The Experts below are selected from a list of 168 Experts worldwide ranked by ideXlab platform
Vincent Murray - One of the best experts on this subject based on the ideXlab platform.
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CpG methylation increases the DNA binding of 9-Aminoacridine carboxamide Pt analogues.
Bioorganic & medicinal chemistry, 2016Co-Authors: Hieronimus W. Kava, Vincent MurrayAbstract:This study investigated the effect of CpG methylation on the DNA binding of cisplatin analogues with an attached aminoacridine intercalator. DNA-targeted 9-Aminoacridine carboxamide Pt complexes are known to bind at 5'-CpG sequences. Their binding to methylated and non-methylated 5'-CpG sequences was determined and compared with cisplatin. The damage profiles of each platinum compound were quantified via a polymerase stop assay with fluorescently labelled primers and capillary electrophoresis. Methylation at 5'-CpG was shown to significantly increase the binding intensity for the 9-Aminoacridine carboxamide compounds, whereas no significant increase was found for cisplatin. 5'-CpG methylation had the largest effect on the 9-ethanolamine-acridine carboxamide Pt complex, followed by the 9-Aminoacridine carboxamide Pt complex and the 7-fluoro complex. The methylation state of a cell's genome is important in maintaining normal gene expression, and is often aberrantly altered in cancer cells. An analogue of cisplatin which differentially targets methylated DNA may be able to improve its therapeutic activity, or alter its range of targets and evade the chemoresistance which hampers cisplatin efficacy in clinical use.
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Characterising the atypical 5′-CG DNA sequence specificity of 9-Aminoacridine carboxamide Pt complexes
Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry, 2014Co-Authors: Hieronimus W. Kava, Anne M. Galea, Farhana Md. Jamil, Yue Feng, Vincent MurrayAbstract:In this study, the DNA sequence specificity of four DNA-targeted 9-Aminoacridine carboxamide Pt complexes was compared with cisplatin, using two specially constructed plasmid templates. One plasmid contained 5'-CG and 5'-GA insert sequences while the other plasmid contained a G-rich transferrin receptor gene promoter insert sequence. The damage profiles of each compound on the different DNA templates were quantified via a polymerase stop assay with fluorescently labelled primers and capillary electrophoresis. With the plasmid that contained 5'-CG and 5'-GA dinucleotides, the four 9-Aminoacridine carboxamide Pt complexes produced distinctly different damage profiles as compared with cisplatin. These 9-Aminoacridine complexes had greatly increased levels of DNA damage at CG and GA dinucleotides as compared with cisplatin. It was shown that the presence of a CG or GA dinucleotide was sufficient to reveal the altered DNA sequence selectivity of the 9-Aminoacridine carboxamide Pt analogues. The DNA sequence specificity of the Pt complexes was also found to be similarly altered utilising the transferrin receptor DNA sequence.
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The sequence selectivity of DNA-targeted 9-Aminoacridine cisplatin analogues in a telomere-containing DNA sequence
Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry, 2011Co-Authors: Moumita Paul, Vincent MurrayAbstract:In this study, the detailed DNA sequence specificity of four acridine Pt complexes was examined and compared with that of cisplatin. The DNA sequence specificity was determined in a telomere-containing DNA sequence using a polymerase stop assay, with a fluorescent primer and an automated capillary DNA sequencer. The Pt compounds included an acridine intercalating moiety that was modified to give a 9-Aminoacridine derivative, a 7-methoxy-9-Aminoacridine derivative, a 7-fluoro-9-Aminoacridine derivative and a 9-ethanolamine-acridine derivative. Compared with cisplatin, the DNA sequence specificity was most altered for the 7-methoxy-9-Aminoacridine compound, followed by the 9-Aminoacridine derivative, the 7-fluoro-9-Aminoacridine compound and the 9-ethanolamine-acridine derivative. The DNA sequence selectivity for the four acridine Pt complexes was shifted away from runs of consecutive guanines towards single guanine bases, especially 5′-GA dinucleotides and sequences that contained 5′-CG. The sequence specificity was examined in telomeric and non-telomeric DNA sequences. Although it was found that telomeric DNA sequences were extensively damaged by the four acridine Pt complexes, there was no extra preference for telomeric sequences.
