{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T08:05:44Z","timestamp":1776413144937,"version":"3.51.2"},"reference-count":43,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2019,7,30]],"date-time":"2019-07-30T00:00:00Z","timestamp":1564444800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2019,7,30]],"date-time":"2019-07-30T00:00:00Z","timestamp":1564444800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Bicuspid aortic valve (BAV) disease is recognized to be a <jats:italic>syndrome<\/jats:italic> with a complex and multifaceted pathophysiology. Its progression is modulated by diverse evolutionary conserved pathways, such as Notch-1 pathway. Emerging evidence is also highlighting the key role of TLR4 signaling pathway in the aortic valve pathologies and their related complications, such as sporadic ascending aorta aneurysms (AAA). Consistent with these observations, we aimed to evaluate the role of TLR4 pathway in both BAV disease and its common complication, such as AAA. To this aim, 70 subjects with BAV (M\/F 50\/20; mean age: 58.8\u2009\u00b1\u200914.8 years) and 70 subjects with tricuspid aortic valve (TAV) (M\/F 35\/35; mean age: 69.1\u2009\u00b1\u200912.8 years), with and without AAA were enrolled. Plasma assessment, tissue and gene expression evaluations were performed. Consistent with data obtained in the previous study on immune clonotypic T and B altered responses, we found reduced levels of systemic TNF-\u03b1, IL-1, IL-6, IL-17 cytokines in BAV cases, either in the presence or absence of AAA, than TAV cases (p\u2009&lt;\u20090.0001 by ANOVA test). Interestingly, we also detected reduced levels of s-TLR4 in BAV cases with or without AAA in comparison to the two groups of TAV subjects (p\u2009&lt;\u20090.0001 by ANOVA test). These results may suggest a deregulation in the activity or in the expression of TLR4 signaling pathway in all BAV cases. Portrait of these data is, indeed, the significantly decreased gene expression of inflammatory cytokines and TLR4, in both normal and aneurysmatic tissue samples, from BAV with AAA than TAV with AAA. In conclusion, our study demonstrates that subjects with BAV display a significant deregulation of TLR4 signaling pathway paralleled by a deregulation of Notch-1 pathway, as previously showed. This data suggests that the crosstalk between the Notch-1 and TLR4 signaling pathways may play a crucial role in both physiological embryological development, and homeostasis and functionality of aortic valve in adult life.<\/jats:p>","DOI":"10.1038\/s41598-019-47412-0","type":"journal-article","created":{"date-parts":[[2019,7,30]],"date-time":"2019-07-30T10:03:13Z","timestamp":1564480993000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Deregulation of TLR4 signaling pathway characterizes Bicuspid Aortic valve syndrome"],"prefix":"10.1038","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5393-1007","authenticated-orcid":false,"given":"Carmela R.","family":"Balistreri","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antonino G. M.","family":"Marullo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michele","family":"Madonna","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elena","family":"Cavarretta","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alberto","family":"Allegra","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Valeriana","family":"Cesarini","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alessandra","family":"Iaccarino","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sonia","family":"Schiavon","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mariangela","family":"Peruzzi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ernesto","family":"Greco","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