesis of CH and hyperthyroidism heart disease. ..
  13. Frau C, Loi R, Petrelli A, Perra A, Menegon S, Kowalik M, et al. Local hypothyroidism favors the progression of preneoplastic lesions to hepatocellular carcinoma in rats. Hepatology. 2015;61:249-59 pubmed publisher
  14. Prieur X, Huby T, Coste H, Schaap F, Chapman M, Rodriguez J. Thyroid hormone regulates the hypotriglyceridemic gene APOA5. J Biol Chem. 2005;280:27533-43 pubmed
    ..Here we report that 3,5,3'-triiodo-L-thyronine (T3) and a synthetic thyroid receptor beta (TRbeta) ligand increase APOA5 mRNA and protein levels in hepatocytes...
  15. Leach P, Kenney J, Connor D, Gould T. Thyroid receptor β involvement in the effects of acute nicotine on hippocampus-dependent memory. Neuropharmacology. 2015;93:155-63 pubmed publisher
    ..Acute nicotine enhances learning and these effects may involve processes regulated by the transcription factor TRβ. ..
  16. Koenig R, Warne R, Brent G, Harney J, Larsen P, Moore D. Isolation of a cDNA clone encoding a biologically active thyroid hormone receptor. Proc Natl Acad Sci U S A. 1988;85:5031-5 pubmed
    ..Reporter gene expression directed by this hybrid promoter was T3 inducible only if this plasmid was cotransfected with an erb62-expressing plasmid. ..
  17. Dellovade T, Chan J, Vennstrom B, Forrest D, Pfaff D. The two thyroid hormone receptor genes have opposite effects on estrogen-stimulated sex behaviors. Nat Neurosci. 2000;3:472-5 pubmed
    ..Deletion of TRalpha 1 reduced them, whereas deletion of TRbeta actually increased them...
  18. Silva J, Dominguez G, González Sancho J, Garcia J, Silva J, García Andrade C, et al. Expression of thyroid hormone receptor/erbA genes is altered in human breast cancer. Oncogene. 2002;21:4307-16 pubmed
    ..Our results reveal specific alterations in the expression of TRbeta and TRalpha genes in a subset of breast cancer patients, suggesting that deregulation of thyroid hormone target ..
  19. Xu B, Koenig R. An RNA-binding domain in the thyroid hormone receptor enhances transcriptional activation. J Biol Chem. 2004;279:33051-6 pubmed
    ..We conclude that thyroid hormone receptors bind RNA through a novel domain and that the interaction of this domain with SRA, and perhaps other RNAs, enhances thyroid hormone receptor function. ..
  20. Malik I, Baumgartner B, Naz N, Sheikh N, Moriconi F, Ramadori G. Changes in gene expression of DOR and other thyroid hormone receptors in rat liver during acute-phase response. Cell Tissue Res. 2010;342:261-72 pubmed publisher
    ..Their down-regulation is attributable to the decreased serum level of thyroid hormones and most probably also to the direct action of the main acute-phase cytokines. ..
  21. Weiss R, Murata Y, Cua K, Hayashi Y, Seo H, Refetoff S. Thyroid hormone action on liver, heart, and energy expenditure in thyroid hormone receptor beta-deficient mice. Endocrinology. 1998;139:4945-52 pubmed
    ..In contrast, except for HR and EE, the full manifestation of TH-mediated action required the presence of TR beta. ..
  22. Gauthier K, Billon C, Bissler M, Beylot M, Lobaccaro J, Vanacker J, et al. Thyroid hormone receptor beta (TRbeta) and liver X receptor (LXR) regulate carbohydrate-response element-binding protein (ChREBP) expression in a tissue-selective manner. J Biol Chem. 2010;285:28156-63 pubmed publisher
    ..Using genetic and molecular approaches, ChREBP is shown to be specifically regulated by TRbeta but not by TRalpha in vivo, even in WAT where both TR isoforms are expressed...
