toll like receptor 9

Summary

Gene Symbol: toll like receptor 9
Description: toll-like receptor 9
Alias: toll-like receptor 9
Species: rat
Products:     toll like receptor 9

Top Publications

  1. Ng M, van t Hof R, Crockett J, Hope M, Berry S, Thomson J, et al. Increase in NF-kappaB binding affinity of the variant C allele of the toll-like receptor 9 -1237T/C polymorphism is associated with Helicobacter pylori-induced gastric disease. Infect Immun. 2010;78:1345-52 pubmed publisher
    ..Collectively, these findings confirm that the TLR9 -1237T/C polymorphism is a risk factor for the development of H. pylori-induced premalignant gastric changes and provide a plausible mechanistic explanation. ..
  2. Ramaprakash H, Ito T, Standiford T, Kunkel S, Hogaboam C. Toll-like receptor 9 modulates immune responses to Aspergillus fumigatus conidia in immunodeficient and allergic mice. Infect Immun. 2009;77:108-19 pubmed publisher
    ..Together, these data suggest that TLR9 modulates pulmonary antifungal immune responses to swollen conidia, possibly through the regulation of dectin-1 expression. ..
  3. Hemmi H, Takeuchi O, Kawai T, Kaisho T, Sato S, Sanjo H, et al. A Toll-like receptor recognizes bacterial DNA. Nature. 2000;408:740-5 pubmed
    ..The in vivo CpG-DNA-mediated T-helper type-1 response was also abolished in TLR9-/- mice. Thus, vertebrate immune systems appear to have evolved a specific Toll-like receptor that distinguishes bacterial DNA from self-DNA. ..
  4. Zhou X, LV J, Cheng W, Yu L, Zhao M, Zhang H. Association of TLR9 gene polymorphisms with lupus nephritis in a Chinese Han population. Clin Exp Rheumatol. 2010;28:397-400 pubmed
    ..However, no significance was achieved. The present study suggested that TLR9 gene have a role in establishing an autoimmune background and pathogenesis in human LN. ..
  5. Papadimitraki E, Tzardi M, Bertsias G, Sotsiou E, Boumpas D. Glomerular expression of toll-like receptor-9 in lupus nephritis but not in normal kidneys: implications for the amplification of the inflammatory response. Lupus. 2009;18:831-5 pubmed publisher
    ..Activation of TLR-9 expressing glomerular cells by endogenous nucleic acids (nucleosomes) may amplify the inflammatory response. ..
  6. Park B, Brinkmann M, Spooner E, Lee C, Kim Y, Ploegh H. Proteolytic cleavage in an endolysosomal compartment is required for activation of Toll-like receptor 9. Nat Immunol. 2008;9:1407-14 pubmed publisher
    ..Lysosomal proteolysis thus contributes to innate immunity by facilitating specific cleavage of TLR9. ..
  7. Ewald S, Lee B, Lau L, Wickliffe K, Shi G, Chapman H, et al. The ectodomain of Toll-like receptor 9 is cleaved to generate a functional receptor. Nature. 2008;456:658-62 pubmed publisher
    ..We propose that ectodomain cleavage represents a strategy to restrict receptor activation to endolysosomal compartments and prevent TLRs from responding to self nucleic acids. ..
  8. Lachheb J, Dhifallah I, Chelbi H, Hamzaoui K, Hamzaoui A. Toll-like receptors and CD14 genes polymorphisms and susceptibility to asthma in Tunisian children. Tissue Antigens. 2008;71:417-25 pubmed publisher
    ..It was concluded that TLR9 and CD14 gene polymorphisms may contribute to an inherited predisposition to asthma in Tunisian children. ..
  9. Droemann D, Albrecht D, Gerdes J, Ulmer A, Branscheid D, Vollmer E, et al. Human lung cancer cells express functionally active Toll-like receptor 9. Respir Res. 2005;6:1 pubmed
    ..The expression of functionally active TLR9 in human malignant tumors might affect treatment approaches using CpG-ODN and shows that malignant cells can be regarded as active players in tumor-immunology. ..

