Genomes and Genes
Summary: A protease of broad specificity, obtained from dried pancreas. Molecular weight is approximately 25,000. The enzyme breaks down elastin, the specific protein of elastic fibers, and digests other proteins such as fibrin, hemoglobin, and albumin. EC 188.8.131.52.
- Inoue K, Yanagisawa R, Koike E, Nakamura R, Ichinose T, Tasaka S, et al. Effects of carbon black nanoparticles on elastase-induced emphysematous lung injury in mice. Basic Clin Pharmacol Toxicol. 2011;108:234-40 pubmed publisher..of pulmonary exposure to carbon black nanoparticles (CBNP) on emphysematous lung injury induced by porcine pancreatic elastase (PPE) in mice. Vehicle, two sizes (14 and 56 nm) of CBNP (50 ?g/body: 4 mg/kg), PPE (0...
- Zhang Q, Huang J, Xia R, Duan X, Jiang Y, Jiang Q, et al. Suppression of experimental abdominal aortic aneurysm in a rat model by the phosphodiesterase 3 inhibitor cilostazol. J Surg Res. 2011;167:e385-93 pubmed publisher..Selective PDE3 inhibition may offer an additional method to pharmacologically inhibit AAAs. ..
- Palmieri D, Pane B, Barisione C, Spinella G, Garibaldi S, Ghigliotti G, et al. Resveratrol counteracts systemic and local inflammation involved in early abdominal aortic aneurysm development. J Surg Res. 2011;171:e237-46 pubmed publisher..These data suggest that Resveratrol might be tested in selected patients with small AAA to modulate the early systemic and local inflammatory response associated to AAA progression. ..
- Chang J, Liaw C, Fazary A, Hwang T, Shen Y. New Briarane diterpenoids from the gorgonian coral Junceella juncea. Mar Drugs. 2012;10:1321-30 pubmed publisher..The anti-inflammatory activities tested on superoxide anion generation and elastase release by human neutrophils in response to FMLP/CB were evaluated...
- Sung P, Li G, Su Y, Lin M, Chang Y, Kung T, et al. Excavatoids O and P, new 12-hydroxybriaranes from the octocoral Briareum excavatum. Mar Drugs. 2010;8:2639-46 pubmed publisher..The structures of briaranes 1 and 2 were established on the basis of extensive spectral data analysis. Excavatoid P (2) is the first metabolite which possesses a 6? -chlorine atom in briarane analogues. ..
- Boyer L, Plantier L, Dagouassat M, Lanone S, Goven D, Caramelle P, et al. Role of nitric oxide synthases in elastase-induced emphysema. Lab Invest. 2011;91:353-62 pubmed publisher..In conclusion, in the elastase-injured lung, iNOS mediates protein nitration in alveolar type 2 cells and alleviates oxidative injury. Neither eNOS nor iNOS are required for the development of elastase-induced emphysema. ..
- Herzig K, Purhonen A, Räsänen K, Idziak J, Juvonen P, Phillps R, et al. Fecal pancreatic elastase-1 levels in older individuals without known gastrointestinal diseases or diabetes mellitus. BMC Geriatr. 2011;11:4 pubmed publisher..In our study one fifth of healthy older individuals without any gastrointestinal disorder, surgery or diabetes mellitus suffer from pancreatic exocrine insufficiency and might benefit from enzyme supplementation therapy. ..
- Liaw C, Kuo Y, Lin Y, Hwang T, Shen Y. Frajunolides L-O, four new 8-Hydroxybriarane diterpenoids from the Gorgonian Junceella fragilis. Mar Drugs. 2011;9:1477-86 pubmed publisher..Compounds 1 and 4 showed weak anti-inflammatory activity as tested by superoxide anion generation and elastase release by human neutrophil in response to fMLP/CB. Compound 3 showed selective inhibition on elastase release in vitro...
- Dai J, Michineau S, Franck G, Desgranges P, Becquemin J, Gervais M, et al. Long term stabilization of expanding aortic aneurysms by a short course of cyclosporine A through transforming growth factor-beta induction. PLoS ONE. 2011;6:e28903 pubmed publisher..Our study demonstrates that pharmacological induction of TGF-beta1 by a short course of CsA administration represents a new approach to induce aneurysm stabilization by shifting the degradation/repair balance towards healing. ..