  23. Ling Y, Xu X, Hao J, Ling X, Du X, Liu X, et al. Aberrant methylation of the THRB gene in tissue and plasma of breast cancer patients. Cancer Genet Cytogenet. 2010;196:140-5 pubmed publisher
    ..b>THRB, the gene encoding TRbeta1, is considered a potential cancer suppressor...
  24. Kawaguchi M, Morohoshi K, Saita E, Yanagisawa R, Watanabe G, Takano H, et al. Developmental exposure to pentachlorophenol affects the expression of thyroid hormone receptor beta1 and synapsin I in brain, resulting in thyroid function vulnerability in rats. Endocrine. 2008;33:277-84 pubmed publisher
    ..No overt signs of toxicity were noted throughout this study. Our results show that PCP exposure during development causes thyroid function vulnerability, testicular hypertrophy in adults, and aberrations of brain gene expression. ..
  25. Liu Y, Kogai T, Schultz J, Mody K, Brent G. Thyroid hormone receptor isoform-specific modification by small ubiquitin-like modifier (SUMO) modulates thyroid hormone-dependent gene regulation. J Biol Chem. 2012;287:36499-508 pubmed publisher
    ..These findings demonstrate that conjugation of SUMO to TR has a TR-isoform preference and is important for T3-dependent gene induction and repression. ..
  26. Sandler B, Webb P, Apriletti J, Huber B, Togashi M, Cunha Lima S, et al. Thyroxine-thyroid hormone receptor interactions. J Biol Chem. 2004;279:55801-8 pubmed
    ..We determined x-ray crystal structures of the TRbeta LBD in complex with T(3) and T(4) at 2.5-A and 3.1-A resolution...
  27. Schwarzenbach H, Chun F, Müller I, Seidel C, Urban K, Erbersdobler A, et al. Microsatellite analysis of allelic imbalance in tumour and blood from patients with prostate cancer. BJU Int. 2008;102:253-8 pubmed publisher
    ..There were high frequencies of LOH at the markers THRB, D7S522 and D8S137 in both types of specimens...
  28. Erion M, Cable E, Ito B, Jiang H, Fujitaki J, Finn P, et al. Targeting thyroid hormone receptor-beta agonists to the liver reduces cholesterol and triglycerides and improves the therapeutic index. Proc Natl Acad Sci U S A. 2007;104:15490-5 pubmed
    ..TR agonists selective for the TRbeta isoform exhibit modest cardiac sparing in rodents and primates but are unable to lower lipids without inducing ..
  29. Pantos C, Mourouzis I, Xinaris C, Kokkinos A, Markakis K, Dimopoulos A, et al. Time-dependent changes in the expression of thyroid hormone receptor alpha 1 in the myocardium after acute myocardial infarction: possible implications in cardiac remodelling. Eur J Endocrinol. 2007;156:415-24 pubmed
    ..Furthermore, down-regulation of TR beta 1 also contributes to fetal phenotypic changes. alpha1-adrenergic signalling is, at least in part, involved in this response. ..
  30. Harvey C, Bassett J, Maruvada P, Yen P, Williams G. The rat thyroid hormone receptor (TR) Deltabeta3 displays cell-, TR isoform-, and thyroid hormone response element-specific actions. Endocrinology. 2007;148:1764-73 pubmed
    The THRB gene encodes the well-described thyroid hormone (T3) receptor (TR) isoforms TRbeta1 and TRbeta2 and two additional variants, TRbeta3 and TRDeltabeta3, of unknown physiological significance...
  31. Winter H, Braig C, Zimmermann U, Geisler H, Fränzer J, Weber T, et al. Thyroid hormone receptors TRalpha1 and TRbeta differentially regulate gene expression of Kcnq4 and prestin during final differentiation of outer hair cells. J Cell Sci. 2006;119:2975-84 pubmed
    Thyroid hormone (TH or T3) and TH-receptor beta (TRbeta) have been reported to be relevant for cochlear development and hearing function. Mutations in the TRbeta gene result in deafness associated with resistance to TH syndrome...