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The interaction of DNA-targeted 9-Aminoacridine-4-carboxamide platinum complexes with DNA in intact human cells.
Biochimica et biophysica acta, 2002Co-Authors: Mark D. Temple, William A. Denny, Rodney J. Holmes, W. David Mcfadyen, Patsy Recabarren, Vincent MurrayAbstract:Abstract As part of an ongoing drug development programme, this paper describes the sequence specificity and time course of DNA adduct formation for a series of novel DNA-targeted analogues of cis-diaminedichloroplatinum(II) (cisplatin) (9-Aminoacridine-4-carboxamide Pt complexes) in intact HeLa cells. The sequence specificity of DNA damage caused by cisplatin and analogues in human (HeLa) cells was studied using Taq DNA polymerase and a linear amplification/polymerase stop assay. Primer extension is inhibited by a Pt–DNA adduct, and hence the sites of these lesions can be analysed on DNA sequencing gels. The repetitive alphoid DNA sequence was used as the target DNA in human cells. The 9-Aminoacridine-4-carboxamide Pt complexes exhibited a markedly different sequence specificity relative to cisplatin and other analogues. The sequence specificity of the 9-Aminoacridine-4-carboxamide Pt complexes is shifted away from a preference for runs of guanines. The 9-Aminoacridine-4-carboxamide Pt complexes have an enhanced preference for GA dinucleotides. This is the first occasion that an altered DNA sequence specificity has been demonstrated for a cisplatin analogue in human cells. A time course of DNA damage revealed that the DNA-targeted Pt complexes, consisting of four 9-Aminoacridine-4-carboxamide Pt complexes and one acridine-4-carboxamide Pt complex, damaged DNA more rapidly compared to cisplatin and non-targeted analogues. A comparison of the time taken to reach half the maximum relative intensity indicated that the DNA-targeted Pt complexes reacted approximately 4-fold faster than cisplatin and the non-targeted analogues.
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cis-Dichloroplatinum(II) complexes tethered to 9-Aminoacridine-4-carboxamides: synthesis and action in resistant cell lines in vitro.
Journal of Inorganic Biochemistry, 2001Co-Authors: Rodney J. Holmes, William A. Denny, Vincent Murray, Mark J. Mckeage, W. David McfadyenAbstract:A series of intercalator-tethered platinum(II) complexes PtLCl(2) have been prepared where L are the diamine ligands N-[2-[(aminoethyl)amino]ethyl]-9-Aminoacridine-4-carboxamide, N-[3-[(2-aminoethyl)amino]propyl]-9-Aminoacridine-4-carboxamide, N-[4-[(2-aminoethyl)amino]butyl]-9-Aminoacridine-4-carboxamide and N-[5-[(aminoethyl)amino]pentyl]-9-Aminoacridine-4-carboxamide and N-[6-[(aminoethyl)amino]hexyl]-9-Aminoacridine-4-carboxamide. The activity of the complexes was assessed in the CH-1, CH-1cisR, 41M, 41McisR and SKOV-3 cell lines. The compounds with the shorter linker chain lengths are generally the most active against these cell lines and are much more toxic than Pt(en)C1(2). For example, for the n=2 compound the IC(50) values are 0.017 microM (CH-1), 1.7 microM (41M), 1.4 microM (SKOV-3) and the resistance ratios are 51 (CH-1cisR) and 1.6 (41McisR). For the untethered analogue Pt(en)C1(2) the IC(50) values are 2.5 microM (CH-1), 2.9 microM (41M), 45 microM (SKOV-3) and the resistance ratios are 2.8 (CH-1cisR) and 4.1 (41McisR). The very large differential in IC(50) values between the CH-1 and CH-1cisR pair of cell lines for the 9-Aminoacridine-4-carboxamide tethered platinum complexes indicates that repair of platinum-induced DNA damage may be a major determinant of the activity of these compounds.
William A. Denny - One of the best experts on this subject based on the ideXlab platform.
