Cckar

Summary

Gene Symbol: Cckar
Description: cholecystokinin A receptor
Alias: AW106902, cholecystokinin receptor type A, CCK-A receptor, CCK-AR, CCK1-R, cholecystokinin-1 receptor
Species: mouse
Products:     Cckar

Top Publications

  1. Lacourse K, Lay J, Swanberg L, Jenkins C, Samuelson L. Molecular structure of the mouse CCK-A receptor gene. Biochem Biophys Res Commun. 1997;236:630-5 pubmed
    We have cloned the mouse CCK-A receptor gene (Cckar), determined its nucleotide sequence, and analyzed its expression. The receptor protein is encoded in five exons distributed over 9 kb of genomic DNA...
  2. Tsujino N, Yamanaka A, Ichiki K, Muraki Y, Kilduff T, Yagami K, et al. Cholecystokinin activates orexin/hypocretin neurons through the cholecystokinin A receptor. J Neurosci. 2005;25:7459-69 pubmed
    ..The evidence presented here expands our understanding of the regulation of orexin neurons and the physiological role of CCK in the CNS. ..
  3. Mohammad S, Ozaki T, Takeuchi K, Unno K, Yamoto K, Morioka E, et al. Functional compensation between cholecystokinin-1 and -2 receptors in murine paraventricular nucleus neurons. J Biol Chem. 2012;287:39391-401 pubmed publisher
    ..Compensatory CCK signaling via CCK-2 receptors in CCK1R(-/-) mice shed light on currently controversial satiety-controlling mechanisms. ..
  4. Miyasaka K, Ichikawa M, Ohta M, Kanai S, Yoshida Y, Masuda M, et al. Energy metabolism and turnover are increased in mice lacking the cholecystokinin-B receptor. J Nutr. 2002;132:739-41 pubmed
    ..Energy metabolism and energy turnover were increased in mice with a disruption of the CCK-BR gene, although the underlying mechanism is unknown. ..
  5. Lay J, Gillespie P, Samuelson L. Murine prenatal expression of cholecystokinin in neural crest, enteric neurons, and enteroendocrine cells. Dev Dyn. 1999;216:190-200 pubmed
    ..5, suggesting that CCK signaling is established early in mouse development. Dev Dyn 1999;216:190-200. ..
  6. Takiguchi S, Suzuki S, Sato Y, Kanai S, Miyasaka K, Jimi A, et al. Role of CCK-A receptor for pancreatic function in mice: a study in CCK-A receptor knockout mice. Pancreas. 2002;24:276-83 pubmed
    ..The CCK-A receptor is important for pancreatic exocrine secretion, but not essential for maintaining glucose concentration and pancreatic growth in mice. ..
  7. Lay J, Jenkins C, Friis Hansen L, Samuelson L. Structure and developmental expression of the mouse CCK-B receptor gene. Biochem Biophys Res Commun. 2000;272:837-42 pubmed
    ..The expression pattern was similar to the adult pattern, suggesting that receptor transcription is an early event in gastrointestinal development. ..
  8. Sakurai C, Ohta M, Kanai S, Uematsu H, Funakoshi A, Miyasaka K. Lack of ghrelin secretion in response to fasting in cholecystokinin-A (-1), -B (-2) receptor-deficient mice. J Physiol Sci. 2006;56:441-7 pubmed
    ..In conclusion, CCK-AR(-/-)BR(-/-) mice showed lower food intake as well as lower response to exogenous ghrelin, and a lower plasma ghrelin level after fasting, though which receptor is more important is unknown. ..
  9. Ingram M, Wozniak E, Duvick L, Yang R, Bergmann P, Carson R, et al. Cerebellar Transcriptome Profiles of ATXN1 Transgenic Mice Reveal SCA1 Disease Progression and Protection Pathways. Neuron. 2016;89:1194-1207 pubmed publisher
    ..Furthermore, we found that upregulation of cholecystokinin (Cck) and subsequent interaction with the Cck1 receptor likely underlies the lack of progressive Purkinje cell pathology in Pcp2-ATXN1[30Q]D776 mice. ..