- Tasaka S, Inoue K, Miyamoto K, Nakano Y, Kamata H, Shinoda H, et al. Role of interleukin-6 in elastase-induced lung inflammatory changes in mice. Exp Lung Res. 2010;36:362-72 pubmed publisher..Wild-type (WT) and IL-6-deficient mice received either phosphate-buffered saline (PBS) or porcine pancreatic elastase (PPE) intratracheally...
- Hwang T, Wang C, Kuo Y, Huang H, Wu Y, Kuo L, et al. The hederagenin saponin SMG-1 is a natural FMLP receptor inhibitor that suppresses human neutrophil activation. Biochem Pharmacol. 2010;80:1190-200 pubmed publisher..Taken together, our results demonstrate that SMG-1 is a natural inhibitor of the FMLP receptor, which may have the potential to be developed into a useful new therapeutic agent for treating neutrophilic inflammatory diseases...
- Su J, Chen B, Hwang T, Chen Y, Huang I, Lin M, et al. Excavatoids L-N, new 12-hydroxybriaranes from the cultured octocoral Briareum excavatum (Briareidae). Chem Pharm Bull (Tokyo). 2010;58:662-5 pubmed..The structures of new briaranes 1-3 were elucidated by the interpretations of spectroscopic methods. Excavatoid L (1) displayed moderate inhibitory effects on superoxide anion generation and elastase release by human neutrophils. ..
- Nema N, Maity N, Sarkar B, Mukherjee P. Cucumis sativus fruit-potential antioxidant, anti-hyaluronidase, and anti-elastase agent. Arch Dermatol Res. 2011;303:247-52 pubmed publisher..5 ± 0.23% w/w. CSLJ is the rich source of ascorbic acid and this study thereby rationalizes the use of C. sativus as potential anti-wrinkle agent in cosmetic products...
- Chen Y, Tai C, Su Y, Chang Y, Lu M, Weng C, et al. Discovery of new eunicellins from an Indonesian octocoral Cladiella sp. Mar Drugs. 2011;9:934-43 pubmed publisher..The previously reported structures of two eunicellin-based compounds, cladielloides A and B, are corrected in this study. ..
- Jin X, Deng L, Li H, Zhang Z, He Q, Yang C, et al. Identification and characterization of a serine protease inhibitor with two trypsin inhibitor-like domains from the human hookworm Ancylostoma duodenale. Parasitol Res. 2011;108:287-95 pubmed publisher..These results suggested that AduTIL-1 may be involved in the survival of A. duodenale in host by targeting related digestive enzymes and neutrophil elastase. ..
- Tsujimoto H, Kotsyfakis M, Francischetti I, Eum J, Strand M, Champagne D. Simukunin from the salivary glands of the black fly Simulium vittatum inhibits enzymes that regulate clotting and inflammatory responses. PLoS ONE. 2012;7:e29964 pubmed publisher..We conclude that Simukunin preferentially inhibits Factor Xa. The inhibition of elastase and cathepsin G further suggests this protein may modulate inflammation, which could potentially affect pathogen transmission. ..
- Lu J, Yang H, Yu H, Gao W, Lai R, Liu J, et al. A novel serine protease inhibitor from Bungarus fasciatus venom. Peptides. 2008;29:369-74 pubmed publisher..These findings strongly suggest that snake Kunitz/BPTI protease inhibitors and neurotoxic homologs may have originated from a common ancestor...
- Tanaka A, Hasegawa T, Chen Z, Okita Y, Okada K. A novel rat model of abdominal aortic aneurysm using a combination of intraluminal elastase infusion and extraluminal calcium chloride exposure. J Vasc Surg. 2009;50:1423-32 pubmed publisher..An ideal animal model of abdominal aortic aneurysm (AAA) is of great importance for clarifying unknown complex mechanisms of the pathogenesis. We introduce a new, simple technique to create reliable AAAs that simulate human aneurysms...
- Lowrey G, Henderson N, Blakey J, Corne J, Johnson S. MMP-9 protein level does not reflect overall MMP activity in the airways of patients with COPD. Respir Med. 2008;102:845-51 pubmed publisher..Further studies of MMPs in COPD should comprise activity measures in addition to protein levels. ..
