{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T14:34:14Z","timestamp":1761921254276,"version":"build-2065373602"},"reference-count":48,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2024,6,29]],"date-time":"2024-06-29T00:00:00Z","timestamp":1719619200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001807","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado de S\u00e3o Paulo","doi-asserted-by":"publisher","award":["2015\/02345-0","0727\/2022","421697\/2021-0","04.13.0462.03"],"award-info":[{"award-number":["2015\/02345-0","0727\/2022","421697\/2021-0","04.13.0462.03"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Coordena\u00e7\u00e3o de Aperfeicoamento de Pessoal de N\u00edvel Superior Proex","award":["2015\/02345-0","0727\/2022","421697\/2021-0","04.13.0462.03"],"award-info":[{"award-number":["2015\/02345-0","0727\/2022","421697\/2021-0","04.13.0462.03"]}]},{"name":"Conselho Nacionnal do Desenvolvimento Cient\u00edfico e Tecnol\u00f3gico","award":["2015\/02345-0","0727\/2022","421697\/2021-0","04.13.0462.03"],"award-info":[{"award-number":["2015\/02345-0","0727\/2022","421697\/2021-0","04.13.0462.03"]}]},{"DOI":"10.13039\/501100004809","name":"Financiadora de Estudos e Projetos","doi-asserted-by":"publisher","award":["2015\/02345-0","0727\/2022","421697\/2021-0","04.13.0462.03"],"award-info":[{"award-number":["2015\/02345-0","0727\/2022","421697\/2021-0","04.13.0462.03"]}],"id":[{"id":"10.13039\/501100004809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Dupuytren\u2019s disease (DD) is a prevalent fibroproliferative disorder of the hand, shaped by genetic, epigenetic, and environmental influences. The extracellular matrix (ECM) is a complex assembly of diverse macromolecules. Alterations in the ECM\u2019s content, structure and organization can impact both normal physiological functions and pathological conditions. This study explored the content and organization of glycosaminoglycans, proteoglycans, and collagen in the ECM of patients at various stages of DD, assessing their potential as prognostic indicators. This research reveals, for the first time, relevant changes in the complexity of chondroitin\/dermatan sulfate structures, specifically an increase of disaccharides containing iduronic acid residues covalently linked to either N-acetylgalactosamine 6-O-sulfated or N-acetylgalactosamine 4-O-sulfated, correlating with the disease\u2019s severity. Additionally, we noted an increase in versican expression, a high molecular weight proteoglycan, across stages I to IV, while decorin, a small leucine-rich proteoglycan, significantly diminishes as DD progresses, both confirmed by mRNA analysis and protein detection via confocal microscopy. Coherent anti-Stokes Raman scattering (CARS) microscopy further demonstrated that collagen fibril architecture in DD varies importantly with disease stages. Moreover, the urinary excretion of both hyaluronic and sulfated glycosaminoglycans markedly decreased among DD patients.Our findings indicate that specific proteoglycans with galactosaminoglycan chains and collagen arrangements could serve as biomarkers for DD progression. The reduction in glycosaminoglycan excretion suggests a systemic manifestation of the disease.<\/jats:p>","DOI":"10.3390\/ijms25137192","type":"journal-article","created":{"date-parts":[[2024,7,2]],"date-time":"2024-07-02T12:58:42Z","timestamp":1719925122000},"page":"7192","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Alterations in the Structure, Composition, and Organization of Galactosaminoglycan-Containing Proteoglycans and Collagen Correspond to the Progressive Stages of Dupuytren\u2019s Disease"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3558-6710","authenticated-orcid":false,"given":"Luiz Guilherme S.","family":"Lenzi","sequence":"first","affiliation":[{"name":"Department of Orthopaedics and Traumatology, Escola Paulista de Medicina, Universidade Federal de S\u00e3o Paulo, S\u00e3o Paulo 04038-032, SP, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0199-6578","authenticated-orcid":false,"given":"Jo\u00e3o Baptista","family":"Gomes dos Santos","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics and Traumatology, Escola Paulista de Medicina, Universidade Federal de S\u00e3o Paulo, S\u00e3o Paulo 04038-032, SP, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3961-4419","authenticated-orcid":false,"given":"Renan P.","family":"Cavalheiro","sequence":"additional","affiliation":[{"name":"Molecular Biology Program, Instituto de Farmacologia e Biologia Molecular, Escola Paulista de Medicina, Universidade Federal de S\u00e3o Paulo, S\u00e3o Paulo 04024-002, SP, Brazil"},{"name":"Faculdade de Medicina ABC, Centro Universit\u00e1rio, Santo Andr\u00e9 09060-870, SP, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9255-0429","authenticated-orcid":false,"given":"Aline","family":"Mendes","sequence":"additional","affiliation":[{"name":"Molecular