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Homobivalent Conjugation Increases the Allosteric Effect of 9-Aminoacridine at the α1-Adrenergic Receptors
Molecular pharmacology, 2016Co-Authors: Adrian P. Campbell, William A. Denny, Laurence P. G. Wakelin, Angela M. FinchAbstract:The α1-adrenergic receptors are targets for a number of cardiovascular and central nervous system conditions, but the current drugs for these receptors lack specificity to be of optimal clinical value. Allosteric modulators offer an alternative mechanism of action to traditional α1-adrenergic ligands, yet there is little information describing this drug class at the α1-adrenergic receptors. We have identified a series of 9-Aminoacridine compounds that demonstrate allosteric modulation of the α1A- and α1B-adrenergic receptors. The 9-Aminoacridines increase the rate of [3H]prazosin dissociation from the α1A- and α1B-adrenergic receptors and noncompetitively inhibit receptor activation by the endogenous agonist norepinephrine. The structurally similar compound, tacrine, which is a known allosteric modulator of the muscarinic receptors, is also shown to be a modulator of the α1-adrenergic receptors, which suggests a general lack of selectivity for allosteric binding sites across aminergic G protein-coupled receptor. Conjugation of two 9-Aminoacridine pharmacophores, using linkers of varying length, increases the potency and efficacy of the allosteric effects of this ligand, likely through optimization of bitopic engagement of the allosteric and orthosteric binding sites of the receptor. Such a bivalent approach may provide a mechanism for fine tuning the efficacy of allosteric compounds in future drug design efforts.
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The interaction of DNA-targeted 9-Aminoacridine-4-carboxamide platinum complexes with DNA in intact human cells.
Biochimica et biophysica acta, 2002Co-Authors: Mark D. Temple, William A. Denny, Rodney J. Holmes, W. David Mcfadyen, Patsy Recabarren, Vincent MurrayAbstract:Abstract As part of an ongoing drug development programme, this paper describes the sequence specificity and time course of DNA adduct formation for a series of novel DNA-targeted analogues of cis-diaminedichloroplatinum(II) (cisplatin) (9-Aminoacridine-4-carboxamide Pt complexes) in intact HeLa cells. The sequence specificity of DNA damage caused by cisplatin and analogues in human (HeLa) cells was studied using Taq DNA polymerase and a linear amplification/polymerase stop assay. Primer extension is inhibited by a Pt–DNA adduct, and hence the sites of these lesions can be analysed on DNA sequencing gels. The repetitive alphoid DNA sequence was used as the target DNA in human cells. The 9-Aminoacridine-4-carboxamide Pt complexes exhibited a markedly different sequence specificity relative to cisplatin and other analogues. The sequence specificity of the 9-Aminoacridine-4-carboxamide Pt complexes is shifted away from a preference for runs of guanines. The 9-Aminoacridine-4-carboxamide Pt complexes have an enhanced preference for GA dinucleotides. This is the first occasion that an altered DNA sequence specificity has been demonstrated for a cisplatin analogue in human cells. A time course of DNA damage revealed that the DNA-targeted Pt complexes, consisting of four 9-Aminoacridine-4-carboxamide Pt complexes and one acridine-4-carboxamide Pt complex, damaged DNA more rapidly compared to cisplatin and non-targeted analogues. A comparison of the time taken to reach half the maximum relative intensity indicated that the DNA-targeted Pt complexes reacted approximately 4-fold faster than cisplatin and the non-targeted analogues.
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cis-Dichloroplatinum(II) complexes tethered to 9-Aminoacridine-4-carboxamides: synthesis and action in resistant cell lines in vitro.
Journal of Inorganic Biochemistry, 2001Co-Authors: Rodney J. Holmes, William A. Denny, Vincent Murray, Mark J. Mckeage, W. David McfadyenAbstract:A series of intercalator-tethered platinum(II) complexes PtLCl(2) have been prepared where L are the diamine ligands N-[2-[(aminoethyl)amino]ethyl]-9-Aminoacridine-4-carboxamide, N-[3-[(2-aminoethyl)amino]propyl]-9-Aminoacridine-4-carboxamide, N-[4-[(2-aminoethyl)amino]butyl]-9-Aminoacridine-4-carboxamide and N-[5-[(aminoethyl)amino]pentyl]-9-Aminoacridine-4-carboxamide and N-[6-[(aminoethyl)amino]hexyl]-9-Aminoacridine-4-carboxamide. The activity of the complexes was assessed in the CH-1, CH-1cisR, 41M, 41McisR and SKOV-3 cell lines. The compounds with the shorter linker chain lengths are generally the most active against these cell lines and are much more toxic than Pt(en)C1(2). For example, for the n=2 compound the IC(50) values are 0.017 microM (CH-1), 1.7 microM (41M), 1.4 microM (SKOV-3) and the resistance ratios are 51 (CH-1cisR) and 1.6 (41McisR). For the untethered analogue Pt(en)C1(2) the IC(50) values are 2.5 microM (CH-1), 2.9 microM (41M), 45 microM (SKOV-3) and the resistance ratios are 2.8 (CH-1cisR) and 4.1 (41McisR). The very large differential in IC(50) values between the CH-1 and CH-1cisR pair of cell lines for the 9-Aminoacridine-4-carboxamide tethered platinum complexes indicates that repair of platinum-induced DNA damage may be a major determinant of the activity of these compounds.