- Sajjan U, Ganesan S, Comstock A, Shim J, Wang Q, Nagarkar D, et al. Elastase- and LPS-exposed mice display altered responses to rhinovirus infection. Am J Physiol Lung Cell Mol Physiol. 2009;297:L931-44 pubmed publisher..Similar mechanisms may be operative in COPD. ..
- Bilgin M, Balci N, Momtahen A, Bilgin Y, Klör H, Rau W. MRI and MRCP findings of the pancreas in patients with diabetes mellitus: compared analysis with pancreatic exocrine function determined by fecal elastase 1. J Clin Gastroenterol. 2009;43:165-70 pubmed publisher..The frequency and severity of MRI/MRCP findings increase when the patients have combined DM and pancreatic exocrine insufficiency. ..
- Ailawadi G, Moehle C, Pei H, Walton S, Yang Z, Kron I, et al. Smooth muscle phenotypic modulation is an early event in aortic aneurysms. J Thorac Cardiovasc Surg. 2009;138:1392-9 pubmed publisher..These events in experimental models occur before aneurysm formation. Targeting smooth muscle cells to a reparative phenotype might provide a novel therapy in the treatment of aortic aneurysms. ..
- Couillin I, Vasseur V, Charron S, Gasse P, Tavernier M, Guillet J, et al. IL-1R1/MyD88 signaling is critical for elastase-induced lung inflammation and emphysema. J Immunol. 2009;183:8195-202 pubmed publisher..In conclusion, elastase-mediated lung pathology depends on inflammasome activation with IL-1beta production. IL-1beta therefore represents a critical mediator and a possible therapeutic target of lung inflammation leading to emphysema. ..
- Plantier L, Marchand Adam S, Antico Arciuch V, Antico V, Boyer L, De Coster C, et al. Keratinocyte growth factor protects against elastase-induced pulmonary emphysema in mice. Am J Physiol Lung Cell Mol Physiol. 2007;293:L1230-9 pubmed..We conclude that KGF pretreatment protected against elastase-induced pulmonary inflammation, activation of MMPs, alveolar cell DNA damage, and subsequent emphysema in mice. ..
- Quaniers J, Leruth J, Albert A, Limet R, Defraigne J. Comparison of inflammatory responses after off-pump and on-pump coronary surgery using surface modifying additives circuit. Ann Thorac Surg. 2006;81:1683-90 pubmed..Except for the complement system and elastase, on-pump surgery with SMA-coated circuits did not elicit any greater inflammatory response than off-pump surgery. ..
- Sun J, Sukhova G, Yang M, Wolters P, MacFarlane L, Libby P, et al. Mast cells modulate the pathogenesis of elastase-induced abdominal aortic aneurysms in mice. J Clin Invest. 2007;117:3359-68 pubmed
- Chen C, Tsai W, Wu H, Syu M, Wu C, Shiesh S. Diagnostic role of biliary pancreatic elastase for cholangiocarcinoma in patients with cholestasis. Clin Chim Acta. 2008;390:82-9 pubmed publisher..The diagnostic efficacy was assessed by receiver operating characteristic (ROC) curve analysis. Pancreatic elastase (PE) 3B was identified as a biomarker for cholangiocarcinoma...
- Kim Y, Kim K, Han C, Yang H, Park S, Ko K, et al. Inhibitory effects of natural plants of Jeju Island on elastase and MMP-1 expression. J Cosmet Sci. 2007;58:19-33 pubmed..The results showed that four of the 60 plant extracts may hold potential for use as natural active ingredients for anti-aging cosmetics. ..
- Thring T, Hili P, Naughton D. Anti-collagenase, anti-elastase and anti-oxidant activities of extracts from 21 plants. BMC Complement Altern Med. 2009;9:27 pubmed publisher..These included white tea which was found to have very high phenolic content, along with high TEAC and SOD activities. ..
- Sawada M, Ohno Y, La B, Funaguchi N, Asai T, Yuhgetsu H, et al. The Fas/Fas-ligand pathway does not mediate the apoptosis in elastase-induced emphysema in mice. Exp Lung Res. 2007;33:277-88 pubmedPorcine pancreatic elastase (PPE), which induces emphysema via apoptosis, was administered to wild-type and Fas-deficient (lpr) mice...
