{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T15:27:23Z","timestamp":1788449243603,"version":"build-2803163510"},"reference-count":83,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,10,6]],"date-time":"2021-10-06T00:00:00Z","timestamp":1633478400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,10,6]],"date-time":"2021-10-06T00:00:00Z","timestamp":1633478400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"current research funds 2020 of IRCCS \u201cCentro Neurolesi Bonino-Pulejo\u201d"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Recent studies have focused their attention on conjunctivitis as one of the symptoms of coronavirus disease 2019 (COVID-19). Therefore, tear samples were taken from COVID-19 patients and the presence of SARS-CoV-2 was evidenced using Real Time reverse transcription polymerase chain reaction. The main aim of this study was to analyze mRNA expression in the tears of patients with COVID-19 compared with healthy subjects using Next Generation Sequencing (NGS). The functional evaluation of the transcriptome highlighted 25 genes that differ statistically between healthy individuals and patients affected by COVID-19. In particular, the NGS analysis identified the presence of several genes involved in B cell signaling and keratinization. In particular, the genes involved in B cell signaling were downregulated in the tears of COVID-19 patients, while those involved in keratinization were upregulated. The results indicated that SARS-CoV-2 may induce a process of ocular keratinization and a defective B cell response.<\/jats:p>","DOI":"10.1038\/s41598-021-99344-3","type":"journal-article","created":{"date-parts":[[2021,10,8]],"date-time":"2021-10-08T00:09:47Z","timestamp":1633651787000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Transcriptomic analysis revealed increased expression of genes involved in keratinization in the tears of COVID-19 patients"],"prefix":"10.1038","volume":"11","author":[{"given":"Leonardo","family":"Mastropasqua","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"Toto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luigi","family":"Chiricosta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Diomede","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agnese","family":"Gugliandolo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Serena","family":"Silvestro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guya Diletta","family":"Marconi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruna","family":"Sinjari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacopo","family":"Vecchiet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Cipollone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Damiano","family":"D\u2019Ardes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Auricchio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuela","family":"Lanzini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergio","family":"Caputi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rossella","family":"D\u2019Aloisio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emanuela","family":"Mazzon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oriana","family":"Trubiani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,10,6]]},"reference":[{"key":"99344_CR1","doi-asserted-by":"publisher","DOI":"10.3390\/cells9051267","author":"M Romano","year":"2020","unstructured":"Romano, M., Ruggiero, A., Squeglia, F., Maga, G. & Berisio, R. A structural view of SARS-CoV-2 RNA replication machinery: RNA synthesis, proofreading and final capping. Cells https:\/\/doi.org\/10.3390\/cells9051267 (2020).","journal-title":"Cells"},{"key":"99344_CR2","doi-asserted-by":"publisher","first-page":"192","DOI":"10.1111\/joim.13091","volume":"288","author":"G Pascarella","year":"2020","unstructured":"Pascarella, G. et al. COVID-19 diagnosis and management: A comprehensive review. J. Intern. Med. 288, 192\u2013206. https:\/\/doi.org\/10.1111\/joim.13091 (2020).","journal-title":"J. Intern. Med."},{"key":"99344_CR3","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21186833","author":"F Diomede","year":"2020","unstructured":"Diomede, F., Marconi, G. D., Fonticoli, L., Pizzicannella, J. & Trubiani, O. Stem cells secretome from oral tissue could represent a promising therapeutic approach in COVID-19-disease?. Int. J. Mol. Sci. https:\/\/doi.org\/10.3390\/ijms21186833 (2020).","journal-title":"Int. J. Mol. Sci."