  32. Storey N, Gentile S, Ullah H, Russo A, Muessel M, Erxleben C, et al. Rapid signaling at the plasma membrane by a nuclear receptor for thyroid hormone. Proc Natl Acad Sci U S A. 2006;103:5197-201 pubmed
    ..potassium channel stimulation in a rat pituitary cell line (GH(4)C(1)) by a nuclear receptor for thyroid hormone, TRbeta, acting rapidly at the plasma membrane through phosphatidylinositol 3-kinase (PI3K) to slow the deactivation of ..
  33. Keijzer R, Blommaart P, Labruyere W, Vermeulen J, Doulabi B, Bakker O, et al. Expression of thyroid hormone receptors A and B in developing rat tissues; evidence for extensive posttranscriptional regulation. J Mol Endocrinol. 2007;38:523-35 pubmed
    ..changes in the pattern of expression of the thyroid hormone receptor (TR) isoforms TRalpha (1) TRalpha (2), TRbeta (1), and TRbeta (2) were investigated using in situ hybridization and immunohistochemistry, and RT-PCR and western ..
  34. Forrest D, Erway L, Ng L, Altschuler R, Curran T. Thyroid hormone receptor beta is essential for development of auditory function. Nat Genet. 1996;13:354-7 pubmed
    ..We demonstrate that Tr beta-deficient (Thrb-/-) mice exhibit a permanent deficit in auditory function across a wide range of frequencies, although they show no ..
  35. Gauthier K, Chassande O, Plateroti M, Roux J, Legrand C, Pain B, et al. Different functions for the thyroid hormone receptors TRalpha and TRbeta in the control of thyroid hormone production and post-natal development. EMBO J. 1999;18:623-31 pubmed
    The biological activities of thyroid hormones are thought to be mediated by receptors generated by the TRalpha and TRbeta loci...
  36. Chen Y, Young M. Structure of a thyroid hormone receptor DNA-binding domain homodimer bound to an inverted palindrome DNA response element. Mol Endocrinol. 2010;24:1650-64 pubmed publisher
    ..Mutational analysis shows that intersubunit contacts at the DBD C terminus account for some, but not all, of the cooperative homodimer TR binding to the inverted repeat class TRE. ..
  37. Maruvada P, Dmitrieva N, East Palmer J, Yen P. Cell cycle-dependent expression of thyroid hormone receptor-beta is a mechanism for variable hormone sensitivity. Mol Biol Cell. 2004;15:1895-903 pubmed
    ..We thus developed a stable expression system to express green fluorescent protein-TRbeta in HeLa cells under tetracycline regulation, and studied TR expression during the cell cycle by laser scanning ..
  38. Columbano A, Pibiri M, Deidda M, Cossu C, Scanlan T, Chiellini G, et al. The thyroid hormone receptor-beta agonist GC-1 induces cell proliferation in rat liver and pancreas. Endocrinology. 2006;147:3211-8 pubmed
    ..class of halogen-free high-affinity thyroid hormone agonists has been developed that are highly selective for the TRbeta subtype...
  39. van Beeren H, Kwakkel J, Ackermans M, Wiersinga W, Fliers E, Boelen A. Action of specific thyroid hormone receptor ?(1) and ?(1) antagonists in the central and peripheral regulation of thyroid hormone metabolism in the rat. Thyroid. 2012;22:1275-82 pubmed publisher
    ..Our results suggest an important role for TR?1 in the regulation of hypothalamic TRH mRNA expression, whereas TR? plays a dominant role in pituitary and liver thyroid hormone metabolism. ..
  40. Eckey M, Tenbaum S, Munoz A, Baniahmad A. Mixed lineage kinase 2 enhances trans-repression of Alien and nuclear receptors. Mol Cell Endocrinol. 2003;213:71-8 pubmed
    ..This novel cross-talk may represent a link between MLK2-mediated signaling and transcriptional repression of target genes during neuronal differentiation processes. ..
  41. Hashimoto S, Imaoka S. Protein-disulfide isomerase regulates the thyroid hormone receptor-mediated gene expression via redox factor-1 through thiol reduction-oxidation. J Biol Chem. 2013;288:1706-16 pubmed publisher
    ..Our studies suggested that Ref-1 contributes to TR-mediated gene expression and that the redox state of Ref-1 is regulated by PDI. Redox regulation of PDI via Ref-1 is a new aspect of PDI function. ..