More Information

Publications62

  1. Shintani Y, Kapoor A, Kaneko M, Smolenski R, D Acquisto F, Coppen S, et al. TLR9 mediates cellular protection by modulating energy metabolism in cardiomyocytes and neurons. Proc Natl Acad Sci U S A. 2013;110:5109-14 pubmed publisher
    ..These data propose an intriguing model that the same ligand-receptor can concomitantly increase the stress tolerance in cardiomyocytes and neurons, whereas immune cells induce inflammation upon tissue injury. ..
  2. Tabeta K, Hoebe K, Janssen E, Du X, Georgel P, Crozat K, et al. The Unc93b1 mutation 3d disrupts exogenous antigen presentation and signaling via Toll-like receptors 3, 7 and 9. Nat Immunol. 2006;7:156-64 pubmed
    ..Innate responses to nucleic acids and exogenous antigen presentation, which both initiate in endosomes, thus seem to depend on an endoplasmic reticulum-resident protein, which suggests communication between these organellar systems. ..
  3. Kim Y, Brinkmann M, Paquet M, Ploegh H. UNC93B1 delivers nucleotide-sensing toll-like receptors to endolysosomes. Nature. 2008;452:234-8 pubmed publisher
    ..By inhibiting the interaction between UNC93B1 and TLRs it should be possible to achieve specific regulation of the nucleotide-sensing TLRs without compromising signalling via the cell-surface-disposed TLRs. ..
  4. Liu Y, Zhu L, Fatheree N, Liu X, Pacheco S, Tatevian N, et al. Changes in intestinal Toll-like receptors and cytokines precede histological injury in a rat model of necrotizing enterocolitis. Am J Physiol Gastrointest Liver Physiol. 2009;297:G442-50 pubmed publisher
    ..In conclusion, the intestinal expression of TLRs and cytokines precedes histological injury in the experimental NEC. ..
  5. Carvalho A, Pasqualotto A, Pitzurra L, Romani L, Denning D, Rodrigues F. Polymorphisms in toll-like receptor genes and susceptibility to pulmonary aspergillosis. J Infect Dis. 2008;197:618-21 pubmed publisher
    ..49; P =. 043). No particular polymorphism was associated with severe asthma with fungal sensitization. These findings reinforce the importance of innate immunity in the pathogenesis of different forms of aspergillosis. ..
  6. Summers S, Steinmetz O, Ooi J, Gan P, O Sullivan K, Visvanathan K, et al. Toll-like receptor 9 enhances nephritogenic immunity and glomerular leukocyte recruitment, exacerbating experimental crescentic glomerulonephritis. Am J Pathol. 2010;177:2234-44 pubmed publisher
  7. Bhan U, Lukacs N, Osterholzer J, Newstead M, Zeng X, Moore T, et al. TLR9 is required for protective innate immunity in Gram-negative bacterial pneumonia: role of dendritic cells. J Immunol. 2007;179:3937-46 pubmed
  8. Sarangi P, Kim B, Kurt Jones E, Rouse B. Innate recognition network driving herpes simplex virus-induced corneal immunopathology: role of the toll pathway in early inflammatory events in stromal keratitis. J Virol. 2007;81:11128-38 pubmed
    ..We discuss the possible mechanisms by which early recognition of HSV constituents impacts the subsequent development of immunopathological lesions. ..
  9. Ramanathan M, Lee W, Dubin M, Lin S, Spannhake E, Lane A. Sinonasal epithelial cell expression of toll-like receptor 9 is decreased in chronic rhinosinusitis with polyps. Am J Rhinol. 2007;21:110-6 pubmed
    ..These findings suggest that impaired innate immune responses to pathogens via TLR9 on sinonasal epithelial cells may represent a critical mechanism in chronic inflammatory sinus disease. ..
  10. Kastelijn E, van Moorsel C, Rijkers G, Ruven H, Karthaus V, Kwakkel van Erp J, et al. Polymorphisms in innate immunity genes associated with development of bronchiolitis obliterans after lung transplantation. J Heart Lung Transplant. 2010;29:665-71 pubmed publisher
    ..Polymorphisms in TLR2, TLR4 and TLR9 that recognize bacterial and viral pathogens are associated with BOS after lung transplantation. ..
