{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T13:37:54Z","timestamp":1792762674221,"version":"4.5.0"},"reference-count":66,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2023,12,22]],"date-time":"2023-12-22T00:00:00Z","timestamp":1703203200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2023,12,22]],"date-time":"2023-12-22T00:00:00Z","timestamp":1703203200000},"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>Meibomian gland dysfunction is the most common cause of dry eye disease and leads to significantly reduced quality of life and social burdens. Because meibomian gland dysfunction results in impaired function of the tear film lipid layer, studying the expression of tear proteins might increase the understanding of the etiology of the condition. Machine learning is able to detect patterns in complex data. This study applied machine learning to classify levels of meibomian gland dysfunction from tear proteins. The aim was to investigate proteomic changes between groups with different severity levels of meibomian gland dysfunction, as opposed to only separating patients with and without this condition. An established feature importance method was used to identify the most important proteins for the resulting models. Moreover, a new method that can take the uncertainty of the models into account when creating explanations was proposed. By examining the identified proteins, potential biomarkers for meibomian gland dysfunction were discovered. The overall findings are largely confirmatory, indicating that the presented machine learning approaches are promising for detecting clinically relevant proteins. While this study provides valuable insights into proteomic changes associated with varying severity levels of meibomian gland dysfunction, it should be noted that it was conducted without a healthy control group. Future research could benefit from including such a comparison to further validate and extend the findings presented here.<\/jats:p>","DOI":"10.1038\/s41598-023-50342-7","type":"journal-article","created":{"date-parts":[[2023,12,22]],"date-time":"2023-12-22T08:05:56Z","timestamp":1703232356000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Using machine learning model explanations to identify proteins related to severity of meibomian gland dysfunction"],"prefix":"10.1038","volume":"13","author":[{"given":"Andrea M.","family":"Stor\u00e5s","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fredrik","family":"Fineide","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Morten","family":"Magn\u00f8","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernd","family":"Thiede","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangjun","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inga","family":"Str\u00fcmke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P\u00e5l","family":"Halvorsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hilde","family":"Galtung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janicke L.","family":"Jensen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tor P.","family":"Utheim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael A.","family":"Riegler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,12,22]]},"reference":[{"key":"50342_CR1","doi-asserted-by":"publisher","first-page":"1922","DOI":"10.1167\/iovs.10-6997a","volume":"52","author":"KK Nichols","year":"2011","unstructured":"Nichols, K. K. et al. The international workshop on meibomian gland dysfunction: Executive summary. Investig. Ophthalmol. Vis. Sci. 52, 1922\u20131929. https:\/\/doi.org\/10.1167\/iovs.10-6997a (2011).","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"50342_CR2","doi-asserted-by":"publisher","first-page":"334","DOI":"10.1016\/j.jtos.2017.05.003","volume":"15","author":"F Stapleton","year":"2017","unstructured":"Stapleton, F. et al. TFOS DEWS II epidemiology report. Ocul. Surf. 15, 334\u2013365. https:\/\/doi.org\/10.1016\/j.jtos.2017.05.003 (2017).","journal-title":"Ocul. Surf."