},{"key":"99344_CR4","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.552925","volume":"11","author":"NM Beeraka","year":"2020","unstructured":"Beeraka, N. M. et al. Strategies for targeting SARS CoV-2: Small molecule inhibitors-the current status. Front. Immunol. 11, 552925. https:\/\/doi.org\/10.3389\/fimmu.2020.552925 (2020).","journal-title":"Front. Immunol."},{"key":"99344_CR5","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(20)30313-5","volume":"395","author":"CW Lu","year":"2020","unstructured":"Lu, C. W., Liu, X. F. & Jia, Z. F. 2019-nCoV transmission through the ocular surface must not be ignored. Lancet 395, e39. https:\/\/doi.org\/10.1016\/S0140-6736(20)30313-5 (2020).","journal-title":"Lancet"},{"key":"99344_CR6","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0023710","volume":"6","author":"J Lang","year":"2011","unstructured":"Lang, J. et al. Inhibition of SARS pseudovirus cell entry by lactoferrin binding to heparan sulfate proteoglycans. PLoS ONE 6, e23710. https:\/\/doi.org\/10.1371\/journal.pone.0023710 (2011).","journal-title":"PLoS ONE"},{"key":"99344_CR7","doi-asserted-by":"publisher","first-page":"537","DOI":"10.1016\/j.jtos.2020.06.007","volume":"18","author":"L Zhou","year":"2020","unstructured":"Zhou, L. et al. ACE2 and TMPRSS2 are expressed on the human ocular surface, suggesting susceptibility to SARS-CoV-2 infection. Ocul. Surf. 18, 537\u2013544. https:\/\/doi.org\/10.1016\/j.jtos.2020.06.007 (2020).","journal-title":"Ocul. Surf."},{"key":"99344_CR8","doi-asserted-by":"publisher","first-page":"1049","DOI":"10.1007\/s00417-020-04641-8","volume":"258","author":"THT Lai","year":"2020","unstructured":"Lai, T. H. T., Tang, E. W. H., Chau, S. K. Y., Fung, K. S. C. & Li, K. K. W. Stepping up infection control measures in ophthalmology during the novel coronavirus outbreak: An experience from Hong Kong. Graefes Arch. Clin. Exp. Ophthalmol. 258, 1049\u20131055. https:\/\/doi.org\/10.1007\/s00417-020-04641-8 (2020).","journal-title":"Graefes Arch. Clin. Exp. Ophthalmol."},{"key":"99344_CR9","doi-asserted-by":"publisher","first-page":"242","DOI":"10.7326\/M20-1176","volume":"173","author":"F Colavita","year":"2020","unstructured":"Colavita, F. et al. SARS-CoV-2 isolation from ocular secretions of a patient with COVID-19 in Italy with prolonged viral RNA detection. Ann. Intern. Med. 173, 242\u2013243. https:\/\/doi.org\/10.7326\/M20-1176 (2020).","journal-title":"Ann. Intern. Med."},{"key":"99344_CR10","doi-asserted-by":"publisher","first-page":"1708","DOI":"10.1056\/NEJMoa2002032","volume":"382","author":"WJ Guan","year":"2020","unstructured":"Guan, W. J. et al. Clinical characteristics of coronavirus disease 2019 in China. N. Engl. J. Med. 382, 1708\u20131720. https:\/\/doi.org\/10.1056\/NEJMoa2002032 (2020).","journal-title":"N. Engl. J. Med."},{"key":"99344_CR11","doi-asserted-by":"publisher","DOI":"10.1001\/jamaophthalmol.2020.5464","volume":"4","author":"C Azzolini","year":"2021","unstructured":"Azzolini, C. et al. SARS-CoV-2 on ocular surfaces in a cohort of patients with COVID-19 from the Lombardy Region. Italy. JAMA Ophthalmol. 4, e205464. https:\/\/doi.org\/10.1001\/jamaophthalmol.2020.5464 (2021).","journal-title":"JAMA Ophthalmol."},{"issue":"7","key":"99344_CR12","doi-asserted-by":"publisher","first-page":"977","DOI":"10.1016\/j.ophtha.2020.03.02612","volume":"127","author":"IYJ Seah","year":"2020","unstructured":"Seah, I. Y. J. et al. Assessing viral shedding and infectivity of tears in coronavirus disease 2019 (COVID-19) patients. Ophthalmology 127(7), 977\u2013979. https:\/\/doi.org\/10.1016\/j.ophtha.2020.03.02612 (2020).","journal-title":"Ophthalmology"},{"issue":"7","key":"99344_CR13","doi-asserted-by":"publisher","first-page":"982","DOI":"10.1016\/j.ophtha.2020.04.02813","volume":"127","author":"Y Zhou","year":"2020","unstructured":"Zhou, Y. et al. Ocular findings and proportion with conjunctival SARS-COV-2 in COVID-19 patients. Ophthalmology 127(7), 982\u2013983. https:\/\/doi.org\/10.1016\/j.ophtha.2020.04.02813 (2020).","journal-title":"Ophthalmology"},{"key":"99344_CR14","doi-asserted-by":"publisher","first-page":"155","DOI":"10.3389\/fpubh.2020.0015514","volume":"8","author":"CB Sun","year":"2020","unstructured":"Sun, C. B., Wang, Y. Y., Liu, G. H. & Liu, Z. Role of the eye in transmitting human coronavirus: What we know and what we do not know. Front Public Health 8, 155. https:\/\/doi.org\/10.3389\/fpubh.2020.0015514 (2020).","journal-title":"Front Public Health"},{"key":"99344_CR15","doi-asserted-by":"publisher","first-page":"589","DOI":"10.1002\/jmv.25725","volume":"92","author":"J Xia","year":"2020","unstructured":"Xia, J., Tong, J., Liu, M., Shen, Y. & Guo, D. Evaluation of coronavirus in tears and conjunctival secretions of patients with SARS-CoV-2 infection. J. Med. Virol. 