- Rios Steiner J, Murakami M, Tulinsky A, Arni R. Active and exo-site inhibition of human factor Xa: structure of des-Gla factor Xa inhibited by NAP5, a potent nematode anticoagulant protein from Ancylostoma caninum. J Mol Biol. 2007;371:774-86 pubmed..This indicates that NAP5 can bind to fXa at the active site, or the exosite, and to fX at the exosite. However, unlike NAPc2, NAP5 does not inhibit fVIIa of the fVIIa/TF complex...
- Ewald N, Bretzel R, Fantus I, Hollenhorst M, Kloer H, Hardt P. Pancreatin therapy in patients with insulin-treated diabetes mellitus and exocrine pancreatic insufficiency according to low fecal elastase 1 concentrations. Results of a prospective multi-centre trial. Diabetes Metab Res Rev. 2007;23:386-91 pubmed..Pancreatin therapy can be used safely in patients with diabetes mellitus and exocrine dysfunction. Parameters of glucose metabolism were not improved by enzyme replacement therapy. ..
- Baldus S, Rudolph V, Roiss M, Ito W, Rudolph T, Eiserich J, et al. Heparins increase endothelial nitric oxide bioavailability by liberating vessel-immobilized myeloperoxidase. Circulation. 2006;113:1871-8 pubmed..These data add to the growing body of evidence for a causal role of MPO in compromised vascular NO signaling in humans. ..
- Taori K, Matthew S, Rocca J, Paul V, Luesch H. Lyngbyastatins 5-7, potent elastase inhibitors from Floridian marine cyanobacteria, Lyngbya spp. J Nat Prod. 2007;70:1593-600 pubmed..Compounds 1- 4 were found to selectively inhibit elastase over several other serine proteases, with IC50 values for porcine pancreatic elastase ranging from 3 to 10 nM.
- Sung P, Chen B, Lin M, Hwang T, Wang W, Sheu J, et al. Excavatoids E and F: discovery of two new briaranes from the cultured octocoral Briareum excavatum. Mar Drugs. 2009;7:472-82 pubmed publisher..The structures of compounds 1 and 2 were established on the basis of extensive spectral data analysis. Briaranes 1 and 2 were found to exhibit moderate inhibitory effects on elastase release by human neutrophils. ..
- Matthew S, Paul V, Luesch H. Tiglicamides A-C, cyclodepsipeptides from the marine cyanobacterium Lyngbya confervoides. Phytochemistry. 2009;70:2058-63 pubmed publisher..Compounds 1-3 moderately inhibited porcine pancreatic elastase in vitro with IC(50) values from 2.14 to 7.28 microM...
- Matthew S, Ross C, Rocca J, Paul V, Luesch H. Lyngbyastatin 4, a dolastatin 13 analogue with elastase and chymotrypsin inhibitory activity from the marine cyanobacterium Lyngbya confervoides. J Nat Prod. 2007;70:124-7 pubmed..Lyngbyastatin 4 (1) selectively inhibits elastase and chymotrypsin in vitro over other serine proteases with IC50 values of 0.03 and 0.30 microM, respectively. ..
- Suzuki M, Betsuyaku T, Ito Y, Nagai K, Odajima N, Moriyama C, et al. Curcumin attenuates elastase- and cigarette smoke-induced pulmonary emphysema in mice. Am J Physiol Lung Cell Mol Physiol. 2009;296:L614-23 pubmed publisher..Nine-week-old male C57BL/6J mice were treated with intratracheal porcine pancreatic elastase (PPE) or exposed to mainstream cigarette smoke (CS) (60 min/day for 10 consecutive days or 5 days/wk for 12 ..
- Liaw C, Shen Y, Lin Y, Hwang T, Kuo Y, Khalil A. Frajunolides E-K, briarane diterpenes from Junceella fragilis. J Nat Prod. 2008;71:1551-6 pubmed publisher..The structures of 1-7 were determined by analysis of HRESIMS and 2D NMR spectroscopic data. Cytotoxicity and in vitro anti-inflammatory activities of compounds 1-7 were also evaluated. ..
- Bilgin M, Bilgin S, Balci N, Momtahen A, Bilgin Y, Klör H, et al. Magnetic resonance imaging and magnetic resonance cholangiopancreatography findings compared with fecal elastase 1 measurement for the diagnosis of chronic pancreatitis. Pancreas. 2008;36:e33-9 pubmed publisher..Magnetic resonance imaging/MRCP findings correlate with fecal elastase 1 concentration and may precede pancreatic exocrine insufficiency in the early stages of chronic pancreatitis. ..