},{"key":"50342_CR3","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1016\/j.jtos.2021.05.006","volume":"21","author":"MK Morthen","year":"2021","unstructured":"Morthen, M. K. et al. The physical and mental burden of dry eye disease: A large population-based study investigating the relationship with health-related quality of life and its determinants. Ocul. Surf. 21, 107\u2013117. https:\/\/doi.org\/10.1016\/j.jtos.2021.05.006 (2021).","journal-title":"Ocul. Surf."},{"key":"50342_CR4","doi-asserted-by":"publisher","first-page":"379","DOI":"10.1097\/ICO.0b013e3181f7f363","volume":"30","author":"J Yu","year":"2011","unstructured":"Yu, J., Asche, C. V. & Fairchild, C. J. The economic burden of dry eye disease in the United States: A decision tree analysis. Cornea 30, 379\u2013387. https:\/\/doi.org\/10.1097\/ICO.0b013e3181f7f363 (2011).","journal-title":"Cornea"},{"key":"50342_CR5","doi-asserted-by":"publisher","first-page":"848","DOI":"10.1136\/bjo.2010.185256","volume":"95","author":"L Tong","year":"2011","unstructured":"Tong, L., Zhou, L., Beuerman, R. W., Zhao, S. Z. & Li, X. R. Association of tear proteins with Meibomian gland disease and dry eye symptoms. Br. J. Ophthalmol. 95, 848\u2013852. https:\/\/doi.org\/10.1136\/bjo.2010.185256 (2011).","journal-title":"Br. J. Ophthalmol."},{"key":"50342_CR6","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/srep29629","volume":"6","author":"N Perumal","year":"2016","unstructured":"Perumal, N., Funke, S., Pfeiffer, N. & Grus, F. H. Proteomics analysis of human tears from aqueous-deficient and evaporative dry eye patients. Sci. Rep. 6, 1\u201312. https:\/\/doi.org\/10.1038\/srep29629 (2016).","journal-title":"Sci. Rep."},{"key":"50342_CR7","doi-asserted-by":"publisher","first-page":"3877","DOI":"10.1016\/j.jprot.2012.04.053","volume":"75","author":"L Zhou","year":"2012","unstructured":"Zhou, L. et al. In-depth analysis of the human tear proteome. J. Proteom. 75, 3877\u20133885. https:\/\/doi.org\/10.1016\/j.jprot.2012.04.053 (2012).","journal-title":"J. Proteom."},{"key":"50342_CR8","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1016\/j.jtos.2022.03.001","volume":"24","author":"CJ Jackson","year":"2022","unstructured":"Jackson, C. J., Gundersen, K. G., Tong, L. & Utheim, T. P. Dry eye disease and proteomics. Ocul. Surf. 24, 119\u2013128. https:\/\/doi.org\/10.1016\/j.jtos.2022.03.001 (2022).","journal-title":"Ocul. Surf."},{"key":"50342_CR9","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1136\/bjophthalmol-2018-313173","volume":"103","author":"DSW Ting","year":"2019","unstructured":"Ting, D. S. W. et al. Artificial intelligence and deep learning in ophthalmology. Br. J. Ophthalmol. 103, 167\u2013175. https:\/\/doi.org\/10.1136\/bjophthalmol-2018-313173 (2019).","journal-title":"Br. J. Ophthalmol."},{"key":"50342_CR10","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1016\/j.jtos.2021.11.004","volume":"23","author":"AM Stor\u00e5s","year":"2022","unstructured":"Stor\u00e5s, A. M. et al. Artificial intelligence in dry eye disease. Ocul. Surf. 23, 74\u201386. https:\/\/doi.org\/10.1016\/j.jtos.2021.11.004 (2022).","journal-title":"Ocul. Surf."},{"key":"50342_CR11","doi-asserted-by":"publisher","first-page":"21416","DOI":"10.1038\/s41598-022-25821-y","volume":"12","author":"F Fineide","year":"2022","unstructured":"Fineide, F. et al. Predicting an unstable tear film through artificial intelligence. Sci. Rep. 12, 21416. https:\/\/doi.org\/10.1038\/s41598-022-25821-y (2022).","journal-title":"Sci. Rep."