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Excited-State Proton Transfers in 9-Aminoacridine Carboxamides
The Journal of Physical Chemistry, 1995Co-Authors: Charles Andrew Smith, Hai-chou Chang, Walter S. Struve, Graham J. Atwell, William A. DennyAbstract:Excited-state proton transfers have been investigated for several isomeric and homologous N-((dimethylamino)-alkyl)-9-Aminoacridine carboxamides in a time-correlated single photon counting fluorescence study. The pH behavior of these DNA intercalators` steady-state absorption and fluorescence spectra has also been investigated. While the excited-state pK{sub a}* for removal of a proton from the singly protonated species is close to the ground-state pK{sub a} in the parent molecule 9-Aminoacridine, the presence of the carboxamide substituent renders pK{sub a}* much lower than pK{sub a} for the corresponding deprotonation in the present compounds. This fact, along with the presence of an additional deprotonation site at the distal N atom of the side chain, endows these molecules with complex pH dependence in their excited-state kinetics. Triexponential model functions are generally required to fit the experimental fluorescence decays. The pH dependence of the component lifetimes and preexponential factors can be simulated with a kinetic model for sequential deprotonations involving four aminoacridine species in both the ground and fluorescing states. These results provide a baseline study for comparisons with these intercalators` excited-state kinetics in DNA. 37 refs., 12 figs., 2 tabs.
W. David Mcfadyen - One of the best experts on this subject based on the ideXlab platform.
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The interaction of DNA-targeted 9-Aminoacridine-4-carboxamide platinum complexes with DNA in intact human cells.
Biochimica et biophysica acta, 2002Co-Authors: Mark D. Temple, William A. Denny, Rodney J. Holmes, W. David Mcfadyen, Patsy Recabarren, Vincent MurrayAbstract:Abstract As part of an ongoing drug development programme, this paper describes the sequence specificity and time course of DNA adduct formation for a series of novel DNA-targeted analogues of cis-diaminedichloroplatinum(II) (cisplatin) (9-Aminoacridine-4-carboxamide Pt complexes) in intact HeLa cells. The sequence specificity of DNA damage caused by cisplatin and analogues in human (HeLa) cells was studied using Taq DNA polymerase and a linear amplification/polymerase stop assay. Primer extension is inhibited by a Pt–DNA adduct, and hence the sites of these lesions can be analysed on DNA sequencing gels. The repetitive alphoid DNA sequence was used as the target DNA in human cells. The 9-Aminoacridine-4-carboxamide Pt complexes exhibited a markedly different sequence specificity relative to cisplatin and other analogues. The sequence specificity of the 9-Aminoacridine-4-carboxamide Pt complexes is shifted away from a preference for runs of guanines. The 9-Aminoacridine-4-carboxamide Pt complexes have an enhanced preference for GA dinucleotides. This is the first occasion that an altered DNA sequence specificity has been demonstrated for a cisplatin analogue in human cells. A time course of DNA damage revealed that the DNA-targeted Pt complexes, consisting of four 9-Aminoacridine-4-carboxamide Pt complexes and one acridine-4-carboxamide Pt complex, damaged DNA more rapidly compared to cisplatin and non-targeted analogues. A comparison of the time taken to reach half the maximum relative intensity indicated that the DNA-targeted Pt complexes reacted approximately 4-fold faster than cisplatin and the non-targeted analogues.
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cis-Dichloroplatinum(II) complexes tethered to 9-Aminoacridine-4-carboxamides: synthesis and action in resistant cell lines in vitro.