  11. Mantani Y, Yokoo Y, Kamezaki A, Udayanga K, Takahara E, Takeuchi T, et al. Immunohistochemical detection of toll-like receptor-2, -4 and -9 in exocrine glands associated with rat alimentary tract. J Vet Med Sci. 2012;74:1429-38 pubmed
  12. Nickerson K, Cullen J, Kashgarian M, Shlomchik M. Exacerbated autoimmunity in the absence of TLR9 in MRL.Fas(lpr) mice depends on Ifnar1. J Immunol. 2013;190:3889-94 pubmed publisher
    ..Thus, IFN-I signaling is an important mediator of lupus pathogenesis and anti-RNA Ab production that is dysregulated in the absence of Tlr9. ..
  13. Sivagnanam V, Zhu X, Schlichter L. Dominance of E. coli phagocytosis over LPS in the inflammatory response of microglia. J Neuroimmunol. 2010;227:111-9 pubmed publisher
    ..coli. Importantly, when added with LPS, E. coli dominated the microglial responses for 11/13 genes examined...
  14. Chen M, Zhang W, Xu W, Zhang F, Xiong S. Blockade of TLR9 signaling in B cells impaired anti-dsDNA antibody production in mice induced by activated syngenic lymphocyte-derived DNA immunization. Mol Immunol. 2011;48:1532-9 pubmed publisher
  15. Chun E, Lee S, Lee S, Shim E, Cho S, Min K, et al. Toll-like receptor expression on peripheral blood mononuclear cells in asthmatics; implications for asthma management. J Clin Immunol. 2010;30:459-64 pubmed publisher
  16. Wald D, Qin J, Zhao Z, Qian Y, Naramura M, Tian L, et al. SIGIRR, a negative regulator of Toll-like receptor-interleukin 1 receptor signaling. Nat Immunol. 2003;4:920-7 pubmed
    ..Finally, biochemical analysis indicated that SIGIRR binds to the TLR-IL-1R signaling components in a ligand-dependent way. Our data show that SIGIRR functions as a biologically important modulator of TLR-IL-1R signaling. ..
  17. He C, Lu X, Yan Z, Wu M, Liu S, Yu Y, et al. Therapeutic effect of leflunomide on the development of experimental lupus nephritis in mice. Rheumatol Int. 2012;32:633-8 pubmed publisher
    ..The therapeutic effect of leflunomide on the lupus-prone mice was partially due to the inhibition of TLR9 signaling pathway, which was an important component of innate immune system. ..
  18. Ramaprakash H, Hogaboam C. Intranasal CpG therapy attenuated experimental fungal asthma in a TLR9-dependent and -independent manner. Int Arch Allergy Immunol. 2010;152:98-112 pubmed publisher
    ..Together, these data show that IN CpG has a therapeutic effect during established fungal asthma, which is TLR9 dependent and independent. ..
  19. Sathe A, Reddy K. TLR9 and RIG-I signaling in human endocervical epithelial cells modulates inflammatory responses of macrophages and dendritic cells in vitro. PLoS ONE. 2014;9:e83882 pubmed publisher
    ..In summary, the results of our study indicate that EEC's play an indispensable role in modulating anti-viral immune responses at the female lower genital tract. ..
  20. Ilvesaro J, Merrell M, Li L, Wakchoure S, Graves D, Brooks S, et al. Toll-like receptor 9 mediates CpG oligonucleotide-induced cellular invasion. Mol Cancer Res. 2008;6:1534-43 pubmed publisher
    ..Further, our findings suggest that the structure and/or stability of DNA may influence the induction of TLR9-mediated invasion in breast cancer. ..
  21. Srivastava P, Singh A, Kesarwani P, Jaiswal P, Singh V, Mittal R. Association studies of Toll-like receptor gene polymorphisms with allograft survival in renal transplant recipients of North India. Clin Transplant. 2012;26:581-8 pubmed publisher
    ..044). These TLR gene polymorphisms, upon further evaluation, may be helpful in elucidation of immunobiological mechanisms associated with renal graft rejection. ..
  22. Deng Y, Zhou W. Expression of TLR4 and TLR9 mRNA in Lewis rats with experimental allergic neuritis. Neuroimmunomodulation. 2007;14:337-43 pubmed publisher
    ..05). TLR4 and TLR9 may play a role in the pathogenesis of EAN by taking part in the activation phage and effector phage. ..