},{"key":"50342_CR12","doi-asserted-by":"publisher","DOI":"10.1186\/s13075-019-1961-4","author":"LA Aqrawi","year":"2019","unstructured":"Aqrawi, L. A. et al. Proteomic and histopathological characterisation of sicca subjects and primary Sj\u00f6gren\u2019s syndrome patients reveals promising tear, saliva and extracellular vesicle disease biomarkers. Arthritis Res. Ther.https:\/\/doi.org\/10.1186\/s13075-019-1961-4 (2019).","journal-title":"Arthritis Res. Ther."},{"key":"50342_CR13","doi-asserted-by":"publisher","DOI":"10.3390\/ijms23073714","author":"H Hynne","year":"2022","unstructured":"Hynne, H. et al. Proteomic profiling of saliva and tears in radiated head and neck cancer patients as compared to primary Sj\u00f6gren\u2019s syndrome patients. Int. J. Mol. Sci.https:\/\/doi.org\/10.3390\/ijms23073714 (2022).","journal-title":"Int. J. Mol. Sci."},{"key":"50342_CR14","doi-asserted-by":"publisher","first-page":"108","DOI":"10.1016\/S1542-0124(12)70083-6","volume":"5","author":"AJ Bron","year":"2007","unstructured":"Bron, A. J. et al. Methodologies to diagnose and monitor dry eye disease: Report of the diagnostic methodology subcommittee of the International Dry Eye WorkShop (2007). Ocul. Surf. 5, 108\u2013152. https:\/\/doi.org\/10.1016\/S1542-0124(12)70083-6 (2007).","journal-title":"Ocul. Surf."},{"key":"50342_CR15","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1016\/j.clae.2011.08.003","volume":"35","author":"H Pult","year":"2012","unstructured":"Pult, H. & Riede-Pult, B. Non-contact meibography: Keep it simple but effective. Contact Lens Anterior Eye 35, 77\u201380. https:\/\/doi.org\/10.1016\/j.clae.2011.08.003 (2012).","journal-title":"Contact Lens Anterior Eye"},{"key":"50342_CR16","first-page":"588","volume":"53","author":"H Pult","year":"2012","unstructured":"Pult, H. & Riede-Pult, B. H. An assement of subjective and objective grading of meibography image. Investig. Ophthalmol. Vis. Sci. 53, 588 (2012).","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"50342_CR17","volume-title":"Advances in Neural Information Processing Systems","author":"G Ke","year":"2017","unstructured":"Ke, G. et al. LightGBM: A highly efficient gradient boosting decision tree. In Advances in Neural Information Processing Systems Vol. 30 (eds Guyon, I. et al.) (Curran Associates, Inc., 2017)."},{"key":"50342_CR18","doi-asserted-by":"publisher","unstructured":"Lundberg, S.\u00a0M. et\u00a0al. Explainable ai for trees: From local explanations to global understanding. https:\/\/doi.org\/10.48550\/arXiv.1905.04610 (2019). arXiv:1905.04610.","DOI":"10.48550\/arXiv.1905.04610"},{"key":"50342_CR19","doi-asserted-by":"crossref","unstructured":"Shapley, L.\u00a0S. A value for n-person games. In Contributions to the Theory of Games (AM-28), Volume II (1953).","DOI":"10.1515\/9781400881970-018"},{"key":"50342_CR20","doi-asserted-by":"publisher","first-page":"1239","DOI":"10.1214\/12-EJS710","volume":"6","author":"F Huettner","year":"2012","unstructured":"Huettner, F. & Sunder, M. Axiomatic arguments for decomposing goodness of fit according to Shapley and Owen values. Electron. J. Stat. 6, 1239\u20131250. https:\/\/doi.org\/10.1214\/12-EJS710 (2012).","journal-title":"Electron. J. Stat."},{"key":"50342_CR21","doi-asserted-by":"publisher","unstructured":"Lundberg, S.\u00a0M., Erion, G.\u00a0G. & Lee, S.-I. Consistent individualized feature attribution for tree ensembles. https:\/\/doi.org\/10.48550\/ARXIV.1802.03888 (2018).","DOI":"10.48550\/ARXIV.1802.03888"},{"key":"50342_CR22","first-page":"2825","volume":"12","author":"F Pedregosa","year":"2011","unstructured":"Pedregosa, F. et al. Scikit-learn: Machine learning in Python. J. Mach. Learn. Res. 12, 2825\u20132830 (2011).","journal-title":"J. Mach. Learn. Res."