More Information

Publications60

  1. Xu X, Coats J, Yang C, Wang A, Ahmed O, Alvarado M, et al. Modular genetic control of sexually dimorphic behaviors. Cell. 2012;148:596-607 pubmed publisher
    ..Indeed, we find that mice with targeted disruptions of each of four of these genes (Brs3, Cckar, Irs4, Sytl4) exhibit extremely specific deficits in sex specific behaviors, with single genes controlling the ..
  2. Zhu G, Yan J, Smith W, Moran T, Bi S. Roles of dorsomedial hypothalamic cholecystokinin signaling in the controls of meal patterns and glucose homeostasis. Physiol Behav. 2012;105:234-41 pubmed publisher
    ..Our study also shows a novel role of DMH CCK signaling in glucose homeostasis. ..
  3. Kim H, Gieske M, Hudgins S, Kim B, Krust A, Chambon P, et al. Estrogen receptor alpha-induced cholecystokinin type A receptor expression in the female mouse pituitary. J Endocrinol. 2007;195:393-405 pubmed
    ..Taken together, this study finds CCK-AR to be an ERalpha downstream gene in the pituitary and suggests that CCK-AR may play a role in the estrogen sensitization of the pituitary response to GnRH. ..
  4. Bi S, Chen J, Behles R, Hyun J, Kopin A, Moran T. Differential body weight and feeding responses to high-fat diets in rats and mice lacking cholecystokinin 1 receptors. Am J Physiol Regul Integr Comp Physiol. 2007;293:R55-63 pubmed
    ..Together, these data provide further evidence for differential roles of CCK1 receptors in the controls of food intake and body weight in rats and mice...
  5. Hao S, Sternini C, Raybould H. Role of CCK1 and Y2 receptors in activation of hindbrain neurons induced by intragastric administration of bitter taste receptor ligands. Am J Physiol Regul Integr Comp Physiol. 2008;294:R33-8 pubmed
    ..T2Rs may regulate GI function via release of regulatory peptides and activation of the vagal reflex pathway. ..
  6. Huppi K, Siwarski D, Pisegna J, Wank S. Chromosomal localization of the gastric and brain receptors for cholecystokinin (CCKAR and CCKBR) in human and mouse. Genomics. 1995;25:727-9 pubmed
    Receptors for cholcystokinin (CCK) can be pharmacologically classified into at least two distinct subtypes, CCKAR and CCKBR...
  7. Miyamoto S, Shikata K, Miyasaka K, Okada S, Sasaki M, Kodera R, et al. Cholecystokinin plays a novel protective role in diabetic kidney through anti-inflammatory actions on macrophage: anti-inflammatory effect of cholecystokinin. Diabetes. 2012;61:897-907 pubmed publisher
    ..These results suggest that CCK suppresses the activation of macrophage and expression of proinflammatory genes in diabetic kidney. Our findings may provide a novel strategy of therapy for the early stage of diabetic nephropathy. ..
  8. Takata Y, Takiguchi S, Kataoka K, Funakoshi A, Miyasaka K, Kono A. Mouse cholecystokinin type-A receptor gene and its structural analysis. Gene. 1997;187:267-71 pubmed
    ..The shorter isoform may encode an 48 amino acid open reading frame due to frameshift of translation. These two mRNA isoforms were expressed equally in the mouse gallbladders. ..
  9. Miyasaka K, Ohta M, Kanai S, Yoshida Y, Sato N, Nagata A, et al. Enhanced gastric emptying of a liquid gastric load in mice lacking cholecystokinin-B receptor: a study of CCK-A,B, and AB receptor gene knockout mice. J Gastroenterol. 2004;39:319-23 pubmed
    ..We examined whether gastric emptying of a nonnutrient liquid load was modified in CCK-AR, BR, and ARBR gene knockout mice. ..
  10. Lyons M, Wittenburg H, Li R, Walsh K, Leonard M, Churchill G, et al. New quantitative trait loci that contribute to cholesterol gallstone formation detected in an intercross of CAST/Ei and 129S1/SvImJ inbred mice. Physiol Genomics. 2003;14:225-39 pubmed
    ..Our work continues to demonstrate the genetic complexity and to elucidate the pathophysiology of cholesterol gallstone formation. It should facilitate the development of new approaches for treating this common human disorder. ..