92, 589\u2013594. https:\/\/doi.org\/10.1002\/jmv.25725 (2020).","journal-title":"J. Med. Virol."},{"key":"99344_CR16","doi-asserted-by":"publisher","first-page":"2129","DOI":"10.1101\/gr.772403","volume":"13","author":"PD Thomas","year":"2003","unstructured":"Thomas, P. D. et al. PANTHER: A library of protein families and subfamilies indexed by function. Genome Res. 13, 2129\u20132141. https:\/\/doi.org\/10.1101\/gr.772403 (2003).","journal-title":"Genome Res."},{"key":"99344_CR17","doi-asserted-by":"publisher","DOI":"10.1126\/science.aal3321","author":"PJ Thul","year":"2017","unstructured":"Thul, P. J. et al. A subcellular map of the human proteome. Science https:\/\/doi.org\/10.1126\/science.aal3321 (2017).","journal-title":"Science"},{"key":"99344_CR18","unstructured":"Atlas, H.P. Availabe online: http:\/\/www.proteinatlas.org"},{"key":"99344_CR19","doi-asserted-by":"publisher","first-page":"3017","DOI":"10.2147\/OPTH.S269868","volume":"14","author":"M Peng","year":"2020","unstructured":"Peng, M., Dai, J., Sugali, C. K., Rayana, N. P. & Mao, W. The role of the ocular tissue in SARS-CoV-2 transmission. Clin. Ophthalmol. 14, 3017\u20133024. https:\/\/doi.org\/10.2147\/OPTH.S269868 (2020).","journal-title":"Clin. Ophthalmol."},{"key":"99344_CR20","doi-asserted-by":"publisher","first-page":"772","DOI":"10.1002\/cyto.a.24172","volume":"97","author":"W Huang","year":"2020","unstructured":"Huang, W. et al. Lymphocyte subset counts in COVID-19 patients: A meta-analysis. Cytometry Part A J. Int. Soc. Anal. Cytol. 97, 772\u2013776. https:\/\/doi.org\/10.1002\/cyto.a.24172 (2020).","journal-title":"Cytometry Part A J. Int. Soc. Anal. Cytol."},{"key":"99344_CR21","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1194\/jlr.M044826","volume":"55","author":"SM Lam","year":"2014","unstructured":"Lam, S. M. et al. Extensive characterization of human tear fluid collected using different techniques unravels the presence of novel lipid amphiphiles. J. Lipid Res. 55, 289\u2013298 (2014).","journal-title":"J. Lipid Res."},{"issue":"12","key":"99344_CR22","doi-asserted-by":"publisher","first-page":"4293","DOI":"10.1167\/iovs.03-1145","volume":"45","author":"L Luo","year":"2004","unstructured":"Luo, L. et al. Experimental dry eye stimulates production of inflammatory cytokines and MMP-9 and activates MAPK signaling pathways on the ocular surface. Invest. Ophthalmol. Vis. Sci. 45(12), 4293\u20134301 (2004).","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"issue":"84\u201396","key":"99344_CR23","first-page":"22","volume":"26","author":"NJ Van Haeringen","year":"1981","unstructured":"Van Haeringen, N. J. Clinical biochemistry of tears. Surv. Ophthalmol. 26(84\u201396), 22 (1981).","journal-title":"Surv. Ophthalmol."},{"key":"99344_CR24","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.exer.2013.10.008","volume":"117","author":"DA Dartt","year":"2013","unstructured":"Dartt, D. A. & Willcox, M. D. Complexity of the tear film: Importance in homeostasis and dysfunction during disease. Exp. Eye Res. 117, 1\u20133 (2013).","journal-title":"Exp. Eye Res."},{"key":"99344_CR25","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1111\/j.1463-5224.2004.00325.x","volume":"7","author":"HJ Davidson","year":"2004","unstructured":"Davidson, H. J. & Kuonen, V. J. The tear film and ocular mucins. Vet. Ophthalmol. 7, 71\u201377 (2004).","journal-title":"Vet. Ophthalmol."},{"key":"99344_CR26","first-page":"2055","volume":"16","author":"I Lema","year":"2010","unstructured":"Lema, I., Brea, D., Rodriguez-Gonzalez, R., Diez-Feijoo, E. & Sobrino, T. Proteomic analysis of the tear film in patients with keratoconus. Mol. Vis. 16, 2055\u20132061 (2010).","journal-title":"Mol. Vis."},{"key":"99344_CR27","doi-asserted-by":"publisher","first-page":"1028","DOI":"10.1111\/ceo.13569","volume":"47","author":"A Kuot","year":"2019","unstructured":"Kuot, A. et al. Reduced expression of apolipoprotein E and immunoglobulin heavy constant gamma 1 proteins in Fuchs endothelial corneal dystrophy. Clin. Exp. Ophthalmol. 47, 1028\u20131042. https:\/\/doi.org\/10.1111\/ceo.13569 (2019).","journal-title":"Clin. Exp. Ophthalmol."