},{"key":"50342_CR23","doi-asserted-by":"publisher","first-page":"5052","DOI":"10.1167\/iovs.11-9022","volume":"53","author":"S Srinivasan","year":"2012","unstructured":"Srinivasan, S., Thangavelu, M., Zhang, L., Green, K. B. & Nichols, K. K. iTRAQ quantitative proteomics in the analysis of tears in dry eye patients. Investig. Ophthalmol. Vis. Sci. 53, 5052\u20135059. https:\/\/doi.org\/10.1167\/iovs.11-9022 (2012).","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"50342_CR24","doi-asserted-by":"publisher","first-page":"2469","DOI":"10.1002\/pmic.201200230","volume":"13","author":"L Zhou","year":"2013","unstructured":"Zhou, L. et al. Proteomic analysis revealed the altered tear protein profile in a rabbit model of Sj\u00f6gren\u2019s syndrome-associated dry eye. Proteomics 13, 2469\u20132481. https:\/\/doi.org\/10.1002\/pmic.201200230 (2013).","journal-title":"Proteomics"},{"key":"50342_CR25","doi-asserted-by":"publisher","first-page":"3370","DOI":"10.1002\/pmic.201400239","volume":"15","author":"N Perumal","year":"2015","unstructured":"Perumal, N., Funke, S., Wolters, D., Pfeiffer, N. & Grus, F. H. Characterization of human reflex tear proteome reveals high expression of lacrimal proline-rich protein 4 (prr4). Proteomics 15, 3370\u20133381. https:\/\/doi.org\/10.1002\/pmic.201400239 (2015).","journal-title":"Proteomics"},{"key":"50342_CR26","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1371\/journal.pone.0200702","volume":"13","author":"Z Huang","year":"2018","unstructured":"Huang, Z., Du, C.-X. & Pan, X.-D. The use of in-strip digestion for fast proteomic analysis on tear fluid from dry eye patients. PLoS ONE 13, 1\u201312. https:\/\/doi.org\/10.1371\/journal.pone.0200702 (2018).","journal-title":"PLoS ONE"},{"key":"50342_CR27","doi-asserted-by":"publisher","first-page":"1764","DOI":"10.3390\/ijms18081764","volume":"18","author":"M Nebbioso","year":"2017","unstructured":"Nebbioso, M. et al. Analysis of the pathogenic factors and management of dry eye in ocular surface disorders. Int. J. Mol. Sci. 18, 1764. https:\/\/doi.org\/10.3390\/ijms18081764 (2017).","journal-title":"Int. J. Mol. Sci."},{"key":"50342_CR28","doi-asserted-by":"publisher","DOI":"10.3389\/fmed.2022.873483","author":"M Amorim","year":"2022","unstructured":"Amorim, M. et al. Putative biomarkers in tears for diabetic retinopathy diagnosis. Front. Med.https:\/\/doi.org\/10.3389\/fmed.2022.873483 (2022).","journal-title":"Front. Med."},{"key":"50342_CR29","doi-asserted-by":"publisher","first-page":"571","DOI":"10.1183\/09031936.01.00228801","volume":"18","author":"C Pilette","year":"2001","unstructured":"Pilette, C., Ouadrhiri, Y., Godding, V., Vaerman, J.-P. & Sibille, Y. Lung mucosal immunity: Immunoglobulin-A revisited. Eur. Respir. J. 18, 571\u2013588. https:\/\/doi.org\/10.1183\/09031936.01.00228801 (2001).","journal-title":"Eur. Respir. J."},{"key":"50342_CR30","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1016\/j.jare.2020.11.001","volume":"29","author":"Y-C Liu","year":"2021","unstructured":"Liu, Y.-C. et al. Comparison of tear proteomic and neuromediator profiles changes between small incision lenticule extraction (SMILE) and femtosecond laser-assisted in-situ keratomileusis (LASIK). J. Adv. Res. 29, 67\u201381. https:\/\/doi.org\/10.1016\/j.jare.2020.11.001 (2021).","journal-title":"J. Adv. Res."},{"key":"50342_CR31","doi-asserted-by":"publisher","first-page":"321","DOI":"10.1136\/bjo.68.5.321","volume":"68","author":"IA Mackie","year":"1984","unstructured":"Mackie, I. A. & Seal, D. V. Diagnostic implications of tear protein profiles. Br. J. Ophthalmol. 68, 321\u2013324. https:\/\/doi.org\/10.1136\/bjo.68.5.321 (1984).","journal-title":"Br. J. Ophthalmol."