  11. Pin C, Rukstalis J, Johnson C, Konieczny S. The bHLH transcription factor Mist1 is required to maintain exocrine pancreas cell organization and acinar cell identity. J Cell Biol. 2001;155:519-30 pubmed
    ..Based on these observations, we propose that Mist1(KO) mice represent a new genetic model for chronic pancreas injury and that the Mist1 protein serves as a key regulator of acinar cell function, stability, and identity. ..
  12. Ji B, Kopin A, Logsdon C. Species differences between rat and mouse CCKA receptors determine the divergent acinar cell response to the cholecystokinin analog JMV-180. J Biol Chem. 2000;275:19115-20 pubmed
    ..These data suggest that species differences in the CCK(A) receptor of rats and mice account for the observed divergence in the acinar cell response to JMV-180. ..
  13. Stanic D, Paratcha G, Ledda F, Herzog H, Kopin A, Hokfelt T. Peptidergic influences on proliferation, migration, and placement of neural progenitors in the adult mouse forebrain. Proc Natl Acad Sci U S A. 2008;105:3610-5 pubmed publisher
    ..These findings suggest that both NPY and CCK through their receptors help to regulate the proliferation of precursor cells, the amount of neuroblast cells in the SVZ and RMS, and influence the differentiation of OB interneurons. ..
  14. Ferraro T, Smith G, Schwebel C, Lohoff F, Furlong P, Berrettini W, et al. Quantitative trait locus for seizure susceptibility on mouse chromosome 5 confirmed with reciprocal congenic strains. Physiol Genomics. 2007;31:458-62 pubmed
  15. Gong Y, Si X, Lin L, Lu J. Mechanisms of cholecystokinin-induced calcium mobilization in gastric antral interstitial cells of Cajal. World J Gastroenterol. 2012;18:7184-93 pubmed publisher
    ..CCK-8S increases [Ca(2+)]i in ICC via the CCK(1) receptor. This effect depends on the release of InsP(3)R-operated Ca(2+) stores, which is negatively regulated by PKC-mediated phosphorylation of InsP(3)R3. ..
  16. Samuelson L, Isakoff M, Lacourse K. Localization of the murine cholecystokinin A and B receptor genes. Mamm Genome. 1995;6:242-6 pubmed
    ..The CCKA receptor gene (Cckar) mapped to mouse Chromosome (Chr) 5, in tight linkage with the DNA marker D5Bir8...
  17. Whited K, Thao D, Lloyd K, Kopin A, Raybould H. Targeted disruption of the murine CCK1 receptor gene reduces intestinal lipid-induced feedback inhibition of gastric function. Am J Physiol Gastrointest Liver Physiol. 2006;291:G156-62 pubmed
    ..Thus, despite a relatively normal phenotype, intestinal feedback in response to lipid is severely impaired in these mice. ..
  18. Kopin A, Mathes W, McBride E, Nguyen M, Al Haider W, Schmitz F, et al. The cholecystokinin-A receptor mediates inhibition of food intake yet is not essential for the maintenance of body weight. J Clin Invest. 1999;103:383-91 pubmed
    ..Our results suggest that although cholecystokinin plays a role in the short-term inhibition of food intake, this pathway is not essential for the long-term maintenance of body weight. ..
  19. Xu G, Xu C, Chen H, Liu S, Teng X, Xu G, et al. Association of caveolin-3 and cholecystokinin A receptor with cholesterol gallstone disease in mice. World J Gastroenterol. 2014;20:9513-8 pubmed publisher
    To investigate the role of caveolin-3 (CAV3) and cholecystokinin A receptor (CCKAR) in cholesterol gallstone disease (CGD). To establish a mouse model of CGD, male C57BL/6 mice were fed with a lithogenic diet containing 1...
  20. Nomoto S, Ohta M, Kanai S, Yoshida Y, Takiguchi S, Funakoshi A, et al. Absence of the cholecystokinin-A receptor deteriorates homeostasis of body temperature in response to changes in ambient temperature. Am J Physiol Regul Integr Comp Physiol. 2004;287:R556-61 pubmed
    ..Mice without CCK-AR showed larger hysteresis than mice with CCK-AR. From these results, we conclude that the lack of CCK-AR causes homeostasis of T(c) in rats and mice to deteriorate...
  21. Konno K, Takahashi Iwanaga H, Uchigashima M, Miyasaka K, Funakoshi A, Watanabe M, et al. Cellular and subcellular localization of cholecystokinin (CCK)-1 receptors in the pancreas, gallbladder, and stomach of mice. Histochem Cell Biol. 2015;143:301-12 pubmed publisher
    ..Especially, the subcellular localization in the acinar cells completes the investigation for the detection of circulating CCK by the basolateral membrane. ..