},{"key":"99344_CR28","doi-asserted-by":"publisher","first-page":"487","DOI":"10.1080\/14728222.2018.1472768","volume":"22","author":"D Rostamzadeh","year":"2018","unstructured":"Rostamzadeh, D., Kazemi, T., Amirghofran, Z. & Shabani, M. Update on Fc receptor-like (FCRL) family: New immunoregulatory players in health and diseases. Expert Opin. Ther. Targets 22, 487\u2013502. https:\/\/doi.org\/10.1080\/14728222.2018.1472768 (2018).","journal-title":"Expert Opin. Ther. Targets"},{"key":"99344_CR29","doi-asserted-by":"publisher","first-page":"4741","DOI":"10.4049\/jimmunol.1102651","volume":"188","author":"TJ Wilson","year":"2012","unstructured":"Wilson, T. J., Fuchs, A. & Colonna, M. Cutting edge: Human FcRL4 and FcRL5 are receptors for IgA and IgG. J. Immunol. 188, 4741\u20134745. https:\/\/doi.org\/10.4049\/jimmunol.1102651 (2012).","journal-title":"J. Immunol."},{"key":"99344_CR30","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1016\/j.imlet.2009.05.005","volume":"125","author":"N Okamoto","year":"2009","unstructured":"Okamoto, N. et al. Possible contribution of DNase gamma to immunoglobulin V gene diversification. Immunol. Lett. 125, 22\u201330. https:\/\/doi.org\/10.1016\/j.imlet.2009.05.005 (2009).","journal-title":"Immunol. Lett."},{"key":"99344_CR31","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1016\/j.bbrc.2004.11.142","volume":"327","author":"M Okamoto","year":"2005","unstructured":"Okamoto, M. et al. Involvement of DNase gamma in the resected double-strand DNA breaks in immunoglobulin genes. Biochem. Biophys. Res. Commun. 327, 76\u201383. https:\/\/doi.org\/10.1016\/j.bbrc.2004.11.142 (2005).","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"99344_CR32","doi-asserted-by":"publisher","first-page":"522","DOI":"10.3389\/fimmu.2017.00522","volume":"8","author":"G Shi","year":"2017","unstructured":"Shi, G., Abbott, K. N., Wu, W., Salter, R. D. & Keyel, P. A. Dnase1L3 regulates inflammasome-dependent cytokine secretion. Front. Immunol. 8, 522. https:\/\/doi.org\/10.3389\/fimmu.2017.00522 (2017).","journal-title":"Front. Immunol."},{"key":"99344_CR33","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1093\/emboj\/21.1.83","volume":"21","author":"K Yokoyama","year":"2002","unstructured":"Yokoyama, K. et al. BANK regulates BCR-induced calcium mobilization by promoting tyrosine phosphorylation of IP(3) receptor. EMBO J. 21, 83\u201392. https:\/\/doi.org\/10.1093\/emboj\/21.1.83 (2002).","journal-title":"EMBO J."},{"key":"99344_CR34","doi-asserted-by":"publisher","first-page":"18537","DOI":"10.1074\/jbc.M109.012807","volume":"284","author":"SA Graham","year":"2009","unstructured":"Graham, S. A. et al. Prolectin, a glycan-binding receptor on dividing B cells in germinal centers. J. Biol. Chem. 284, 18537\u201318544. https:\/\/doi.org\/10.1074\/jbc.M109.012807 (2009).","journal-title":"J. Biol. Chem."},{"key":"99344_CR35","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1186\/1748-717X-2-25","volume":"2","author":"H Edvardsen","year":"2007","unstructured":"Edvardsen, H. et al. Linkage disequilibrium pattern of the ATM gene in breast cancer patients and controls; association of SNPs and haplotypes to radio-sensitivity and post-lumpectomy local recurrence. Radiat. Oncol. 2, 25. https:\/\/doi.org\/10.1186\/1748-717X-2-25 (2007).","journal-title":"Radiat. Oncol."},{"key":"99344_CR36","doi-asserted-by":"publisher","first-page":"3137","DOI":"10.4049\/jimmunol.1801033","volume":"202","author":"L Nicolas","year":"2019","unstructured":"Nicolas, L. et al. Cutting edge: ATM influences germinal center integrity. J. Immunol. 202, 3137\u20133142. https:\/\/doi.org\/10.4049\/jimmunol.1801033 (2019).","journal-title":"J. Immunol."},{"key":"99344_CR37","doi-asserted-by":"publisher","first-page":"142","DOI":"10.1111\/j.0105-2896.2006.00361.x","volume":"209","author":"IR Matei","year":"2006","unstructured":"Matei, I. R., Guidos, C. J. & Danska, J. S. ATM-dependent DNA damage surveillance in T-cell development and leukemogenesis: the DSB connection. Immunol. Rev. 209, 142\u2013158. https:\/\/doi.org\/10.1111\/j.0105-2896.2006.00361.x (2006).","journal-title":"Immunol. Rev."},{"key":"99344_CR38","doi-asserted-by":"publisher","first-page":"2","DOI":"10.3390\/biom6010002","volume":"6","author":"EL Ryan","year":"2016","unstructured":"Ryan, E. L., Hollingworth, R. & Grand, R. J. Activation of the DNA damage response by RNA viruses. Biomolecules 6, 2. https:\/\/doi.org\/10.3390\/biom6010002 (2016).","journal-title":"Biomolecules"},{"key":"99344_CR39","doi-asserted-by":"publisher","first-page":"2211","DOI":"10.1084\/jem.20171514","volume":"215","author":"S Xing","year":"2018","unstructured":"Xing, S. et al. Tle corepressors are differentially partitioned to instruct CD8(+) T cell lineage choice and identity. J. Exp. Med. 215, 2211\u20132226. https:\/\/doi.org\/10.1084\/jem.20171514 (2018).","journal-title":"J. Exp. Med."