Biology Program, Instituto de Farmacologia e Biologia Molecular, Escola Paulista de Medicina, Universidade Federal de S\u00e3o Paulo, S\u00e3o Paulo 04024-002, SP, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elsa Y.","family":"Kobayashi","sequence":"additional","affiliation":[{"name":"Molecular Biology Program, Instituto de Farmacologia e Biologia Molecular, Escola Paulista de Medicina, Universidade Federal de S\u00e3o Paulo, S\u00e3o Paulo 04024-002, SP, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7569-2166","authenticated-orcid":false,"given":"Helena B.","family":"Nader","sequence":"additional","affiliation":[{"name":"Molecular Biology Program, Instituto de Farmacologia e Biologia Molecular, Escola Paulista de Medicina, Universidade Federal de S\u00e3o Paulo, S\u00e3o Paulo 04024-002, SP, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Flavio","family":"Faloppa","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics and Traumatology, Escola Paulista de Medicina, Universidade Federal de S\u00e3o Paulo, S\u00e3o Paulo 04038-032, SP, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,6,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1016\/j.molmed.2022.12.001","article-title":"Dupuytren\u2019s disease: A localised and accessible human fibrotic disorder","volume":"29","author":"Layton","year":"2023","journal-title":"Trends Mol. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1186\/s13018-020-01999-7","article-title":"The worldwide prevalence of the Dupuytren disease: A comprehensive systematic review and meta-analysis","volume":"15","author":"Salari","year":"2020","journal-title":"J. Orthop. Surg. Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1002\/jor.22535","article-title":"Down-regulation of collagen synthesis and matrix metalloproteinase expression in myofibroblasts from Dupuytren nodule using adenovirus-mediated relaxin gene therapy","volume":"32","author":"Kang","year":"2014","journal-title":"J. Orthop. Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1016\/j.jhsa.2006.12.010","article-title":"A complete expression profile of matrix-degrading metalloproteinases in Dupuytren\u2019s disease","volume":"32","author":"Johnston","year":"2007","journal-title":"J. Hand Surg. Am."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Oezel, L., Wohltmann, M., Gondorf, N., Wille, J., G\u00fcven, I., Windolf, J., Thelen, S., Jaekel, C., and Grotheer, V. (2023). Dupuytren\u2019s Disease Is Mediated by Insufficient TGF-\u03b21 Release and Degradation. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms242015097"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"469","DOI":"10.3109\/03008207.2012.686542","article-title":"Expression of MMP-2, TIMP-2, TGF-beta1, and decorin in Dupuytren\u2019s contracture","volume":"53","author":"Gosk","year":"2012","journal-title":"Connect. Tissue Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1007\/s12079-016-0331-0","article-title":"Update on the role of molecular factors and fibroblasts in the pathogenesis of Dupuytren\u2019s disease","volume":"10","author":"Tripoli","year":"2016","journal-title":"J. Cell Commun. Signal"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"E928","DOI":"10.1073\/pnas.1301100110","article-title":"Unraveling the signaling pathways promoting fibrosis in Dupuytren\u2019s disease reveals TNF as a therapeutic target","volume":"110","author":"Verjee","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1590\/1413-785220162402154342","article-title":"Glycosaminoglycans and Proteoglycans in Palmar Fascia of Patients with Dupuytren","volume":"24","author":"Nascimento","year":"2016","journal-title":"Acta Ortop. Bras."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1186\/s13069-016-0046-0","article-title":"Matrix and cell phenotype differences in Dupuytren\u2019s disease","volume":"9","author":"Werker","year":"2016","journal-title":"Fibrogenesis Tissue Repair."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1016\/S1054-3589(05)53011-4","article-title":"Emergence and structural characteristics of chondroitin sulfates in the animal kingdom","volume":"53","author":"Sampaio","year":"2006","journal-title":"Adv. Pharmacol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1590\/S0001-37652009000300007","article-title":"Heparan sulfate proteoglycans: Structure, protein interactions and cell signaling","volume":"81","author":"Dreyfuss","year":"2009","journal-title":"An. Acad. Bras. Cienc."},{"key":"ref_13","unstructured":"Varki, A., Cummings, R.D., Esko, J.D., Stanley, P., Hart, G.W., Aebi, M., Mohnen, D., Kinoshita, T., Packer, N.H., Prestegard, J.H., Schnaar, R.L., and Seeberger, P.H. (2022). Proteoglycans and Sulfated Glycosaminoglycans. Essentials of Glycobiology, Cold Spring Harbor Laboratory Press. [4th ed.]."