  23. Xu C, Zhang W, Pan H, Li X, Xu J, Ye D. Association study of a single nucleotide polymorphism in the exon 2 region of toll-like receptor 9 (TLR9) gene with susceptibility to systemic lupus erythematosus among Chinese. Mol Biol Rep. 2009;36:2245-8 pubmed publisher
    ..004, P = 0.045067). Our study suggests that a single nucleotide polymorphism (rs352140) in the exon 2 region of TLR9 gene may be a susceptibility factor for SLE in Chinese population. ..
  24. Ronkainen H, Hirvikoski P, Kauppila S, Vuopala K, Paavonen T, Selander K, et al. Absent Toll-like receptor-9 expression predicts poor prognosis in renal cell carcinoma. J Exp Clin Cancer Res. 2011;30:84 pubmed publisher
    ..We conclude that TLR9 expression is an independent prognostic marker of RCC and the absence of TLR9 expression is related to poorer prognosis in RCC. ..
  25. Albiger B, Dahlberg S, Sandgren A, Wartha F, Beiter K, Katsuragi H, et al. Toll-like receptor 9 acts at an early stage in host defence against pneumococcal infection. Cell Microbiol. 2007;9:633-44 pubmed
    ..Our data suggest that in the airways, pneumococcal infection triggers a TLR9 and MyD88-dependent activation of phagocytic activity from resident macrophages leading to an early clearance of bacteria from the lower respiratory tract. ..
  26. Schickel J, Pasquali J, Soley A, Knapp A, Decossas M, Kern A, et al. Carabin deficiency in B cells increases BCR-TLR9 costimulation-induced autoimmunity. EMBO Mol Med. 2012;4:1261-75 pubmed publisher
  27. Nakamura T, Ito T, Oono T, Igarashi H, Fujimori N, Uchida M, et al. Bacterial DNA promotes proliferation of rat pancreatic stellate cells thorough toll-like receptor 9: potential mechanisms for bacterially induced fibrosis. Pancreas. 2011;40:823-31 pubmed publisher
    ..Our findings demonstrate that bacterial DNA promotes migration and proliferation of PSCs and suggest that bacterial DNA can initiate and sustain pancreatic inflammation and fibrosis by means of TLR9. ..
  28. Wang Y, Liang Q, Ramkalawan H, Zhang W, Zhou W, Xiao B, et al. Inactivation of TLR9 by a suppressive oligodeoxynucleotides can ameliorate the clinical signs of EAN. Immunol Invest. 2012;41:171-82 pubmed publisher
    ..Our study suggests that TLR9 may be involved in the pathogenesis of EAN. ..
  29. Ank N, Iversen M, Bartholdy C, Staeheli P, Hartmann R, Jensen U, et al. An important role for type III interferon (IFN-lambda/IL-28) in TLR-induced antiviral activity. J Immunol. 2008;180:2474-85 pubmed
    ..In this compartment, epithelial cells responded to IFN-lambda and directly restricted virus replication. Our data suggest type III IFN to target a specific subset of cells and to contribute to the antiviral response evoked by TLRs. ..
  30. Krüger B, Banas M, Walberer A, Böger C, Farkas S, Hoffmann U, et al. A comprehensive genotype-phenotype interaction of different Toll-like receptor variations in a renal transplant cohort. Clin Sci (Lond). 2010;119:535-44 pubmed publisher
    ..In conclusion, our present study in renal transplant recipients suggests that the TLR system may be involved in both acute rejection and MACE. Modulation of the TLR system may be a promising target in future therapeutic strategies. ..
  31. So N, Ostrowski M, Gray Owen S. Vigorous response of human innate functioning IgM memory B cells upon infection by Neisseria gonorrhoeae. J Immunol. 2012;188:4008-22 pubmed publisher
    ..This unfocused T-independent response explains the localized Ig response that occurs, despite an absence of immunologic memory elicited during gonorrhea...
  32. Kim G, Cho M, Park Y, Yoo W, Kim J, Oh H, et al. Expression of TLR2, TLR4, and TLR9 in dermatomyositis and polymyositis. Clin Rheumatol. 2010;29:273-9 pubmed publisher
    ..These results suggest that the involvement of TLR4 and TLR9 in immunopathogenesis of DM and PM might be connected with activation of CD4(+) T cells. ..