},{"key":"99344_CR40","doi-asserted-by":"publisher","first-page":"2312","DOI":"10.7150\/jca.30376","volume":"10","author":"R Lara-Lemus","year":"2019","unstructured":"Lara-Lemus, R. On the role of myelin and lymphocyte protein (MAL) in cancer: A puzzle with two faces. J Cancer 10, 2312\u20132318. https:\/\/doi.org\/10.7150\/jca.30376 (2019).","journal-title":"J Cancer"},{"key":"99344_CR41","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01739-19","author":"JA Lopez-Guerrero","year":"2020","unstructured":"Lopez-Guerrero, J. A. et al. Herpes simplex virus 1 spread in oligodendrocytic cells is highly dependent on MAL proteolipid. J. Virol. https:\/\/doi.org\/10.1128\/JVI.01739-19 (2020).","journal-title":"J. Virol."},{"key":"99344_CR42","doi-asserted-by":"publisher","first-page":"3201","DOI":"10.1084\/jem.20080552","volume":"205","author":"O Anton","year":"2008","unstructured":"Anton, O. et al. An essential role for the MAL protein in targeting Lck to the plasma membrane of human T lymphocytes. J. Exp. Med. 205, 3201\u20133213. https:\/\/doi.org\/10.1084\/jem.20080552 (2008).","journal-title":"J. Exp. Med."},{"issue":"2","key":"99344_CR43","doi-asserted-by":"publisher","first-page":"706","DOI":"10.1167\/iovs.13-13461","volume":"55","author":"O Alekseev","year":"2014","unstructured":"Alekseev, O., Donovan, K. & Azizkhan-Clifford, J. Inhibition of ataxia telangiectasia mutated (ATM) kinase suppresses herpes simplex virus type 1 (HSV-1) keratitis. Invest. Ophthalmol. Vis. Sci. 55(2), 706\u2013715. https:\/\/doi.org\/10.1167\/iovs.13-13461 (2014).","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"99344_CR44","doi-asserted-by":"publisher","first-page":"6345","DOI":"10.4049\/jimmunol.1003771","volume":"186","author":"OM Anton","year":"2011","unstructured":"Anton, O. M., Andres-Delgado, L., Reglero-Real, N., Batista, A. & Alonso, M. A. MAL protein controls protein sorting at the supramolecular activation cluster of human T lymphocytes. J. Immunol. 186, 6345\u20136356. https:\/\/doi.org\/10.4049\/jimmunol.1003771 (2011).","journal-title":"J. Immunol."},{"key":"99344_CR45","doi-asserted-by":"publisher","first-page":"220","DOI":"10.1016\/j.coi.2010.12.016","volume":"23","author":"ES Alonzo","year":"2011","unstructured":"Alonzo, E. S. & Sant\u2019Angelo, D. B. Development of PLZF-expressing innate T cells. Curr. Opin. Immunol. 23, 220\u2013227. https:\/\/doi.org\/10.1016\/j.coi.2010.12.016 (2011).","journal-title":"Curr. Opin. Immunol."},{"key":"99344_CR46","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2020.08.031","author":"JT Sims","year":"2020","unstructured":"Sims, J. T. et al. Characterization of the cytokine storm reflects hyperinflammatory endothelial dysfunction in COVID-19. J. Allergy Clin. Immunol. https:\/\/doi.org\/10.1016\/j.jaci.2020.08.031 (2020).","journal-title":"J. Allergy Clin. Immunol."},{"key":"99344_CR47","doi-asserted-by":"publisher","first-page":"5147","DOI":"10.4049\/jimmunol.181.7.5147","volume":"181","author":"Z Li","year":"2008","unstructured":"Li, Z. et al. Gene expression profiling in autoimmune noninfectious uveitis disease. J. Immunol. 181, 5147\u20135157. https:\/\/doi.org\/10.4049\/jimmunol.181.7.5147 (2008).","journal-title":"J. Immunol."},{"key":"99344_CR48","doi-asserted-by":"publisher","first-page":"991","DOI":"10.1111\/j.1600-0625.2006.00516.x","volume":"15","author":"S Kunz","year":"2006","unstructured":"Kunz, S. et al. Interleukin (IL)-19, IL-20 and IL-24 are produced by and act on keratinocytes and are distinct from classical ILs. Exp. Dermatol. 15, 991\u20131004. https:\/\/doi.org\/10.1111\/j.1600-0625.2006.00516.x (2006).","journal-title":"Exp. Dermatol."},{"issue":"3","key":"99344_CR49","doi-asserted-by":"publisher","first-page":"284","DOI":"10.1002\/hon.2718","volume":"38","author":"V Vela","year":"2020","unstructured":"Vela, V. et al. 39 High throughput sequencing reveals high specificity of TNFAIP3 mutations in ocular adnexal marginal zone B-cell lymphomas. Hematol. Oncol. 38(3), 284\u2013292. https:\/\/doi.org\/10.1002\/hon.2718 (2020).","journal-title":"Hematol. Oncol."},{"key":"99344_CR50","doi-asserted-by":"publisher","DOI":"10.1016\/j.anndiagpath.2019.151432","volume":"44","author":"J Jha","year":"2020","unstructured":"Jha, J. et al. Expression of BAP1 and ATM proteins: Association with AJCC tumor category in uveal melanoma. Ann. Diagn. Pathol. 44, 151432. https:\/\/doi.org\/10.1016\/j.anndiagpath.2019.151432 (2020).","journal-title":"Ann. Diagn. Pathol."