},{"key":"50342_CR32","doi-asserted-by":"publisher","first-page":"1651","DOI":"10.3390\/biom11111651","volume":"11","author":"L Latta","year":"2021","unstructured":"Latta, L. et al. Similarities in DSG1 and KRT3 downregulation through retinoic acid treatment and PAX6 knockdown related expression profiles: Does PAX6 affect RA signaling in limbal epithelial cells?. Biomolecules 11, 1651. https:\/\/doi.org\/10.3390\/biom11111651 (2021).","journal-title":"Biomolecules"},{"key":"50342_CR33","doi-asserted-by":"publisher","first-page":"4341","DOI":"10.1167\/iovs.13-11863","volume":"54","author":"J Ding","year":"2013","unstructured":"Ding, J., Kam, W. R., Dieckow, J. & Sullivan, D. A. The influence of 13-cis retinoic acid on human meibomian gland epithelial cells. Investig. Ophthalmol. Vis. Sci. 54, 4341\u20134350. https:\/\/doi.org\/10.1167\/iovs.13-11863 (2013).","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"50342_CR34","doi-asserted-by":"publisher","first-page":"4914","DOI":"10.1167\/iovs.10-6598","volume":"52","author":"F Garreis","year":"2011","unstructured":"Garreis, F. et al. Expression and regulation of antimicrobial peptide Psoriasin (S100A7) at the ocular surface and in the lacrimal apparatus. Investig. Ophthalmol. Vis. Sci. 52, 4914\u20134922. https:\/\/doi.org\/10.1167\/iovs.10-6598 (2011).","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"50342_CR35","doi-asserted-by":"publisher","first-page":"2727","DOI":"10.1167\/iovs.10-6482","volume":"52","author":"S Liu","year":"2011","unstructured":"Liu, S. et al. Changes in gene expression in human meibomian gland dysfunction. Investig. Ophthalmol. Vis. Sci. 52, 2727\u20132740. https:\/\/doi.org\/10.1167\/iovs.10-6482 (2011).","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"50342_CR36","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/ar3523","volume":"13","author":"C Baldini","year":"2011","unstructured":"Baldini, C. et al. Proteomic analysis of saliva: A unique tool to distinguish primary Sj\u00f6gren\u2019s syndrome from secondary Sj\u00f6gren\u2019s syndrome and other sicca syndromes. Arthritis Res. Ther. 13, 1\u201316. https:\/\/doi.org\/10.1186\/ar3523 (2011).","journal-title":"Arthritis Res. Ther."},{"key":"50342_CR37","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1016\/j.exer.2017.09.005","volume":"165","author":"H Nezzar","year":"2017","unstructured":"Nezzar, H. et al. Investigation of antioxidant systems in human meibomian gland and conjunctival tissues. Exp. Eye Res. 165, 99\u2013104. https:\/\/doi.org\/10.1016\/j.exer.2017.09.005 (2017).","journal-title":"Exp. Eye Res."},{"key":"50342_CR38","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1371\/journal.pone.0126561","volume":"10","author":"R Deng","year":"2015","unstructured":"Deng, R. et al. Oxidative stress markers induced by hyperosmolarity in primary human corneal epithelial cells. PLoS ONE 10, 1\u201316. https:\/\/doi.org\/10.1371\/journal.pone.0126561 (2015).","journal-title":"PLoS ONE"},{"key":"50342_CR39","first-page":"1477","volume":"23","author":"J \u010cejkov\u00e1","year":"2008","unstructured":"\u010cejkov\u00e1, J. et al. Decreased expression of antioxidant enzymes in the conjunctival epithelium of dry eye (Sj\u00f6gren\u2019s syndrome) and its possible contribution to the development of ocular surface oxidative injuries. Histol. Histopathol. 23, 1477\u20131483 (2008).","journal-title":"Histol. Histopathol."},{"key":"50342_CR40","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1016\/j.exer.2005.11.009","volume":"83","author":"K Wu","year":"2006","unstructured":"Wu, K. et al. Molecular mechanisms of lacrimal acinar secretory vesicle exocytosis. Exp. Eye Res. 83, 84\u201396. https:\/\/doi.org\/10.1016\/j.exer.2005.11.009 (2006).","journal-title":"Exp. Eye Res."},{"key":"50342_CR41","doi-asserted-by":"publisher","first-page":"294","DOI":"10.1038\/s41419-023-05821-0","volume":"14","author":"A Baris","year":"2023","unstructured":"Baris, A., Fraile-Bethencourt, E., Eubanks, J., Khou, S. & Anand, S. Thymidine phosphorylase facilitates retinoic acid inducible gene-I induced endothelial dysfunction. Cell Death Dis. 14, 294. https:\/\/doi.org\/10.1038\/s41419-023-05821-0 (2023).","journal-title":"Cell Death Dis."