- Ishikawa T, Aoshiba K, Yokohori N, Nagai A. Macrophage colony-stimulating factor aggravates rather than regenerates emphysematous lungs in mice. Respiration. 2006;73:538-45 pubmed..M-CSF stimulated AMs to express MMPs in vitro. These results suggest that M-CSF administration does not support lung regeneration but rather aggravates the lung destruction associated with elastase injury. ..
- Raeder H, Haldorsen I, Ersland L, Grüner R, Taxt T, Søvik O, et al. Pancreatic lipomatosis is a structural marker in nondiabetic children with mutations in carboxyl-ester lipase. Diabetes. 2007;56:444-9 pubmed..Our findings suggest that lipomatosis of the pancreas reflects early events involved in the pathogenesis of diabetes and exocrine pancreatic dysfunction syndrome. ..
- Hwang T, Su Y, Chang H, Leu Y, Chung P, Kuo L, et al. Suppression of superoxide anion and elastase release by C18 unsaturated fatty acids in human neutrophils. J Lipid Res. 2009;50:1395-408 pubmed publisher..We also suggest that both the free carboxy group and the number of double bonds of the C(18) UFA structure are critical to providing the potent anti-inflammatory properties in human neutrophils. ..
- Hwang T, Leu Y, Kao S, Tang M, Chang H. Viscolin, a new chalcone from Viscum coloratum, inhibits human neutrophil superoxide anion and elastase release via a cAMP-dependent pathway. Free Radic Biol Med. 2006;41:1433-41 pubmed..In summary, viscolin is a novel inhibitor of PDE and might be useful for treatment of neutrophilic inflammation...
- Gunasekera S, Miller M, Kwan J, Luesch H, Paul V. Molassamide, a depsipeptide serine protease inhibitor from the marine cyanobacterium Dichothrix utahensis. J Nat Prod. 2010;73:459-62 pubmed publisher..032 and 0.234 muM against elastase and chymotrypsin, respectively. There was no apparent inhibition of trypsin at 10 microM, the highest concentration tested. ..
- Hantos Z, Adamicza A, Janosi T, Szabari M, Tolnai J, Suki B. Lung volumes and respiratory mechanics in elastase-induced emphysema in mice. J Appl Physiol (1985). 2008;105:1864-72 pubmed publisher..inflation, we tracked H and Raw as functions of TGV and Prs in normal mice and mice treated with porcine pancreatic elastase. The presence of emphysema was confirmed by morphometric analysis of histological slices...
- Hynecek R, Derubertis B, Trocciola S, Zhang H, Prince M, Ennis T, et al. The creation of an infrarenal aneurysm within the native abdominal aorta of swine. Surgery. 2007;142:143-9 pubmed..After aneurysm creation, progressive increase in aortic diameter was detectable. Further evaluation will be necessary to more completely characterize the nature and extent of elastase-induced porcine aortic aneurysmal degeneration. ..
- Sheu J, Chen Y, Hwang T, Chiang M, Fang L, Sung P. Junceellolides J-L, 11,20-epoxybriaranes from the gorgonian coral Junceella fragilis. J Nat Prod. 2006;69:269-73 pubmed..The briaranes 2 and 4 showed mild inhibitory effects on human neutrophil elastase release. ..
- Taori K, Paul V, Luesch H. Kempopeptins A and B, serine protease inhibitors with different selectivity profiles from a marine cyanobacterium, Lyngbya sp. J Nat Prod. 2008;71:1625-9 pubmed publisher..Kempopeptin A (1) exhibited an IC50 against elastase of 0.32 microM and against chymotrypsin of 2.6 microM, while kempopeptin B (2) inhibited trypsin with an IC50 of 8.4 microM. ..
- Kim H, Chu T, Kim D, Kim D, Nguyen C, Choi J, et al. The crystal structure of guamerin in complex with chymotrypsin and the development of an elastase-specific inhibitor. J Mol Biol. 2008;376:184-92 pubmed..Furthermore, the M36A guamerin mutant more effectively protected endothelial cells against cell damage caused by elastase than the wild-type guamerin. ..