},{"key":"99344_CR51","doi-asserted-by":"publisher","first-page":"3776","DOI":"10.2174\/138161211798357845","volume":"17","author":"YT Azuma","year":"2011","unstructured":"Azuma, Y. T., Nakajima, H. & Takeuchi, T. IL-19 as a potential therapeutic in autoimmune and inflammatory diseases. Curr. Pharm. Des. 17, 3776\u20133780. https:\/\/doi.org\/10.2174\/138161211798357845 (2011).","journal-title":"Curr. Pharm. Des."},{"key":"99344_CR52","doi-asserted-by":"publisher","first-page":"3448","DOI":"10.1038\/s41598-017-03449-7","volume":"7","author":"M Kulkarni","year":"2017","unstructured":"Kulkarni, M. et al. Genome-wide analysis suggests a differential microRNA signature associated with normal and diabetic human corneal limbus. Sci. Rep. 7, 3448. https:\/\/doi.org\/10.1038\/s41598-017-03449-7 (2017).","journal-title":"Sci. Rep."},{"key":"99344_CR53","doi-asserted-by":"publisher","first-page":"137","DOI":"10.2174\/1874364101206010137","volume":"6","author":"AS Lund","year":"2012","unstructured":"Lund, A. S., Heegaard, S., Prause, J. U., Toft, P. B. & Skov, L. Expression of filaggrin in normal and keratinized conjunctiva. Open Ophthalmol. J. 6, 137\u2013140. https:\/\/doi.org\/10.2174\/1874364101206010137 (2012).","journal-title":"Open Ophthalmol. J."},{"key":"99344_CR54","doi-asserted-by":"publisher","first-page":"857","DOI":"10.1007\/s00403-013-1415-9","volume":"305","author":"F Carregaro","year":"2013","unstructured":"Carregaro, F., Stefanini, A. C., Henrique, T. & Tajara, E. H. Study of small proline-rich proteins (SPRRs) in health and disease: A review of the literature. Arch. Dermatol. Res. 305, 857\u2013866. https:\/\/doi.org\/10.1007\/s00403-013-1415-9 (2013).","journal-title":"Arch. Dermatol. Res."},{"key":"99344_CR55","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1167\/iovs.07-0685","volume":"49","author":"S Li","year":"2008","unstructured":"Li, S. et al. Small proline-rich protein 1B (SPRR1B) is a biomarker for squamous metaplasia in dry eye disease. Invest. Ophthalmol. Vis. Sci. 49, 34\u201341. https:\/\/doi.org\/10.1167\/iovs.07-0685 (2008).","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"99344_CR56","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1016\/j.ajpath.2013.03.017","volume":"183","author":"CK Marko","year":"2013","unstructured":"Marko, C. K. et al. Spdef null mice lack conjunctival goblet cells and provide a model of dry eye. Am. J. Pathol. 183, 35\u201348. https:\/\/doi.org\/10.1016\/j.ajpath.2013.03.017 (2013).","journal-title":"Am. J. Pathol."},{"key":"99344_CR57","doi-asserted-by":"publisher","first-page":"326","DOI":"10.1016\/j.jtos.2019.12.006","volume":"18","author":"J Alam","year":"2020","unstructured":"Alam, J., de Paiva, C. S. & Pflugfelder, S. C. Immune\u2014Goblet cell interaction in the conjunctiva. Ocul. Surf. 18, 326\u2013334. https:\/\/doi.org\/10.1016\/j.jtos.2019.12.006 (2020).","journal-title":"Ocul. Surf."},{"key":"99344_CR58","doi-asserted-by":"publisher","first-page":"978","DOI":"10.1172\/JCI29176","volume":"117","author":"KS Park","year":"2007","unstructured":"Park, K. S. et al. SPDEF regulates goblet cell hyperplasia in the airway epithelium. J. Clin. Investig. 117, 978\u2013988. https:\/\/doi.org\/10.1172\/JCI29176 (2007).","journal-title":"J. Clin. Investig."},{"key":"99344_CR59","doi-asserted-by":"publisher","first-page":"4628","DOI":"10.1242\/dev.117804","volume":"141","author":"HA McCauley","year":"2014","unstructured":"McCauley, H. A. et al. TGFbeta signaling inhibits goblet cell differentiation via SPDEF in conjunctival epithelium. Development 141, 4628\u20134639. https:\/\/doi.org\/10.1242\/dev.117804 (2014).","journal-title":"Development"},{"key":"99344_CR60","doi-asserted-by":"publisher","first-page":"456","DOI":"10.1016\/s0002-9394(14)71404-7","volume":"116","author":"MI Roat","year":"1993","unstructured":"Roat, M. I., Ohji, M., Hunt, L. E. & Thoft, R. A. Conjunctival epithelial cell hypermitosis and goblet cell hyperplasia in atopic keratoconjunctivitis. Am. J. Ophthalmol. 116, 456\u2013463. https:\/\/doi.org\/10.1016\/s0002-9394(14)71404-7 (1993).","journal-title":"Am. J. Ophthalmol."},{"key":"99344_CR61","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1159\/000315014","volume":"45","author":"U Schulze","year":"2010","unstructured":"Schulze, U., Sel, S. & Paulsen, F. P. Trefoil factor family peptide 3 at the ocular surface. A promising therapeutic candidate for patients with dry eye syndrome?. Dev. Ophthalmol. 45, 1\u201311. https:\/\/doi.org\/10.1159\/000315014 (2010).","journal-title":"Dev. Ophthalmol."