sebastiano","family":"Sciarretta","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Calogera","family":"Pisano","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giovanni","family":"Ruvolo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michele","family":"Torella","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giacomo","family":"Frati","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2019,7,30]]},"reference":[{"key":"47412_CR1","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.yjmcc.2017.06.011","volume":"110","author":"CR Balistreri","year":"2017","unstructured":"Balistreri, C. R., Ruvolo, G., Lio, D. & Madonna, R. Toll-like receptor-4 signaling pathway in aorta aging and diseases: \u201cits double nature\u201d. Journal of Molecular and Cellular Cardiology 110, 38\u201353 (2017).","journal-title":"Journal of Molecular and Cellular Cardiology"},{"key":"47412_CR2","doi-asserted-by":"crossref","first-page":"1158","DOI":"10.1161\/circ.105.10.1158","volume":"105","author":"K Edfeldt","year":"2002","unstructured":"Edfeldt, K., Swedenborg, J., Hansson, G. K. & Yan, Z. Q. Expression of toll-like receptors in human atherosclerotic lesions: a possible pathway for plaque activation. Circulation 105, 1158\u201361 (2002).","journal-title":"Circulation"},{"key":"47412_CR3","doi-asserted-by":"crossref","first-page":"1985","DOI":"10.1161\/01.CIR.0000032146.75113.EE","volume":"106","author":"A Vink","year":"2002","unstructured":"Vink, A. et al. In vivo evidence for a role of toll-like receptor 4 in the development of intimal lesions. Circulation 106, 1985\u201390 (2002).","journal-title":"Circulation"},{"key":"47412_CR4","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1161\/01.CIR.0000109140.51366.72","volume":"109","author":"SC Hollestelle","year":"2004","unstructured":"Hollestelle, S. C. et al. Toll-like receptor 4 is involved in outward arterial remodeling. Circulation 109, 393\u20138 (2004).","journal-title":"Circulation"},{"key":"47412_CR5","doi-asserted-by":"crossref","first-page":"1977","DOI":"10.1021\/jf062945r","volume":"55","author":"FY Lin","year":"2007","unstructured":"Lin, F. Y. et al. Ginkgo biloba extract inhibits endotoxin-induced human aortic smooth muscle cell proliferation via suppression of toll-like receptor 4 expression and NADPH oxidase activation. Journal of Agricultural and Food Chemistry 55, 1977\u201384 (2007).","journal-title":"Journal of Agricultural and Food Chemistry"},{"key":"47412_CR6","doi-asserted-by":"crossref","first-page":"2630","DOI":"10.1161\/01.ATV.0000247259.01257.b3","volume":"26","author":"FY Lin","year":"2006","unstructured":"Lin, F. Y. et al. Endotoxin induces toll-like receptor 4 expression in vascular smooth muscle cells via NADPH oxidase activation and mitogen-activated protein kinase signaling pathways. Arteriosclerosis. Thrombosis, Vascular Biology 26, 2630\u20137 (2006).","journal-title":"Thrombosis, Vascular Biology"},{"key":"47412_CR7","doi-asserted-by":"crossref","first-page":"880","DOI":"10.1038\/labinvest.2013.79","volume":"93","author":"Y Pi","year":"2013","unstructured":"Pi, Y. et al. Inhibition of reactive oxygen species generation attenuates TLR4-mediated proinflammatory and proliferative phenotype of vascular smooth muscle cells. Laboratory Investigation. 93, 880\u20137 (2013).","journal-title":"Laboratory Investigation."},{"key":"47412_CR8","doi-asserted-by":"crossref","first-page":"349476","DOI":"10.1155\/2014\/349476","volume":"2014","author":"G Ruvolo","year":"2014","unstructured":"Ruvolo, G. et al. Can the TLR-4-mediated signaling pathway be \u201ca key inflammatory promoter for sporadicTAA. Mediators Inflammation. 2014, 349476 (2014).","journal-title":"Mediators Inflammation."