  22. Irwin N, Montgomery I, Flatt P. Comparison of the metabolic effects of sustained CCK1 receptor activation alone and in combination with upregulated leptin signalling in high-fat-fed mice. Diabetologia. 2013;56:1425-35 pubmed publisher
    ..001) energy expenditure. These studies highlight the potential of (pGlu-Gln)-CCK-8 alone and in combination with [D-Leu-4]-OB3 in the treatment of obesity and diabetes. ..
  23. Cui Z, Yokoi N, Kuramoto T, Kitada K, Serikawa T. Extension of conserved regions in the rat and mouse genomes by chromosomal assignments of 29 rat genes. Exp Anim. 1998;47:83-8 pubmed
    ..In addition, four conserved regions were newly revealed. The method described in this study appears to be simple and efficient for constructing a whole genome comparative map of the rat and mouse. ..
  24. Miyasaka K, Kobayashi S, Ohta M, Kanai S, Yoshida Y, Nagata A, et al. Anxiety-related behaviors in cholecystokinin-A, B, and AB receptor gene knockout mice in the plus-maze. Neurosci Lett. 2002;335:115-8 pubmed
    ..We therefore conclude that a lack of CCK-BR increases the anxiety-related behavior of the mouse in the elevated plus- maze. ..
  25. Ozaki T, Mohammad S, Morioka E, Takiguchi S, Ikeda M. Infant satiety depends on transient expression of cholecystokinin-1 receptors on ependymal cells lining the third ventricle in mice. J Physiol. 2013;591:1295-312 pubmed publisher
    ..Hence, we demonstrate de novo functions of ependymal CCK-1 receptors and reveal a new aspect of infant satiety-controlling mechanisms. ..
  26. Watanabe T, Sadakane Y, Yagama N, Sakurai T, Ezoe H, Kudo M, et al. Nucleotide-binding oligomerization domain 1 acts in concert with the cholecystokinin receptor agonist, cerulein, to induce IL-33-dependent chronic pancreatitis. Mucosal Immunol. 2016;9:1234-49 pubmed publisher
    ..These studies establish chronic pancreatitis as an IL-33-dependent inflammation resulting from synergistic interactions between the NOD1 and CCKR signaling pathways. ..
  27. Gurda G, Wang J, Guo L, Ernst S, Williams J. Profiling CCK-mediated pancreatic growth: the dynamic genetic program and the role of STATs as potential regulators. Physiol Genomics. 2012;44:14-24 pubmed publisher
  28. Richards Smith B, Novak E, Jang E, He P, Haslam R, Castle D, et al. Analyses of proteins involved in vesicular trafficking in platelets of mouse models of Hermansky Pudlak syndrome. Mol Genet Metab. 1999;68:14-23 pubmed
    ..The Snap23 gene was mapped to mouse chromosome 5, demonstrating it cannot encode the gm gene, which maps to chromosome 14. It is likely therefore that the gm gene functions upstream of SNAP-23 in vesicular trafficking. ..
  29. Ma J, Dankulich Nagrudny L, Lowe G. Cholecystokinin: an excitatory modulator of mitral/tufted cells in the mouse olfactory bulb. PLoS ONE. 2013;8:e64170 pubmed publisher
    ..Dynamic plasticity of intrabulbar projections suggests that this could be an experience-dependent amplification mechanism for tuning and optimizing olfactory bulb signal processing in different odor environments. ..
  30. Li H, Ohta H, Izumi H, Matsuda Y, Seki M, Toda T, et al. Behavioral and cortical EEG evaluations confirm the roles of both CCKA and CCKB receptors in mouse CCK-induced anxiety. Behav Brain Res. 2013;237:325-32 pubmed publisher
    ..The present study also proposed a possibility that cortical EEG is useful for assessing anxiety. ..
  31. Carmeliet P, Kieckens L, Schoonjans L, Ream B, van Nuffelen A, Prendergast G, et al. Plasminogen activator inhibitor-1 gene-deficient mice. I. Generation by homologous recombination and characterization. J Clin Invest. 1993;92:2746-55 pubmed
    ..PAI-1-/- mice were viable, produced similar sizes of litters as PAI-1+/+ mice, and showed no apparent macroscopic or microscopic histological abnormalities. ..