  33. Cornelie S, Hoebeke J, Schacht A, Bertin B, Vicogne J, Capron M, et al. Direct evidence that toll-like receptor 9 (TLR9) functionally binds plasmid DNA by specific cytosine-phosphate-guanine motif recognition. J Biol Chem. 2004;279:15124-9 pubmed
    ..Furthermore, we demonstrate that this interaction leads to the activation of the NF-kappaB pathway in mTLR9-expressing cells. Our results provide a molecular basis for the interaction between CpG-DNA and TLR9. ..
  34. Carvalho A, Cunha C, Carotti A, Aloisi T, Guarrera O, Di Ianni M, et al. Polymorphisms in Toll-like receptor genes and susceptibility to infections in allogeneic stem cell transplantation. Exp Hematol. 2009;37:1022-9 pubmed publisher
    ..The finding that defective viral but not fungal sensing may predict susceptibility to infection highlights the divergent function of TLRs in the pathogenesis of opportunistic infections. ..
  35. Böttcher T, von Mering M, Ebert S, Meyding Lamade U, Kuhnt U, Gerber J, et al. Differential regulation of Toll-like receptor mRNAs in experimental murine central nervous system infections. Neurosci Lett. 2003;344:17-20 pubmed
    ..The TLR mRNA regulation observed probably represents a combination of specific response to the causative pathogen and non-specific activation of the innate immune system. ..
  36. Lu K, Yang H, Lin Y, Kao S, Lai C, Chu C, et al. The T-1237C polymorphism of the Toll-like receptor-9 gene is associated with chronic kidney disease in a Han Chinese population. Tohoku J Exp Med. 2011;225:109-16 pubmed
    ..In the Han Chinese population, those who carry the C and A alleles at SNPs T-1237C and G1635A in the TLR-9 gene appear to be more susceptible to the development of CKD. ..
  37. Ramachandran R, Sharma V, Rathi M, Yadav A, Sharma A, Kohli H, et al. Association between -1486 T>C and +1174 G>A single nucleotide polymorphisms in TLR9 gene and severity of lupus nephritis. Indian J Nephrol. 2012;22:125-9 pubmed publisher
    ..CC/CT genotypes at -1486 and AA/AG at +1174 positions are associated with more severe kidney disease at presentation. ..
  38. Kumar H, Kawai T, Akira S. Pathogen recognition by the innate immune system. Int Rev Immunol. 2011;30:16-34 pubmed publisher
    ..In this review, we comprehensively review the recent progress in the field of PAMP recognition by PRRs and the signaling pathways activated by PRRs. ..
  39. Bereczky Veress B, Abdelmagid N, Piehl F, Bergstrom T, Olsson T, Sköldenberg B, et al. Influence of perineurial cells and Toll-like receptors 2 and 9 on Herpes simplex type 1 entry to the central nervous system in rat encephalitis. PLoS ONE. 2010;5:e12350 pubmed publisher
  40. Daud I, Scott M, Ma Y, Shiboski S, Farhat S, Moscicki A. Association between toll-like receptor expression and human papillomavirus type 16 persistence. Int J Cancer. 2011;128:879-86 pubmed publisher
  41. Zhang Y, He F, Fang M, Hua T, Hu B, Zhang Z, et al. Increased expression of Toll-like receptors 4 and 9 in human lung cancer. Mol Biol Rep. 2009;36:1475-81 pubmed publisher
    ..These results suggested that TLR4 and TLR9 may be involved in the development of lung cancer which may have the potentials for the treatment of this malignant tumor. ..
  42. Zhu Y, Miao J, Fan H, Zou S, Chen W. Protective effect of CpG-DNA against mastitis induced by Staphylococcus aureus infection in a rat model. Int Immunopharmacol. 2007;7:435-43 pubmed
    ..aureus in mammary tissue and decreased the activity of NAGase. CpG-DNA also promoted the expression of its specific receptor TLR-9 mRNA in mammary tissue. In conclusion, CpG-DNA protected against S. aureus mastitis in a rat model. ..
  43. Tuon F, Fernandes E, Duarte M, Amato V. The expression of TLR2, TLR4 and TLR9 in the epidermis of patients with cutaneous leishmaniasis. J Dermatol Sci. 2010;59:55-7 pubmed publisher
  44. Bertin S, Samson M, Pons C, Guigonis J, Gavelli A, Baque P, et al. Comparative proteomics study reveals that bacterial CpG motifs induce tumor cell autophagy in vitro and in vivo. Mol Cell Proteomics. 2008;7:2311-22 pubmed publisher
    ..Our findings bring new insights on the effect of bacterial CpG motifs in tumor cells and may be relevant for cancer treatment and more generally for gene therapy approaches in TLR9-positive tissues. ..