},{"key":"47412_CR9","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.vph.2015.09.006","volume":"74","author":"CR Balistreri","year":"2015","unstructured":"Balistreri, C. R. Genetic contribution in sporadic thoracic aortic aneurysm? Emerging evidence of genetic variants related to TLR-4-mediated signaling pathway as risk determinants. Vascular Pharmacology 74, 1\u201310 (2015).","journal-title":"Vascular Pharmacology"},{"key":"47412_CR10","doi-asserted-by":"crossref","first-page":"2789","DOI":"10.1016\/j.jacc.2009.12.068","volume":"55","author":"SC Siu","year":"2010","unstructured":"Siu, S. C. & Silversides, C. K. Bicuspid aortic valve disease. Journal of the American College of Cardiology. 55, 2789\u20132800 (2010).","journal-title":"Journal of the American College of Cardiology."},{"key":"47412_CR11","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1016\/j.yjmcc.2019.05.013","volume":"132","author":"CR Balistreri","year":"2019","unstructured":"Balistreri, C. R. et al. An overview of the molecular mechanisms underlying development and progression of bicuspid aortic valve disease. Journal of Molecular Cellular Cardiology. 132, 146\u2013153 (2019).","journal-title":"Journal of Molecular Cellular Cardiology."},{"key":"47412_CR12","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/j.yjmcc.2019.06.004","volume":"133","author":"CR Balistreri","year":"2019","unstructured":"Balistreri, C. R., Cavarretta, E., Sciarretta, S. & Frati, G. Light on the molecular and cellular mechanisms of bicuspid aortic valve to unveil phenotypic heterogeneity. Journal of Molecular Cellular Cardiology. 133, 113\u2013114 (2019).","journal-title":"Journal of Molecular Cellular Cardiology."},{"key":"47412_CR13","doi-asserted-by":"crossref","first-page":"e180","DOI":"10.1093\/ejcts\/ezs630","volume":"43","author":"CR Balistreri","year":"2013","unstructured":"Balistreri, C. R. et al. Focus on the unique mechanisms involved in thoracic aortic aneurysm formation in bicuspid aortic valve versus tricuspid aortic valve patients: clinical implications of a pilot study. European Journal of Cardiothoracic Surgery 43, e180\u20136 (2013).","journal-title":"European Journal of Cardiothoracic Surgery"},{"key":"47412_CR14","doi-asserted-by":"crossref","first-page":"5879281","DOI":"10.1155\/2018\/5879281","volume":"2018","author":"CR Balistreri","year":"2018","unstructured":"Balistreri, C. R. et al. A Typical Immune T\/B Subset Profile Characterizes Bicuspid Aortic Valve: In an Old Status? Oxidative Medicine and Cellular Longevity 2018, 5879281 (2018).","journal-title":"Oxidative Medicine and Cellular Longevity"},{"key":"47412_CR15","doi-asserted-by":"crossref","DOI":"10.1038\/s41598-018-32170-2","volume":"8","author":"CR Balistreri","year":"2018","unstructured":"Balistreri, C. R. et al. Deregulation of Notch1 pathway and circulating endothelial progenitor cell (EPC) number in patients with bicuspid aortic valve with and without ascending aorta aneurysm. Scientific Reports 8, 13834 (2018).","journal-title":"Scientific Reports"},{"key":"47412_CR16","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.arr.2016.06.004","volume":"29","author":"CR Balistreri","year":"2016","unstructured":"Balistreri, C. R., Madonna, R., Melino, G. & Caruso, C. The emerging role of Notch pathway in ageing: Focus on the related mechanisms in age-related diseases. Ageing Research Reviews 29, 50\u201365 (2016).","journal-title":"Ageing Research Reviews"},{"key":"47412_CR17","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1093\/icvts\/ivt196","volume":"17","author":"N Abdulkareem","year":"2013","unstructured":"Abdulkareem, N., Smelt, J. & Jahangiri, M. Bicuspid aortic valve aortopathy: genetics, pathophysiology and medical therapy. Interactive Cardiovascular Thoracic Surgery. 