},{"key":"50342_CR42","doi-asserted-by":"publisher","first-page":"775","DOI":"10.1016\/j.nmd.2005.07.008","volume":"15","author":"A Bl\u00e1zquez","year":"2005","unstructured":"Bl\u00e1zquez, A. et al. Increased muscle nucleoside levels associated with a novel frameshift mutation in the thymidine phosphorylase gene in a Spanish patient with MNGIE. Neuromuscul. Disord. 15, 775\u2013778. https:\/\/doi.org\/10.1016\/j.nmd.2005.07.008 (2005).","journal-title":"Neuromuscul. Disord."},{"key":"50342_CR43","first-page":"2002","volume":"55","author":"N Perumal","year":"2014","unstructured":"Perumal, N., Funke, S., Wolters, D., Pfeiffer, N. & Grus, F. H. In-depth protein profiling and identification of tear fluid biomarkers in different subgroups of dry eye disease: Proline-rich protein 4 (prr4) as a potential biomarker for aqueous-deficient dry eye syndrome. Investig. Ophthalmol. Vis. Sci. 55, 2002 (2014).","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"50342_CR44","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2021.717730","author":"X Wang","year":"2021","unstructured":"Wang, X. et al. Prostaglandin reductase 1 as a potential therapeutic target for cancer therapy. Front. Pharmacol.https:\/\/doi.org\/10.3389\/fphar.2021.717730 (2021).","journal-title":"Front. Pharmacol."},{"key":"50342_CR45","first-page":"1","volume":"18","author":"OAA La","year":"2001","unstructured":"La, O. A. A. & Brock, J. H. Iron and transferrin. Research and therapeutic applications. Biotecnol. Apl. 18, 1\u20139 (2001).","journal-title":"Biotecnol. Apl."},{"key":"50342_CR46","doi-asserted-by":"publisher","DOI":"10.1186\/s12014-019-9233-5","author":"J N\u00e4ttinen","year":"2019","unstructured":"N\u00e4ttinen, J. et al. Age-associated changes in human tear proteome. Clin. Proteom.https:\/\/doi.org\/10.1186\/s12014-019-9233-5 (2019).","journal-title":"Clin. Proteom."},{"key":"50342_CR47","unstructured":"National Library of Medicine. ADH7 alcohol dehydrogenase 7 (class IV), mu or sigma polypeptide [Homo sapiens (human)], accessed 02 June 2023; https:\/\/www.ncbi.nlm.nih.gov\/gene?Db=gene &Cmd=DetailsSearch &Term=131#gene-expression (2023)."},{"key":"50342_CR48","doi-asserted-by":"publisher","first-page":"362","DOI":"10.1016\/S0014-5793(98)00374-3","volume":"426","author":"A Allali-Hassani","year":"1998","unstructured":"Allali-Hassani, A., Peralba, J. M., Martras, S., Farr\u00e9s, J. & Par\u00e9s, X. Retinoids, $$\\omega$$-hydroxyfatty acids and cytotoxic aldehydes as physiological substrates, and H2-receptor antagonists as pharmacological inhibitors, of human class IV alcohol dehydrogenase. FEBS Lett. 426, 362\u2013366. https:\/\/doi.org\/10.1016\/S0014-5793(98)00374-3 (1998).","journal-title":"FEBS Lett."},{"key":"50342_CR49","doi-asserted-by":"publisher","first-page":"300","DOI":"10.1136\/bjophthalmol-2015-307415","volume":"100","author":"C Baudouin","year":"2016","unstructured":"Baudouin, C. et al. Revisiting the vicious circle of dry eye disease: A focus on the pathophysiology of meibomian gland dysfunction. Br. J. Ophthalmol. 100, 300\u2013306. https:\/\/doi.org\/10.1136\/bjophthalmol-2015-307415 (2016).","journal-title":"Br. J. Ophthalmol."},{"key":"50342_CR50","doi-asserted-by":"publisher","DOI":"10.3390\/ijms23094918","author":"T Kishimoto","year":"2022","unstructured":"Kishimoto, T., Ishida, W., Nakajima, I., Fukuda, K. & Yamashiro, K. Aqueous-deficient dry eye exacerbates signs and symptoms of allergic conjunctivitis in mice. Int. J. Mol. Sci.https:\/\/doi.org\/10.3390\/ijms23094918 (2022).","journal-title":"Int. J. Mol. Sci."