},{"key":"99344_CR62","doi-asserted-by":"publisher","first-page":"3037","DOI":"10.1167\/iovs.13-13423","volume":"55","author":"U Schulze","year":"2014","unstructured":"Schulze, U. et al. Trefoil factor family peptide 3 (TFF3) is upregulated under experimental conditions similar to dry eye disease and supports corneal wound healing effects in vitro. Invest. Ophthalmol. Vis. Sci. 55, 3037\u20133042. https:\/\/doi.org\/10.1167\/iovs.13-13423 (2014).","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"99344_CR63","doi-asserted-by":"publisher","first-page":"819","DOI":"10.1016\/j.peptides.2004.01.023","volume":"25","author":"P Steven","year":"2004","unstructured":"Steven, P. et al. Distribution of TFF peptides in corneal disease and pterygium. Peptides 25, 819\u2013825. https:\/\/doi.org\/10.1016\/j.peptides.2004.01.023 (2004).","journal-title":"Peptides"},{"key":"99344_CR64","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1016\/j.biochi.2008.07.007","volume":"91","author":"JL Flanagan","year":"2009","unstructured":"Flanagan, J. L. & Willcox, M. D. Role of lactoferrin in the tear film. Biochimie 91, 35\u201343. https:\/\/doi.org\/10.1016\/j.biochi.2008.07.007 (2009).","journal-title":"Biochimie"},{"key":"99344_CR65","doi-asserted-by":"publisher","first-page":"2084","DOI":"10.3390\/molecules16032084","volume":"16","author":"K Li","year":"2010","unstructured":"Li, K., Liu, X., Chen, Z., Huang, Q. & Wu, K. Quantification of tear proteins and sPLA2-IIa alteration in patients with allergic conjunctivitis. Mol. Vis. 16, 2084\u20132091 (2010).","journal-title":"Mol. Vis."},{"key":"99344_CR66","doi-asserted-by":"publisher","first-page":"719","DOI":"10.3389\/fphar.2019.00719","volume":"10","author":"RG Snodgrass","year":"2019","unstructured":"Snodgrass, R. G. & Brune, B. Regulation and functions of 15-lipoxygenases in human macrophages. Front. Pharmacol. 10, 719. https:\/\/doi.org\/10.3389\/fphar.2019.00719 (2019).","journal-title":"Front. Pharmacol."},{"key":"99344_CR67","doi-asserted-by":"publisher","first-page":"849","DOI":"10.1167\/iovs.04-1166","volume":"46","author":"MS Chang","year":"2005","unstructured":"Chang, M. S. et al. Detection and subcellular localization of two 15S-lipoxygenases in human cornea. Invest. Ophthalmol. Vis. Sci. 46, 849\u2013856. https:\/\/doi.org\/10.1167\/iovs.04-1166 (2005).","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"99344_CR68","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1016\/j.cell.2020.02.052","volume":"181","author":"M Hoffmann","year":"2020","unstructured":"Hoffmann, M. et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 181, 271. https:\/\/doi.org\/10.1016\/j.cell.2020.02.052 (2020).","journal-title":"Cell"},{"key":"99344_CR69","doi-asserted-by":"publisher","first-page":"12087","DOI":"10.1128\/JVI.01427-14","volume":"88","author":"P Zmora","year":"2014","unstructured":"Zmora, P. et al. DESC1 and MSPL activate influenza A viruses and emerging coronaviruses for host cell entry. J. Virol. 88, 12087\u201312097. https:\/\/doi.org\/10.1128\/JVI.01427-14 (2014).","journal-title":"J. Virol."},{"key":"99344_CR70","doi-asserted-by":"publisher","first-page":"1948","DOI":"10.1167\/iovs.14-16259","volume":"56","author":"YS Byun","year":"2015","unstructured":"Byun, Y. S., Kang, B., Yoo, Y. S. & Joo, C. K. Poly(ADP-ribose) polymerase inhibition improves corneal epithelial innervation and wound healing in diabetic rats. Invest. Ophthalmol. Vis. Sci. 56, 1948\u20131955. https:\/\/doi.org\/10.1167\/iovs.14-16259 (2015).","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"99344_CR71","doi-asserted-by":"publisher","first-page":"341","DOI":"10.1101\/gad.334425.119","volume":"34","author":"AR Fehr","year":"2020","unstructured":"Fehr, A. R. et al. The impact of PARPs and ADP-ribosylation on inflammation and host-pathogen interactions. Genes Dev. 34, 341\u2013359. https:\/\/doi.org\/10.1101\/gad.334425.119 (2020).","journal-title":"Genes Dev."},{"key":"99344_CR72","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1004403","volume":"10","author":"MD Daugherty","year":"2014","unstructured":"Daugherty, M. D., Young, J. M., Kerns, J. A. & Malik, H. S. Rapid evolution of PARP genes suggests a broad role for ADP-ribosylation in host-virus conflicts. PLoS Genet. 10, e1004403. https:\/\/doi.org\/10.1371\/journal.pgen.1004403 (2014).","journal-title":"PLoS Genet."},{"key":"99344_CR73","doi-asserted-by":"publisher","first-page":"e125","DOI":"10.1016\/j.jcjo.2020.03.003","volume":"55","author":"M Cheema","year":"2020","unstructured":"Cheema, M. et al. Keratoconjunctivitis as the initial medical presentation of the novel coronavirus disease 2019 (COVID-19). Can. J. Ophthalmol. 