17, 554\u20139 (2013).","journal-title":"Interactive Cardiovascular Thoracic Surgery."},{"key":"47412_CR18","doi-asserted-by":"crossref","first-page":"1746","DOI":"10.1161\/ATVBAHA.115.305269","volume":"35","author":"MA Dale","year":"2015","unstructured":"Dale, M. A., Ruhlman, M. K. & Baxter, B. T. Inflammatory cell phenotypes in AAAs: their role and potential as targets for therapy. Arteriosclerosis. Thrombosis, Vascular Biology. 35, 1746\u201355 (2015).","journal-title":"Thrombosis, Vascular Biology."},{"key":"47412_CR19","doi-asserted-by":"crossref","first-page":"1274034","DOI":"10.1155\/2017\/1274034","volume":"2017","author":"C Pisano","year":"2017","unstructured":"Pisano, C., Balistreri, C. R., Ricasoli, A. & Ruvolo, G. Cardiovascular Disease in Ageing: An Overview on Thoracic Aortic Aneurysm as an Emerging Inflammatory Disease. Mediators Inflammation. 2017, 1274034 (2017).","journal-title":"Mediators Inflammation."},{"key":"47412_CR20","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1038\/nri1630","volume":"5","author":"FY Liew","year":"2005","unstructured":"Liew, F. Y., Xu, D., Brint, E. K. & O\u2019Neill, L. A. Negative regulation of toll-like receptor-mediated immune responses. Nature Review Immunology 5, 446\u201358 (2005).","journal-title":"Nature Review Immunology"},{"key":"47412_CR21","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.coi.2009.12.002","volume":"22","author":"AF McGettrick","year":"2010","unstructured":"McGettrick, A. F. & O\u2019Neill, L. A. Localisation and trafficking of Toll-like receptors: an important mode of regulation. Current Opinions in Immunology. 22, 20\u20137 (2010).","journal-title":"Current Opinions in Immunology."},{"key":"47412_CR22","doi-asserted-by":"crossref","first-page":"379","DOI":"10.3349\/ymj.2011.52.3.379","volume":"52","author":"E Jeong","year":"2011","unstructured":"Jeong, E. & Lee, J. Y. Intrinsic and extrinsic regulation of innate immune receptors. Yonsei Medicine Journal. 52, 379\u2013392 (2011).","journal-title":"Yonsei Medicine Journal."},{"key":"47412_CR23","first-page":"1004","volume":"1","author":"CR Balistreri","year":"2018","unstructured":"Balistreri, C. R. Bicuspid aortic valve disease: a simple embryonic defect or a complex syndrome? Paradigm or certainty? Annals of Cardiology and Vascular Medicine. 1, 1004 (2018).","journal-title":"Annals of Cardiology and Vascular Medicine."},{"key":"47412_CR24","doi-asserted-by":"crossref","first-page":"2530","DOI":"10.3892\/mmr.2017.6287","volume":"15","author":"W Shen","year":"2017","unstructured":"Shen, W. et al. High mobility group box 1 induces calcification of aortic valve interstitial cells via toll-like receptor 4. Molecular Medicine Reports. 15, 2530\u20132536 (2017).","journal-title":"Molecular Medicine Reports."},{"key":"47412_CR25","doi-asserted-by":"crossref","first-page":"201","DOI":"10.3389\/fphys.2018.00201","volume":"9","author":"C Garc\u00eda-Rodr\u00edguez","year":"2018","unstructured":"Garc\u00eda-Rodr\u00edguez, C. et al. Toll-Like Receptors, Inflammation, and Calcific Aortic Valve Disease. Frontiers in Physiology. 9, 201 (2018).","journal-title":"Frontiers in Physiology."},{"key":"47412_CR26","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1016\/j.athoracsur.2014.07.027","volume":"99","author":"J Jaggers","year":"2015","unstructured":"Jaggers, J. Adult aortic valve interstitial cells have greater responses to toll like receptor 4 stimulation. Annals of Thoracic Surgery 99, 62\u201371 (2015).","journal-title":"Annals of Thoracic Surgery"},{"key":"47412_CR27","doi-asserted-by":"crossref","first-page":"C29","DOI":"10.1152\/ajpcell.00137.2007","volume":"294","author":"X Meng","year":"2008","unstructured":"Meng, X. et al. Expression of functional