  45. Hornung V, Guenthner Biller M, Bourquin C, Ablasser A, Schlee M, Uematsu S, et al. Sequence-specific potent induction of IFN-alpha by short interfering RNA in plasmacytoid dendritic cells through TLR7. Nat Med. 2005;11:263-70 pubmed
    ..Thus sequence-specific TLR7-dependent immune recognition in PDC needs to be considered as an additional biological activity of siRNA, which then should be termed immunostimulatory RNA (isRNA). ..
  46. Hirayama T, Tamaki Y, Takakubo Y, Iwazaki K, Sasaki K, Ogino T, et al. Toll-like receptors and their adaptors are regulated in macrophages after phagocytosis of lipopolysaccharide-coated titanium particles. J Orthop Res. 2011;29:984-92 pubmed publisher
    ..This down- and/or up-regulation of the potential TLR-mediated responses to LPS-coated particles reflects the proactive behavior of effector cells. ..
  47. Stanke F, Becker T, Kumar V, Hedtfeld S, Becker C, Cuppens H, et al. Genes that determine immunology and inflammation modify the basic defect of impaired ion conductance in cystic fibrosis epithelia. J Med Genet. 2011;48:24-31 pubmed publisher
    ..Awareness of non-genetic factors such as improvement of patient care over time is crucial for the interpretation of CF modifier studies. ..
  48. Suzuki H, Suzuki Y, Narita I, Aizawa M, Kihara M, Yamanaka T, et al. Toll-like receptor 9 affects severity of IgA nephropathy. J Am Soc Nephrol. 2008;19:2384-95 pubmed publisher
    ..In summary, these findings suggest that activation of the TLR9/MyD88 pathway by common antigens may affect the severity of IgAN. ..
  49. Knuefermann P, Baumgarten G, Koch A, Schwederski M, Velten M, Ehrentraut H, et al. CpG oligonucleotide activates Toll-like receptor 9 and causes lung inflammation in vivo. Respir Res. 2007;8:72 pubmed
    ..In contrast, the CpG-ODN-induced inflammatory response was abolished in TLR9-D mice. This study suggests that bacterial CpG-ODN causes lung inflammation via TLR9. ..
  50. Takagi M, Tamaki Y, Hasegawa H, Takakubo Y, Konttinen L, Tiainen V, et al. Toll-like receptors in the interface membrane around loosening total hip replacement implants. J Biomed Mater Res A. 2007;81:1017-26 pubmed
    ..This suppression after particle phagocytosis might prevent excessive and harmful host responses, and injury to innocent bystander cells/tissues. ..
  51. Cardoso E, Pereira N, Mitsunari G, Oliveira L, Ruocco R, Francisco R, et al. TLR7/TLR8 Activation Restores Defective Cytokine Secretion by Myeloid Dendritic Cells but Not by Plasmacytoid Dendritic Cells in HIV-Infected Pregnant Women and Newborns. PLoS ONE. 2013;8:e67036 pubmed publisher
    ..Our findings highlight the dysfunction of innate immunity in HIV-infected mother-newborn pairs. The activation of the TLR7/8 pathway could function as an adjuvant to improve maternal-neonatal innate immunity. ..
  52. Olson J, Miller S. Microglia initiate central nervous system innate and adaptive immune responses through multiple TLRs. J Immunol. 2004;173:3916-24 pubmed
    ..Thus, microglia appear to be a unique and important component of both the innate and adaptive immune response, providing the CNS with a means to rapidly and efficiently respond to a wide variety of pathogens. ..
  53. Okazaki S, Nagoya S, Matsumoto H, Mizuo K, Sasaki M, Watanabe S, et al. Development of non-traumatic osteonecrosis of the femoral head requires toll-like receptor 7 and 9 stimulations and is boosted by repression on nuclear factor kappa B in rats. Lab Invest. 2015;95:92-9 pubmed publisher
    ..In conclusion, in the present study, corticosteroid treatment after the administration of TLR7 or TLR9 ligands caused ONFH. Repression in NF-κB activity by corticosteroid treatment boosted the development of ONFH. ..