},{"key":"ref_14","unstructured":"Varki, A., Cummings, R.D., Esko, J.D., Stanley, P., Hart, G.W., Aebi, M., Mohnen, D., Kinoshita, T., Packer, N.H., and Prestegard, J.H. (2022). Essentials of Glycobiology, Cold Spring Harbor Laboratory Press. [4th ed.]."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"La Gatta, A., Stellavato, A., Vassallo, V., Di Meo, C., Toro, G., Iolascon, G., and Schiraldi, C. (2021). Hyaluronan and Derivatives: An In Vitro Multilevel Assessment of Their Potential in Viscosupplementation. Polymers, 13.","DOI":"10.3390\/polym13193208"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"786","DOI":"10.1038\/nrm3904","article-title":"Remodelling the extracellular matrix in development and disease","volume":"15","author":"Bonnans","year":"2014","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1038\/nrm3902","article-title":"Extracellular matrix assembly: A multiscale deconstruction","volume":"15","author":"Mouw","year":"2014","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_18","first-page":"383","article-title":"Molecular mechanisms and treatment strategies for Dupuytren\u2019s disease","volume":"6","author":"Vi","year":"2010","journal-title":"Ther. Clin. Risk Manag."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Samulenas, G., Insodaite, R., Kunceviciene, E., Poceviciute, R., Masionyte, L., Zitkeviciute, U., Pilipaityte, L., and Smalinskiene, A. (2022). The Role of Functional Polymorphisms in the Extracellular Matrix Modulation-Related Genes on Dupuytren\u2019s Contracture. Genes, 13.","DOI":"10.3390\/genes13050743"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1016\/j.hcl.2012.08.003","article-title":"Advances in the Management of Dupuytren Disease Collagenase","volume":"28","author":"Hentz","year":"2012","journal-title":"Hand Clin."},{"key":"ref_21","first-page":"243","article-title":"Dupuytren disease: On our way to a cure ?","volume":"79","author":"Degreef","year":"2013","journal-title":"Acta Orthop. Belg."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1138","DOI":"10.1302\/0301-620X.100B9.BJJ-2017-1194.R2","article-title":"Treatment of Dupuytren\u2019s contracture: A systematic review","volume":"100-B","author":"Soreide","year":"2018","journal-title":"Bone Joint J."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"15","DOI":"10.2147\/DDDT.S144602","article-title":"Intra-articular collagenase injection increases range of motion in a rat knee flexion contracture model","volume":"12","author":"Wong","year":"2018","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1302\/2058-5241.4.180021","article-title":"Dupuytren\u2019s disease: Where do we stand?","volume":"4","author":"Grazina","year":"2019","journal-title":"Efort Open Rev."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e024424","DOI":"10.1136\/bmjopen-2018-024424","article-title":"Surgical fasciectomy versus collagenase injection in treating recurrent Dupuytren disease: Study protocol of a randomised controlled trial","volume":"9","author":"Nordenskjold","year":"2019","journal-title":"BMJ Open"},{"key":"ref_26","first-page":"781","article-title":"Dupuytren\u2019s Disease-Etiology and Treatment","volume":"118","author":"Ruettermann","year":"2021","journal-title":"Dtsch. Arztebl. Int."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"843","DOI":"10.1016\/j.jhsg.2023.07.018","article-title":"Collagenase Treatment for Dupuytren Contracture of the Metacarpophalangeal Joint After Arthrodesis of the Proximal Interphalangeal Joint","volume":"5","author":"Stevens","year":"2023","journal-title":"J. Hand Surg. Glob. Online"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1016\/j.hansur.2023.06.002","article-title":"Full-thickness skin grafting in preventing recurrence of Dupuytren\u2019s disease: A systematic review","volume":"42","author":"Degreef","year":"2023","journal-title":"Hand Surg. Rehabil."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Satish, L., LaFramboise, W.A., Johnson, S., Vi, L., Njarlangattil, A., Raykha, C., Krill-Burger, J.M., Gallo, P.H., O\u2019Gorman, D.B., and Gan, B.S. (2012). Fibroblasts from phenotypically normal palmar fascia exhibit molecular profiles highly similar to fibroblasts from active disease in Dupuytren\u2019s Contracture. BMC Med. Genom., 5.","DOI":"10.1186\/1755-8794-5-15"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1679\/aohc.65.109","article-title":"Collagen fibers, reticular fibers and elastic fibers. A comprehensive understanding from a morphological viewpoint","volume":"65","author":"Ushiki","year":"2002","journal-title":"Arch. Histol. Cytol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.matbio.2016.12.009","article-title":"The nature and biology of basement membranes","volume":"57\u201358","author":"Pozzi","year":"2017","journal-title":"Matrix Biol."