Toll like receptors 2 and 4 in human aortic valve interstitial cells: Potential roles in aortic valve inflammation and stenosis. American Journal of Physiology and Cell Physiology 294, C29\u2013C35 (2008).","journal-title":"American Journal of Physiology and Cell Physiology"},{"key":"47412_CR28","doi-asserted-by":"crossref","first-page":"1580","DOI":"10.1161\/ATVBAHA.112.300912","volume":"33","author":"Q Zeng","year":"2013","unstructured":"Zeng, Q. et al. Notch1 promotes the pro osteogenic response of human aortic valve interstitial cells via modulation of ERK1\/2 and nuclear factor \u03baB activation. Arteriosclerosis. Thrombosis, Vascular Biology 33, 1580\u20131590 (2013).","journal-title":"Thrombosis, Vascular Biology"},{"key":"47412_CR29","doi-asserted-by":"crossref","first-page":"1967","DOI":"10.1084\/jem.20141898","volume":"212","author":"ME Varney","year":"2015","unstructured":"Varney, M. E. et al. Loss of Tifab, a del(5q) MDS gene, alters hematopoiesis through derepression of Toll-like receptor-TRAF6 signaling. Journal of Experimental Medicine 212, 1967\u201385 (2015).","journal-title":"Journal of Experimental Medicine"},{"key":"47412_CR30","doi-asserted-by":"publisher","first-page":"100918","DOI":"10.1016\/j.arr.2019.100918","volume":"54","author":"Carmela Rita Balistreri","year":"2019","unstructured":"Balistreri, C. R., Garagnani, P., Madonna, R., Vaiserman, A. & Melino, G. Developmental Programming of Adult Haematopoiesis System. Ageing Res Rev, 100918, https:\/\/doi.org\/10.1016\/j.arr.2019.100918 [Epub ahead of print] (2019).","journal-title":"Ageing Research Reviews"},{"key":"47412_CR31","doi-asserted-by":"crossref","first-page":"5549","DOI":"10.3892\/mmr.2017.7291","volume":"16","author":"M Yu","year":"2017","unstructured":"Yu, M. et al. Toll like receptor 4 is expressed and functional in late endothelial progenitor cells. Molecular Medicine Reports. 16, 5549\u20135554 (2017).","journal-title":"Molecular Medicine Reports."},{"key":"47412_CR32","doi-asserted-by":"crossref","first-page":"766","DOI":"10.2174\/138161210790883624","volume":"16","author":"MA Panaro","year":"2010","unstructured":"Panaro, M. A. et al. Toll-like receptor 4 mediates LPS-induced release of nitric oxide and tumor necrosis factor-alpha by embryonal cardiomyocytes: biological significance andclinical implications in human pathology. Current Pharmacological Design 16, 766\u201374 (2010).","journal-title":"Current Pharmacological Design"},{"key":"47412_CR33","doi-asserted-by":"crossref","first-page":"165758","DOI":"10.1155\/2014\/165758","volume":"2014","author":"L Scola","year":"2014","unstructured":"Scola, L. et al. Role of TGF-\u03b2 pathway polymorphisms in sporadic thoracic aortic aneurysm: rs900 TGF-\u03b22 is a marker of differential gender susceptibility. Mediators Inflammation. 2014, 165758 (2014).","journal-title":"Mediators Inflammation."},{"key":"47412_CR34","first-page":"463","volume":"25","author":"CR Balistreri","year":"2016","unstructured":"Balistreri, C. R., Allegra, A., Crapanzano, F., Pisano, C. & Ruvolo, G. Matrix Metalloproteinases (MMPs), Their Genetic Variants and miRNA in Mitral Valve Diseases: Potential Biomarker Tools and Targets for Personalized Treatments. Journal of Heart Valve Disease 25, 463\u2013474 (2016).","journal-title":"Journal of Heart Valve Disease"},{"key":"47412_CR35","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1016\/j.carpath.2016.05.004","volume":"25","author":"CR Balistreri","year":"2016","unstructured":"Balistreri, C. R. et al. Associations of rs3918242 and rs2285053 MMP-9 and MMP-2 polymorphisms with the risk, severity, and short- and long-term complications of degenerative mitral valve diseases: a 4.8-year prospective cohort study. Cardiovascular Pathology. 