55, e125\u2013e129. https:\/\/doi.org\/10.1016\/j.jcjo.2020.03.003 (2020).","journal-title":"Can. J. Ophthalmol."},{"key":"99344_CR74","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1186\/s12985-020-01370-6","volume":"17","author":"D Guo","year":"2020","unstructured":"Guo, D. et al. Relapsing viral keratoconjunctivitis in COVID-19: A case report. Virol. J. 17, 97. https:\/\/doi.org\/10.1186\/s12985-020-01370-6 (2020).","journal-title":"Virol. J."},{"key":"99344_CR75","doi-asserted-by":"publisher","first-page":"3805","DOI":"10.2147\/IJN.S162836","volume":"13","author":"F Diomede","year":"2018","unstructured":"Diomede, F. et al. A novel role in skeletal segment regeneration of extracellular vesicles released from periodontal-ligament stem cells. Int. J. Nanomed. 13, 3805\u20133825. https:\/\/doi.org\/10.2147\/IJN.S162836 (2018).","journal-title":"Int. J. Nanomed."},{"key":"99344_CR76","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20236039","author":"L Chiricosta","year":"2019","unstructured":"Chiricosta, L. et al. Transcriptomic analysis of stem cells treated with moringin or cannabidiol: Analogies and differences in inflammation pathways. Int. J. Mol. Sci. https:\/\/doi.org\/10.3390\/ijms20236039 (2019).","journal-title":"Int. J. Mol. Sci."},{"key":"99344_CR77","doi-asserted-by":"publisher","first-page":"126","DOI":"10.1002\/jbm.a.36213","volume":"106","author":"A Gugliandolo","year":"2018","unstructured":"Gugliandolo, A. et al. Transcriptomic analysis of gingival mesenchymal stem cells cultured on 3D bioprinted scaffold: A promising strategy for neuroregeneration. J. Biomed. Mater. Res. Part A 106, 126\u2013137. https:\/\/doi.org\/10.1002\/jbm.a.36213 (2018).","journal-title":"J. Biomed. Mater. Res. Part A"},{"key":"99344_CR78","doi-asserted-by":"publisher","first-page":"2114","DOI":"10.1093\/bioinformatics\/btu170","volume":"30","author":"AM Bolger","year":"2014","unstructured":"Bolger, A. M., Lohse, M. & Usadel, B. Trimmomatic: A flexible trimmer for Illumina sequence data. Bioinformatics 30, 2114\u20132120. https:\/\/doi.org\/10.1093\/bioinformatics\/btu170 (2014).","journal-title":"Bioinformatics"},{"key":"99344_CR79","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1093\/bioinformatics\/bts635","volume":"29","author":"A Dobin","year":"2013","unstructured":"Dobin, A. et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics 29, 15\u201321. https:\/\/doi.org\/10.1093\/bioinformatics\/bts635 (2013).","journal-title":"Bioinformatics"},{"key":"99344_CR80","doi-asserted-by":"publisher","first-page":"166","DOI":"10.1093\/bioinformatics\/btu638","volume":"31","author":"S Anders","year":"2015","unstructured":"Anders, S., Pyl, P. T. & Huber, W. HTSeq\u2013a Python framework to work with high-throughput sequencing data. Bioinformatics 31, 166\u2013169. https:\/\/doi.org\/10.1093\/bioinformatics\/btu638 (2015).","journal-title":"Bioinformatics"},{"key":"99344_CR81","doi-asserted-by":"publisher","DOI":"10.1186\/S13059-014-0550-8","author":"MI Love","year":"2014","unstructured":"Love, M. I., Huber, W. & Anders, S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. https:\/\/doi.org\/10.1186\/S13059-014-0550-8 (2014).","journal-title":"Genome Biol."},{"key":"99344_CR82","doi-asserted-by":"publisher","first-page":"284","DOI":"10.1089\/omi.2011.0118","volume":"16","author":"G Yu","year":"2012","unstructured":"Yu, G., Wang, L. G., Han, Y. & He, Q. Y. clusterProfiler: An R package for comparing biological themes among gene clusters. OMICS 16, 284\u2013287. https:\/\/doi.org\/10.1089\/omi.2011.0118 (2012).","journal-title":"OMICS"},{"key":"99344_CR83","doi-asserted-by":"crossref","unstructured":"Wickham, H. ggplot2: Elegant Graphics for Data Analysis; 2016.","DOI":"10.1007\/978-3-319-24277-4"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-99344-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-99344-3","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-99344-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,3]],"date-time":"2022-12-03T16:18:54Z","timestamp":1670084334000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-99344-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,6]]},"references-count":83,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["99344"],"URL":"https:\/\/doi.org\/10.1038\/s41598-021-99344-3","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,10,6]]},"assertion":[{"value":"9 December 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 September 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"6 October 2021","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":"19817"}}