Journal of Inorganic Biochemistry, 2001Co-Authors: Rodney J. Holmes, William A. Denny, Vincent Murray, Mark J. Mckeage, W. David McfadyenAbstract:A series of intercalator-tethered platinum(II) complexes PtLCl(2) have been prepared where L are the diamine ligands N-[2-[(aminoethyl)amino]ethyl]-9-Aminoacridine-4-carboxamide, N-[3-[(2-aminoethyl)amino]propyl]-9-Aminoacridine-4-carboxamide, N-[4-[(2-aminoethyl)amino]butyl]-9-Aminoacridine-4-carboxamide and N-[5-[(aminoethyl)amino]pentyl]-9-Aminoacridine-4-carboxamide and N-[6-[(aminoethyl)amino]hexyl]-9-Aminoacridine-4-carboxamide. The activity of the complexes was assessed in the CH-1, CH-1cisR, 41M, 41McisR and SKOV-3 cell lines. The compounds with the shorter linker chain lengths are generally the most active against these cell lines and are much more toxic than Pt(en)C1(2). For example, for the n=2 compound the IC(50) values are 0.017 microM (CH-1), 1.7 microM (41M), 1.4 microM (SKOV-3) and the resistance ratios are 51 (CH-1cisR) and 1.6 (41McisR). For the untethered analogue Pt(en)C1(2) the IC(50) values are 2.5 microM (CH-1), 2.9 microM (41M), 45 microM (SKOV-3) and the resistance ratios are 2.8 (CH-1cisR) and 4.1 (41McisR). The very large differential in IC(50) values between the CH-1 and CH-1cisR pair of cell lines for the 9-Aminoacridine-4-carboxamide tethered platinum complexes indicates that repair of platinum-induced DNA damage may be a major determinant of the activity of these compounds.
Rodney J. Holmes - One of the best experts on this subject based on the ideXlab platform.
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The interaction of DNA-targeted 9-Aminoacridine-4-carboxamide platinum complexes with DNA in intact human cells.
Biochimica et biophysica acta, 2002Co-Authors: Mark D. Temple, William A. Denny, Rodney J. Holmes, W. David Mcfadyen, Patsy Recabarren, Vincent MurrayAbstract:Abstract As part of an ongoing drug development programme, this paper describes the sequence specificity and time course of DNA adduct formation for a series of novel DNA-targeted analogues of cis-diaminedichloroplatinum(II) (cisplatin) (9-Aminoacridine-4-carboxamide Pt complexes) in intact HeLa cells. The sequence specificity of DNA damage caused by cisplatin and analogues in human (HeLa) cells was studied using Taq DNA polymerase and a linear amplification/polymerase stop assay. Primer extension is inhibited by a Pt–DNA adduct, and hence the sites of these lesions can be analysed on DNA sequencing gels. The repetitive alphoid DNA sequence was used as the target DNA in human cells. The 9-Aminoacridine-4-carboxamide Pt complexes exhibited a markedly different sequence specificity relative to cisplatin and other analogues. The sequence specificity of the 9-Aminoacridine-4-carboxamide Pt complexes is shifted away from a preference for runs of guanines. The 9-Aminoacridine-4-carboxamide Pt complexes have an enhanced preference for GA dinucleotides. This is the first occasion that an altered DNA sequence specificity has been demonstrated for a cisplatin analogue in human cells. A time course of DNA damage revealed that the DNA-targeted Pt complexes, consisting of four 9-Aminoacridine-4-carboxamide Pt complexes and one acridine-4-carboxamide Pt complex, damaged DNA more rapidly compared to cisplatin and non-targeted analogues. A comparison of the time taken to reach half the maximum relative intensity indicated that the DNA-targeted Pt complexes reacted approximately 4-fold faster than cisplatin and the non-targeted analogues.
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cis-Dichloroplatinum(II) complexes tethered to 9-Aminoacridine-4-carboxamides: synthesis and action in resistant cell lines in vitro.