25, 362\u201370 (2016).","journal-title":"Cardiovascular Pathology."},{"key":"47412_CR36","doi-asserted-by":"crossref","unstructured":"Ferwerda, B. et al. Functional consequences of toll ike receptor 4 polymorphisms. Molecular Medicine 14, 346\u2013352.","DOI":"10.2119\/2007-00135.Ferwerda"},{"key":"47412_CR37","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1210\/er.2014-1100","volume":"36","author":"LA Velloso","year":"2015","unstructured":"Velloso, L. A., Folli, F. & Saad, M. J. TLR4 at the crossroads of nutrients, gut microbiota, and metabolic inflammation. Endocrine Reviews 36, 245\u2013247 (2015).","journal-title":"Endocrine Reviews"},{"key":"47412_CR38","first-page":"141","volume":"43","author":"JC Bessot","year":"2011","unstructured":"Bessot, J. C. & Pauli, G. Mite allergens: an overview Eur. Annals of Allergy. Clinical Immunology 43, 141\u2013156 (2011).","journal-title":"Clinical Immunology"},{"key":"47412_CR39","first-page":"2010","volume":"802078","author":"CR Balistreri","year":"2010","unstructured":"Balistreri, C. R., Caruso, C. & Candore, G. The role of adipose tissue and adipokines in obesity-related inflammatory diseases Mediators and Inflammation. Article 802078, 2010 (2010).","journal-title":"Article"},{"key":"47412_CR40","doi-asserted-by":"crossref","first-page":"1045","DOI":"10.1007\/s00018-013-1487-x","volume":"71","author":"K Takahashi","year":"2014","unstructured":"Takahashi, K. Influence of bacteria on epigenetic gene control. Cellular Molecular Life Science 71, 1045\u20131054 (2014).","journal-title":"Cellular Molecular Life Science"},{"key":"47412_CR41","doi-asserted-by":"crossref","first-page":"1725","DOI":"10.1007\/s12035-017-0450-5","volume":"55","author":"R Goel","year":"2018","unstructured":"Goel, R., Bhat, S. A., Hanif, K., Nath, C. & Shukla, R. Angiotensin II Receptor Blockers Attenuate Lipopolysaccharide-Induced Memory Impairment by Modulation of NF-\u03baB-Mediated BDNF\/CREB Expression and Apoptosis in Spontaneously Hypertensive Rats. Molecular Neurobiology. 55, 1725\u20131739 (2018).","journal-title":"Molecular Neurobiology."},{"key":"47412_CR42","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1016\/j.phrs.2017.06.012","volume":"127","author":"I Aquila","year":"2018","unstructured":"Aquila, I. et al. The use and abuse of Cre\/Lox recombination to identify adult cardiomyocyte renewal rate and origin. Pharmacological Research 127, 116\u2013128 (2018).","journal-title":"Pharmacological Research"},{"key":"47412_CR43","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.yjmcc.2019.02.014","volume":"129","author":"A Forte","year":"2019","unstructured":"Forte, A. et al. Polyamines and microbiota in bicuspid and tricuspid aortic valve aortopathy. Journal of Molecular and Cellular Cardiology. 129, 179\u2013187 (2019).","journal-title":"Journal of Molecular and Cellular Cardiology."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-47412-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-47412-0","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-47412-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,17]],"date-time":"2022-12-17T12:00:02Z","timestamp":1671278402000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-47412-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,7,30]]},"references-count":43,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2019,12]]}},"alternative-id":["47412"],"URL":"https:\/\/doi.org\/10.1038\/s41598-019-47412-0","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,7,30]]},"assertion":[{"value":"27 November 2018","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 July 2019","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 July 2019","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"11028"}}