},{"key":"50342_CR51","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":"50342_CR52","doi-asserted-by":"publisher","first-page":"DES163","DOI":"10.1167\/iovs.17-23402","volume":"59","author":"M Dogru","year":"2018","unstructured":"Dogru, M., Kojima, T., Simsek, C. & Tsubota, K. Potential role of oxidative stress in ocular surface inflammation and dry eye disease. Investig. Ophthalmol. Vis. Sci. 59, DES163\u2013DES168. https:\/\/doi.org\/10.1167\/iovs.17-23402 (2018).","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"50342_CR53","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1006\/clin.1996.0050","volume":"79","author":"CP Robinson","year":"1996","unstructured":"Robinson, C. P., Yamamoto, H., Peck, A. B. & Humphreys-Beher, M. G. Genetically programmed development of salivary gland abnormalities in the nod (nonobese diabetic)-scidmouse in the absence of detectable lymphocytic infiltration: A potential trigger for sialoadenitis of nod mice. Clin. Immunol. Immunopathol. 79, 50\u201359. https:\/\/doi.org\/10.1006\/clin.1996.0050 (1996).","journal-title":"Clin. Immunol. Immunopathol."},{"key":"50342_CR54","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1016\/j.exer.2005.04.019","volume":"82","author":"SR da Costa","year":"2006","unstructured":"da Costa, S. R. et al. Male NOD mouse external lacrimal glands exhibit profound changes in the exocytotic pathway early in postnatal development. Exp. Eye Res. 82, 33\u201345. https:\/\/doi.org\/10.1016\/j.exer.2005.04.019 (2006).","journal-title":"Exp. Eye Res."},{"key":"50342_CR55","doi-asserted-by":"publisher","first-page":"399","DOI":"10.1038\/nrrheum.2012.53","volume":"8","author":"M Ramos-Casals","year":"2012","unstructured":"Ramos-Casals, M., Brito-Zeron, P., Siso-Almirall, A., Bosch, X. & Tzioufas, A. G. Topical and systemic medications for the treatment of primary Sj\u00f6gren\u2019s syndrome. Nat. Rev. Rheumatol. 8, 399\u2013411. https:\/\/doi.org\/10.1038\/nrrheum.2012.53 (2012).","journal-title":"Nat. Rev. Rheumatol."},{"key":"50342_CR56","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1159\/000487487","volume":"59","author":"DA Sullivan","year":"2018","unstructured":"Sullivan, D. A. et al. Meibomian gland dysfunction in primary and secondary Sj\u00f6gren syndrome. Ophthalmic Res. 59, 193\u2013205. https:\/\/doi.org\/10.1159\/000487487 (2018).","journal-title":"Ophthalmic Res."},{"key":"50342_CR57","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s13075-017-1228-x","volume":"19","author":"LA Aqrawi","year":"2017","unstructured":"Aqrawi, L. A. et al. Identification of potential saliva and tear biomarkers in primary Sj\u00f6gren\u2019s syndrome, utilising the extraction of extracellular vesicles and proteomics analysis. Arthritis Res. Ther. 19, 1\u201315. https:\/\/doi.org\/10.1186\/s13075-017-1228-x (2017).","journal-title":"Arthritis Res. Ther."},{"key":"50342_CR58","doi-asserted-by":"publisher","unstructured":"Hubinger, E. An overview of 11 proposals for building safe advanced AI. https:\/\/doi.org\/10.48550\/arXiv.2012.07532 (2020). arXiv:2012.07532.","DOI":"10.48550\/arXiv.2012.07532"},{"key":"#cr-split#-50342_CR59.1","unstructured":"Hubinger, E. Chris Olah's views on AGI safety, accessed 18 October 2023"},{"key":"#cr-split#-50342_CR59.2","unstructured":"https:\/\/www.alignmentforum.org\/posts\/X2i9dQQK3gETCyqh2\/chris-olah-s-views-on-agi-safety (2019)."},{"key":"50342_CR60","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22168997","author":"F Fineide","year":"2021","unstructured":"Fineide, F. et al. Characterization of lipids in saliva, tears and minor salivary glands of Sj\u00f6gren\u2019s syndrome patients using an HPLC\/MS-based approach. Int. J. Mol. Sci.https:\/\/doi.org\/10.3390\/ijms22168997 (2021).","journal-title":"Int. J. Mol. Sci."},{"key":"50342_CR61","doi-asserted-by":"publisher","first-page":"863","DOI":"10.1167\/iovs.04-0448","volume":"46","author":"FH Grus","year":"2005","unstructured":"Grus, F. H. et al. SELDI-TOF-MS ProteinChip array profiling of tears from patients with dry eye. Investig. Ophthalmol. Vis. Sci. 46, 863\u2013876. https:\/\/doi.org\/10.1167\/iovs.04-0448 (2005).","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"50342_CR62","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1016\/j.aanat.2012.10.001","volume":"195","author":"A Posa","year":"2013","unstructured":"Posa, A. et al. Schirmer strip vs. capillary tube method: Non-invasive methods of obtaining proteins from tear fluid. Ann. Anat. Anat. Anz. 195, 137\u2013142. https:\/\/doi.org\/10.1016\/j.aanat.2012.10.001 (2013).","journal-title":"Ann. Anat. Anat. Anz."