Journal of Inorganic Biochemistry, 2001Co-Authors: Rodney J. Holmes, William A. Denny, Vincent Murray, Mark J. Mckeage, W. David McfadyenAbstract:A series of intercalator-tethered platinum(II) complexes PtLCl(2) have been prepared where L are the diamine ligands N-[2-[(aminoethyl)amino]ethyl]-9-Aminoacridine-4-carboxamide, N-[3-[(2-aminoethyl)amino]propyl]-9-Aminoacridine-4-carboxamide, N-[4-[(2-aminoethyl)amino]butyl]-9-Aminoacridine-4-carboxamide and N-[5-[(aminoethyl)amino]pentyl]-9-Aminoacridine-4-carboxamide and N-[6-[(aminoethyl)amino]hexyl]-9-Aminoacridine-4-carboxamide. The activity of the complexes was assessed in the CH-1, CH-1cisR, 41M, 41McisR and SKOV-3 cell lines. The compounds with the shorter linker chain lengths are generally the most active against these cell lines and are much more toxic than Pt(en)C1(2). For example, for the n=2 compound the IC(50) values are 0.017 microM (CH-1), 1.7 microM (41M), 1.4 microM (SKOV-3) and the resistance ratios are 51 (CH-1cisR) and 1.6 (41McisR). For the untethered analogue Pt(en)C1(2) the IC(50) values are 2.5 microM (CH-1), 2.9 microM (41M), 45 microM (SKOV-3) and the resistance ratios are 2.8 (CH-1cisR) and 4.1 (41McisR). The very large differential in IC(50) values between the CH-1 and CH-1cisR pair of cell lines for the 9-Aminoacridine-4-carboxamide tethered platinum complexes indicates that repair of platinum-induced DNA damage may be a major determinant of the activity of these compounds.
Hieronimus W. Kava - One of the best experts on this subject based on the ideXlab platform.
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CpG methylation increases the DNA binding of 9-Aminoacridine carboxamide Pt analogues.
Bioorganic & medicinal chemistry, 2016Co-Authors: Hieronimus W. Kava, Vincent MurrayAbstract:This study investigated the effect of CpG methylation on the DNA binding of cisplatin analogues with an attached aminoacridine intercalator. DNA-targeted 9-Aminoacridine carboxamide Pt complexes are known to bind at 5'-CpG sequences. Their binding to methylated and non-methylated 5'-CpG sequences was determined and compared with cisplatin. The damage profiles of each platinum compound were quantified via a polymerase stop assay with fluorescently labelled primers and capillary electrophoresis. Methylation at 5'-CpG was shown to significantly increase the binding intensity for the 9-Aminoacridine carboxamide compounds, whereas no significant increase was found for cisplatin. 5'-CpG methylation had the largest effect on the 9-ethanolamine-acridine carboxamide Pt complex, followed by the 9-Aminoacridine carboxamide Pt complex and the 7-fluoro complex. The methylation state of a cell's genome is important in maintaining normal gene expression, and is often aberrantly altered in cancer cells. An analogue of cisplatin which differentially targets methylated DNA may be able to improve its therapeutic activity, or alter its range of targets and evade the chemoresistance which hampers cisplatin efficacy in clinical use.
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Characterising the atypical 5′-CG DNA sequence specificity of 9-Aminoacridine carboxamide Pt complexes
Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry, 2014Co-Authors: Hieronimus W. Kava, Anne M. Galea, Farhana Md. Jamil, Yue Feng, Vincent MurrayAbstract:In this study, the DNA sequence specificity of four DNA-targeted 9-Aminoacridine carboxamide Pt complexes was compared with cisplatin, using two specially constructed plasmid templates. One plasmid contained 5'-CG and 5'-GA insert sequences while the other plasmid contained a G-rich transferrin receptor gene promoter insert sequence. The damage profiles of each compound on the different DNA templates were quantified via a polymerase stop assay with fluorescently labelled primers and capillary electrophoresis. With the plasmid that contained 5'-CG and 5'-GA dinucleotides, the four 9-Aminoacridine carboxamide Pt complexes produced distinctly different damage profiles as compared with cisplatin. These 9-Aminoacridine complexes had greatly increased levels of DNA damage at CG and GA dinucleotides as compared with cisplatin. It was shown that the presence of a CG or GA dinucleotide was sufficient to reveal the altered DNA sequence selectivity of the 9-Aminoacridine carboxamide Pt analogues. The DNA sequence specificity of the Pt complexes was also found to be similarly altered utilising the transferrin receptor DNA sequence.