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Alfonso-Rodr\u00edguez, C.A., Garz\u00f3n, I., Garrido-G\u00f3mez, J., Oliveira, A.C.X., Mart\u00edn-Piedra, M.A., Scionti, G., Carriel, V., Hernandez-Cortes, P., Campos, A., and Alaminos, M. (2014). Identification of Histological Patterns in Clinically Affected and Unaffected Palm Regions in Dupuytren\u2019s Disease. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0112457"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"8795","DOI":"10.1021\/bi960773t","article-title":"Proteodermatan and proteokeratan sulfate (decorin, lumican\/fibromodulin) proteins are horseshoe shaped. Implications for their interactions with collagen","volume":"35","author":"Scott","year":"1996","journal-title":"Biochemistry"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1023\/A:1025383913444","article-title":"The role of decorin in collagen fibrillogenesis and skin homeostasis","volume":"19","author":"Reed","year":"2002","journal-title":"Glycoconj. J."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"19065","DOI":"10.1038\/s41598-020-76107-0","article-title":"Distinct effects of different matrix proteoglycans on collagen fibrillogenesis and cell-mediated collagen reorganization","volume":"10","author":"Chen","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Hua, R., and Jiang, J.X. (2021). Small leucine-rich proteoglycans in physiological and biomechanical function of bone. Matrix Biol. Plus, 11.","DOI":"10.1016\/j.mbplus.2021.100063"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.matbio.2023.10.001","article-title":"Molecular cues for immune cells from small leucine-rich repeat proteoglycans in their extracellular matrix-associated and free forms","volume":"123","author":"Maiti","year":"2023","journal-title":"Matrix Biol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1038\/sj.cr.7290318","article-title":"The interaction of versican with its binding partners","volume":"15","author":"Wu","year":"2005","journal-title":"Cell Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/j.joca.2011.12.008","article-title":"Coexistence of fibrotic and chondrogenic process in the capsule of idiopathic frozen shoulders","volume":"20","author":"Hagiwara","year":"2012","journal-title":"Osteoarthr. Cartil."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/S0094-1298(20)30472-7","article-title":"Recurrence and other complications in surgery of Dupuytren\u2019s contracture","volume":"8","author":"Tubiana","year":"1981","journal-title":"Clin. Plast. Surg."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1016\/S0753-9053(86)80043-6","article-title":"Evaluation of deformities in Dupuytren\u2019s disease","volume":"5","author":"Tubiana","year":"1986","journal-title":"Ann. Chir. Main."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/S1297-3203(00)73454-8","article-title":"Classification of finger deformities due to muscle-tendon imbalance","volume":"19","author":"Tubiana","year":"2000","journal-title":"Chir. Main."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"965","DOI":"10.1016\/j.joca.2013.04.007","article-title":"Gradual strenuous running regimen predisposes to osteoarthritis due to cartilage cell death and altered levels of glycosaminoglycans","volume":"21","author":"Franciozi","year":"2013","journal-title":"Osteoarthr. Cartil."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1179","DOI":"10.1016\/j.joca.2017.02.793","article-title":"Different doses of strontium ranelate and mechanical vibration modulate distinct responses in the articular cartilage of ovariectomized rats","volume":"25","author":"Mierzwa","year":"2017","journal-title":"Osteoarthr. Cartil."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/S0003-2697(03)00251-3","article-title":"Practical determination of hyaluronan by a new noncompetitive fluorescence-based assay on serum of normal and cirrhotic patients","volume":"319","author":"Martins","year":"2003","journal-title":"Anal. Biochem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"937","DOI":"10.1016\/j.urology.2008.01.028","article-title":"Urinary glycosaminoglycans as biomarker for urothelial injury: Is it possible to discriminate damage from recovery?","volume":"72","author":"Soler","year":"2008","journal-title":"Urology"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.matbio.2016.12.006","article-title":"Coupling of vinculin to F-actin demands Syndecan-4 proteoglycan","volume":"63","author":"Cavalheiro","year":"2017","journal-title":"Matrix Biol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/13\/7192\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T15:07:48Z","timestamp":1760108868000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/13\/7192"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,6,29]]},"references-count":48,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2024,7]]}},"alternative-id":["ijms25137192"],"URL":"https:\/\/doi.org\/10.3390\/ijms25137192","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2024,6,29]]}}}