},{"key":"50342_CR63","first-page":"456","volume":"14","author":"KB Green-Church","year":"2008","unstructured":"Green-Church, K. B., Nichols, K. K., Kleinholz, N. M., Zhang, L. & Nichols, J. J. Investigation of the human tear film proteome using multiple proteomic approaches. Mol. Vis. 14, 456\u2013470 (2008).","journal-title":"Mol. Vis."},{"key":"50342_CR64","doi-asserted-by":"publisher","first-page":"276","DOI":"10.1016\/j.jtos.2017.05.008","volume":"15","author":"JP Craig","year":"2017","unstructured":"Craig, J. P. et al. TFOS DEWS II definition and classification report. Ocul. Surf. 15, 276\u2013283. https:\/\/doi.org\/10.1016\/j.jtos.2017.05.008 (2017) (TFOS International Dry Eye WorkShop (DEWS II)).","journal-title":"Ocul. Surf."},{"key":"50342_CR65","doi-asserted-by":"publisher","first-page":"366","DOI":"10.1016\/j.jtos.2017.03.006","volume":"15","author":"MD Willcox","year":"2017","unstructured":"Willcox, M. D. et al. TFOS DEWS II tear film report. Ocul. Surf. 15, 366\u2013403. https:\/\/doi.org\/10.1016\/j.jtos.2017.03.006 (2017) (TFOS International Dry Eye WorkShop (DEWS II)).","journal-title":"Ocul. Surf."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-023-50342-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-023-50342-7","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-023-50342-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,12,22]],"date-time":"2023-12-22T08:11:28Z","timestamp":1703232688000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-023-50342-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,12,22]]},"references-count":66,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2023,12]]}},"alternative-id":["50342"],"URL":"https:\/\/doi.org\/10.1038\/s41598-023-50342-7","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,12,22]]},"assertion":[{"value":"14 July 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 December 2023","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 December 2023","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"TPU is co-founder and co-owner of The Norwegian dry eye clinic and the Clinic of eye health, Oslo, Norway, which delivers talks for and\/or receives financial support from the following: ABIGO, Alcon, Allergan, AMWO, Bausch & Lomb, Bayer, European school for advanced studies in ophthalmology, InnZ Medical, Medilens Nordic, Medistim, Novartis, Santen, Specsavers, Shire Pharmaceuticals and Thea Laboratories. He has served on the global scientific advisory board for Novartis and Alcon as well as the European advisory board for Shire Pharmaceuticals. Utheim is the Norwegian Global Ambassador for Tear Film and Ocular Surface Society (TFOS), a Board Member of the International Ocular Surface Society, an International Member of the Japanese Lid and Meibomian gland working group (LIME), a Consultant at the Norwegian Association for the Blind and Partially Sighted, the President of the Oslo Society of ophthalmology, and the Editor-in-Chief of Oftalmolog, an eye journal distributed to all eye doctors in the Nordic region since 1980. Besides publishing articles of presumed interest to our readers, Oftalmolog publishes advertisements from pharmaceutical companies, companies selling ophthalmological equipment, and associations organizing conferences and events in ophthalmology. For more information, visit: oftalmolog.com. All other authors declare no financial or non-financial competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"22946"}}