  32. Schubert S, Lamoureux N, Kilian K, Klein Hitpass L, Hashemolhosseini S. Identification of integrin-alpha4, Rb1, and syncytin a as murine placental target genes of the transcription factor GCMa/Gcm1. J Biol Chem. 2008;283:5460-5 pubmed publisher
    ..5. Our data demonstrate for the first time that genes encoding key regulators of placental tissue formation and architecture are regulated by GCMa. ..
  33. Bi S, Scott K, Kopin A, Moran T. Differential roles for cholecystokinin a receptors in energy balance in rats and mice. Endocrinology. 2004;145:3873-80 pubmed
    ..The deficit in CCK's action in the control of DMH NPY gene expression may play a major role in the obese phenotype in OLETF rats. ..
  34. Giacobini P, Kopin A, Beart P, Mercer L, Fasolo A, Wray S. Cholecystokinin modulates migration of gonadotropin-releasing hormone-1 neurons. J Neurosci. 2004;24:4737-48 pubmed
  35. Wang D, Schmitz F, Kopin A, Carey M. Targeted disruption of the murine cholecystokinin-1 receptor promotes intestinal cholesterol absorption and susceptibility to cholesterol cholelithiasis. J Clin Invest. 2004;114:521-8 pubmed
  36. Lee J, Martin E, Paulino G, de Lartigue G, Raybould H. Effect of ghrelin receptor antagonist on meal patterns in cholecystokinin type 1 receptor null mice. Physiol Behav. 2011;103:181-7 pubmed publisher
    ..The site of action of ghrelin receptors is unclear, but may involve an increase in expression of CART peptide in VAN in HF-fed CCK?R?/? mice. ..
  37. Miyasaka K, Takata Y, Funakoshi A. Association of cholecystokinin A receptor gene polymorphism with cholelithiasis and the molecular mechanisms of this polymorphism. J Gastroenterol. 2002;37 Suppl 14:102-6 pubmed
    ..Deteriorating gallbladder contractions, possibly induced by alterations in the CCK-AR gene, as well as CCK-AR gene polymorphism, promoted gallstone formation. ..
  38. Kanai S, Hosoya H, Akimoto S, Ohta M, Matsui T, Takiguchi S, et al. Gastric acid secretion in cholecystokinin-1 receptor, -2 receptor, and -1, -2 receptor gene knockout mice. J Physiol Sci. 2009;59:23-9 pubmed publisher
    ..In conclusion, CCK-2R is necessary to respond to carbachol as well as to produce the maximal acid secretion, while the role of CCK-1R in acid secretion is less important. ..
  39. Nishimura S, Bilgüvar K, Ishigame K, Sestan N, Günel M, Louvi A. Functional synergy between cholecystokinin receptors CCKAR and CCKBR in mammalian brain development. PLoS ONE. 2015;10:e0124295 pubmed publisher
    ..of the most abundant neuropeptides in vertebrate brain, mediates its actions via two G-protein coupled receptors, CCKAR and CCKBR, respectively active in peripheral organs and the central nervous system...
  40. Giacobini P, Wray S. Cholecystokinin directly inhibits neuronal activity of primary gonadotropin-releasing hormone cells through cholecystokinin-1 receptor. Endocrinology. 2007;148:63-71 pubmed
    ..This study provides evidence that CCK acts directly on GnRH-1 neurons to attenuate GnRH-1 neuronal activity via CCK-1R activation. ..
  41. Sato N, Miyasaka K, Suzuki S, Kanai S, Ohta M, Kawanami T, et al. Lack of cholecystokinin-A receptor enhanced gallstone formation: a study in CCK-A receptor gene knockout mice. Dig Dis Sci. 2003;48:1944-7 pubmed
    ..Sludge and gallstone formation were not observed at 6 months of age. In conclusion, deteriorated gallbladder contraction due to a lack of CCK-AR favored gallstone formation after the middle age of life. ..