  42. Sharma P, Thakran S, Deng X, Elam M, Park E. Nuclear corepressors mediate the repression of phospholipase A2 group IIa gene transcription by thyroid hormone. J Biol Chem. 2013;288:16321-33 pubmed publisher
    ..In contrast with the established role of T3 to promote coactivator association with TR?, our experiments demonstrate a novel inverse recruitment mechanism in which liganded TR? recruits corepressors to inhibit PLA2g2a expression. ..
  43. Lee J, Choi H, Gyuris J, Brent R, Moore D. Two classes of proteins dependent on either the presence or absence of thyroid hormone for interaction with the thyroid hormone receptor. Mol Endocrinol. 1995;9:243-54 pubmed
  44. Diallo E, Thompson D, Koenig R. A method for efficient production of recombinant thyroid hormone receptors reveals that receptor homodimer-DNA binding is enhanced by the coactivator TIF2. Protein Expr Purif. 2005;40:292-8 pubmed
    ..We found the coactivator TIF2 greatly enhances binding of T3-occupied TRs to a subset of TREs, suggesting TRs may activate transcription from these TREs in an RXR-independent manner. ..
  45. Chu T, Shen C, Chiou Y, Lu J, Perng C, Yu M, et al. HPV-associated cervical cancers show frequent allelic loss at 3p14 but no apparent aberration of FHIT mRNA. Int J Cancer. 1998;75:199-204 pubmed
    ..The presence of tumorigenic HPV DNA (91%) did not correlate with the allelic loss at any marker, including THRB (3p22-24) and D3S1228 (3p14) which were found with high LOH rates of 43% (12/28) and 37% (11/30), respectively...
  46. Gassanov N, Er F, Endres Becker J, Wolny M, Schramm C, Hoppe U. Distinct regulation of cardiac I(f) current via thyroid receptors alpha1 and beta1. Pflugers Arch. 2009;458:1061-8 pubmed publisher
    ..TH-induced positive chronotropic effects are likely to be mediated by TR alpha 1 through enhanced expression of I(f) pacemaker current and its underlying genes. ..
  47. Astapova I, Lee L, Morales C, Tauber S, Bilban M, Hollenberg A. The nuclear corepressor, NCoR, regulates thyroid hormone action in vivo. Proc Natl Acad Sci U S A. 2008;105:19544-9 pubmed publisher
    ..Interestingly, NCoR recruitment to LXR is also impaired in this model, leading to activation of LXR-target genes, further demonstrating that NCoR recruitment regulates multiple nuclear receptor signaling pathways. ..
  48. Yanagi Y, Takezawa S, Kato S. Distinct functions of photoreceptor cell-specific nuclear receptor, thyroid hormone receptor beta2 and CRX in one photoreceptor development. Invest Ophthalmol Vis Sci. 2002;43:3489-94 pubmed
    ..Thus, our results partly disclosed the molecular mechanism of cone photoreceptor development, highlighting the distinct functions of PNR and TRbeta2. ..
  49. Lam C, On Kei Chan A, Tong S, Shek C, Cheung Tiu S. DNA-based diagnosis of thyroid hormone resistance syndrome: a novel THRB mutation associated with mild resistance to thyroid hormone. Clin Chim Acta. 2005;358:55-9 pubmed
    ..We used direct DNA sequencing of the THRB gene. We identified a novel missense mutation, I276L, located in exon 8 of the gene...
  50. Nishi H, Ono K, Horie T, Nagao K, Kinoshita M, Kuwabara Y, et al. MicroRNA-27a regulates beta cardiac myosin heavy chain gene expression by targeting thyroid hormone receptor beta1 in neonatal rat ventricular myocytes. Mol Cell Biol. 2011;31:744-55 pubmed publisher
    ..These findings suggested that miR-27a regulates ?-MHC gene expression by targeting TR?1 in cardiomyocytes. ..