- Bergoeing M, Arif B, Hackmann A, Ennis T, Thompson R, Curci J. Cigarette smoking increases aortic dilatation without affecting matrix metalloproteinase-9 and -12 expression in a modified mouse model of aneurysm formation. J Vasc Surg. 2007;45:1217-1227 pubmed..Further understanding of the relationship between smoking and AAA in this model may help unveil the pathophysiologic pathways involved between cigarette smoke and AAAs. ..
- Shimizu K, Mitchell R, Libby P. Inflammation and cellular immune responses in abdominal aortic aneurysms. Arterioscler Thromb Vasc Biol. 2006;26:987-94 pubmed
- Kwan J, Taori K, Paul V, Luesch H. Lyngbyastatins 8-10, elastase inhibitors with cyclic depsipeptide scaffolds isolated from the marine cyanobacterium Lyngbya semiplena. Mar Drugs. 2009;7:528-38 pubmed publisher..Compounds 1-3 are closely related to lyngbyastatins 4-7. Like the latter compounds, we found 1-3 to inhibit porcine pancreatic elastase, with IC(50) values of 123 nM, 210 nM and 120 nM, respectively.
- Cheng S, Wang H, Yu C, Tsao P, Carmeliet P, Cheng S, et al. Prevention of elastase-induced emphysema in placenta growth factor knock-out mice. Respir Res. 2009;10:115 pubmed publisher..was induced in PlGF knock-out (KO) and wild type (WT) mice by intra-tracheal instillation of porcine pancreatic elastase (PPE)...
- Vesterhus M, Raeder H, Johansson S, Molven A, Njølstad P. Pancreatic exocrine dysfunction in maturity-onset diabetes of the young type 3. Diabetes Care. 2008;31:306-10 pubmed..Fecal fat excretion was increased in all patients with MODY3 with fecal elastase deficiency who were investigated, underscoring the potential clinical importance of the exocrine dysfunction. ..
- Naruse S, Ishiguro H, Ko S, Yoshikawa T, Yamamoto T, Yamamoto A, et al. Fecal pancreatic elastase: a reproducible marker for severe exocrine pancreatic insufficiency. J Gastroenterol. 2006;41:901-8 pubmedIn order to apply fecal pancreatic elastase for follow-up of exocrine pancreatic function in chronic pancreatitis and cystic fibrosis, we examined the sensitivity, specificity, and long-term variability of a new polyclonal antibody-based ..
- Collins M, Eberth J, Wilson E, Humphrey J. Acute mechanical effects of elastase on the infrarenal mouse aorta: implications for models of aneurysms. J Biomech. 2012;45:660-5 pubmed publisherIntraluminal exposure of the infrarenal aorta to porcine pancreatic elastase represents one of the most commonly used experimental models of the development and progression of abdominal aortic aneurysms...
- Zhang C, van der Voort D, Shi H, Zhang R, Qing Y, Hiraoka S, et al. Matricellular protein CCN3 mitigates abdominal aortic aneurysm. J Clin Invest. 2016;126:1282-99 pubmed publisher..Together, these results demonstrate that CCN3 is a nodal regulator in AAA biology and identify CCN3 as a potential therapeutic target for vascular disease. ..
- Lefkowitz R, Schmid Schonbein G, Heller M. Whole blood assay for elastase, chymotrypsin, matrix metalloproteinase-2, and matrix metalloproteinase-9 activity. Anal Chem. 2010;82:8251-8 pubmed publisher..Thus, these new substrates demonstrate broad applicability toward clinically relevant detection of important disease-relevant proteases. ..
- Khan M, Ellis R, Inman M, Bates J, Sanderson M, Janssen L. Influence of airway wall stiffness and parenchymal tethering on the dynamics of bronchoconstriction. Am J Physiol Lung Cell Mol Physiol. 2010;299:L98-L108 pubmed publisher..We conclude that airway and parenchymal remodeling as a result of protease activity can have varied effects on the loads opposing ASM shortening, with corresponding consequences for airway responsiveness. ..
- Johnston W, Salmon M, Su G, Lu G, Ailawadi G, Upchurch G. Aromatase is required for female abdominal aortic aneurysm protection. J Vasc Surg. 2015;61:1565-74.e1-4 pubmed publisher..If peripheral aromatase could be targeted, high levels of local estrogen could be produced and may avoid the side effects of systemic estrogen. ..