  42. Lassila M, Fukami K, Jandeleit Dahm K, Semple T, Carmeliet P, Cooper M, et al. Plasminogen activator inhibitor-1 production is pathogenetic in experimental murine diabetic renal disease. Diabetologia. 2007;50:1315-26 pubmed
    ..These results demonstrate that endogenous PAI-1 deficiency protects mice from glomerular injury in longer term diabetes and that endogenous PAI-1 maintains normal renal interstitial structure in ageing not associated with diabetes. ..
  43. Ghanekar D, Hadac E, Holicky E, Miller L. Differences in partial agonist action at cholecystokinin receptors of mouse and rat are dependent on parameters extrinsic to receptor structure: molecular cloning, expression and functional characterization of the mouse type A cholecystokinin recepto. J Pharmacol Exp Ther. 1997;282:1206-12 pubmed
    ..Receptor microenvironment makes an important, yet often ignored, contribution to receptor function. ..
  44. Williams R, Manji S, Parker N, Hancock M, Van Stekelenburg L, Eid J, et al. Identification and characterization of the STIM (stromal interaction molecule) gene family: coding for a novel class of transmembrane proteins. Biochem J. 2001;357:673-85 pubmed
    ..This association into oligomers in vivo indicates a possible functional interaction between STIM1 and STIM2. The structural similarities between STIM1, STIM2 and D-STIM suggest conserved biological functions. ..
  45. Ritie L, Spenlé C, Lacroute J, Bolcato Bellemin A, Lefebvre O, Bole Feysot C, et al. Abnormal Wnt and PI3Kinase signaling in the malformed intestine of lama5 deficient mice. PLoS ONE. 2012;7:e37710 pubmed publisher
    ..Thus deregulated adhesion to laminin-511 may be instrumental in diseases such as human pathologies of the gut where laminin-511 is abnormally expressed as it is shown here. ..
  46. Donovan M, Paulino G, Raybould H. CCK(1) receptor is essential for normal meal patterning in mice fed high fat diet. Physiol Behav. 2007;92:969-74 pubmed
    ..These results suggest that the CCK(1)R is involved in regulating caloric intake on a meal to meal basis, but that other factors are responsible for regulation of daily food intake. ..
  47. Shimazoe T, Morita M, Ogiwara S, Kojiya T, Goto J, Kamakura M, et al. Cholecystokinin-A receptors regulate photic input pathways to the circadian clock. FASEB J. 2008;22:1479-90 pubmed
    ..These data indicate a novel function of CCK-A receptors in the nonimage-forming photoreception presumably via amacrine cell-mediated signal transduction pathways. ..
  48. Whited K, Tso P, Raybould H. Involvement of apolipoprotein A-IV and cholecystokinin1 receptors in exogenous peptide YY3 36-induced stimulation of intestinal feedback. Endocrinology. 2007;148:4695-703 pubmed
    ..The data suggest a role for apo A-IV and the CCK(1)R in PYY(3-36)-induced activation of the vagal afferent pathway and inhibition of gastric emptying, but this is likely not the pathway mediating the effects of PYY(3-36) on food intake. ..
  49. Ibarz G, Oiry C, Carnazzi E, Crespy P, Escrieut C, Fourmy D, et al. Cholecystokinin 1 receptor modulates the MEKK1-induced c-Jun trans-activation: structural requirements of the receptor. Br J Pharmacol. 2006;147:951-8 pubmed
    In cells overexpressing active MEKK1 to enhance c-Jun trans-activation, expression of rat cholecystokinin 1 receptor increased the activity of c-Jun while in the same experimental conditions overexpression of mouse cholecystokinin 1 ..
  50. Zhao C, Kodama Y, Flatberg A, Beisvag V, Kulseng B, Sandvik A, et al. Gene expression profiling of gastric mucosa in mice lacking CCK and gastrin receptors. Regul Pept. 2014;192-193:35-44 pubmed publisher
    ..Taking the present data together with previous findings, we suggest a possible link between gastric PTHLH and vitamin D and bone metabolism. ..
  51. Dong C, Willerford D, Alt F, Cooper M. Genomic organization and chromosomal localization of the mouse Bp3 gene, a member of the CD38/ADP-ribosyl cyclase family. Immunogenetics. 1996;45:35-43 pubmed
    ..Consensus motifs for cytokine responsive factors NF-IL6/C-EBP, H-APF-1/APRF, and AP-1 are also present in the flanking region, and interleukin-6 treatment enhances expression of the Bp3 antigen by a myeloblastoid cell line. ..