{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,4]],"date-time":"2025-11-04T18:34:11Z","timestamp":1762281251966,"version":"build-2065373602"},"reference-count":41,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,11,4]],"date-time":"2025-11-04T00:00:00Z","timestamp":1762214400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"},{"start":{"date-parts":[[2025,11,4]],"date-time":"2025-11-04T00:00:00Z","timestamp":1762214400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"}],"funder":[{"name":"Roche Organ Transplant Research Foundation, Meggen, Switzerland","award":["61800655"],"award-info":[{"award-number":["61800655"]}]},{"DOI":"10.13039\/100000182","name":"US Army Medical Research and Materiel Command","doi-asserted-by":"crossref","award":["W81XWH-16-1-0520"],"award-info":[{"award-number":["W81XWH-16-1-0520"]}],"id":[{"id":"10.13039\/100000182","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Enduring Hearts, Marietta, GA"},{"name":"Additional Ventures, Palo Alto, CA"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"DOI":"10.1038\/s41598-025-21591-5","type":"journal-article","created":{"date-parts":[[2025,11,4]],"date-time":"2025-11-04T18:29:45Z","timestamp":1762280985000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Optimizing post brain death vascularized composite graft quality through ex vivo restoration of S-nitrosothiol homeostasis"],"prefix":"10.1038","volume":"15","author":[{"given":"Lin","family":"Zhu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryan","family":"Nazemian","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mohamed","family":"Awad","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicole R.","family":"Palmer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Edwin Pacheco","family":"Colon","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arshna","family":"Qureshi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew","family":"Moyal","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Doo Hee","family":"Kim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alfred","family":"Hausladen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonathan S.","family":"Stamler","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anand","family":"Kumar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5820-1639","authenticated-orcid":false,"given":"James D.","family":"Reynolds","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,11,4]]},"reference":[{"key":"21591_CR1","doi-asserted-by":"publisher","first-page":"343","DOI":"10.1038\/s41423-019-0215-3","volume":"16","author":"J Iske","year":"2019","unstructured":"Iske, J. et al. Composite tissue allotransplantation: opportunities and challenges. Cell. Mol. Immunol. 16, 343\u2013349. https:\/\/doi.org\/10.1038\/s41423-019-0215-3 (2019).","journal-title":"Cell. Mol. Immunol."},{"key":"21591_CR2","doi-asserted-by":"publisher","first-page":"291","DOI":"10.1111\/ajt.16086","volume":"21","author":"HC Lewis","year":"2021","unstructured":"Lewis, H. C. & Cendales, L. C. Vascularized composite allotransplantation in the United States: A retrospective analysis of the Organ Procurement and Transplantation Network data after 5 years of the Final Rule. Am J Transplant 21, 291\u2013296. https:\/\/doi.org\/10.1111\/ajt.16086 (2021).","journal-title":"Am J Transplant"},{"key":"21591_CR3","doi-asserted-by":"crossref","unstructured":"Siemionow, M. Z. & Zor, F. in Plastic Surgery - Principles and Practice (eds Rostam D. Farhadieh, Neil W. Bulstrode, Babak J. Mehrara, & Sabrina Cugno) 131\u2013145 (Elsevier, 2022).","DOI":"10.1016\/B978-0-323-65381-7.00011-3"},{"key":"21591_CR4","doi-asserted-by":"publisher","unstructured":"Hernandez, J. A. et al. OPTN\/SRTR 2021 Annual Data Report: Vascularized Composite Allograft. Am J Transplant 23, S523-S545 (2023). https:\/\/doi.org\/10.1016\/j.ajt.2023.02.012","DOI":"10.1016\/j.ajt.2023.02.012"},{"key":"21591_CR5","doi-asserted-by":"crossref","unstructured":"Wilks, D. & Kay, S. Vascularized composite allotransplantation. Oxford Textbook of Plastic and Reconstructive Surgery, 105 (2020).","DOI":"10.1093\/med\/9780199682874.003.0015"},{"key":"21591_CR6","doi-asserted-by":"publisher","unstructured":"Zhang, L. et al. Challenges and opportunities in vascularized composite allotransplantation of joints: a systematic literature review. Frontiers in Immunology 14 (2023). https:\/\/doi.org\/10.3389\/fimmu.2023.1179195","DOI":"10.3389\/fimmu.2023.1179195"},{"key":"21591_CR7","doi-asserted-by":"publisher","first-page":"971","DOI":"10.1097\/SLA.0b013e3182822c52","volume":"257","author":"BM Yurcisin","year":"2013","unstructured":"Yurcisin, B. M. et al. Repletion of S-nitrosohemoglobin improves organ function and physiological status in swine after brain death. Ann Surg 257, 971\u2013977. https:\/\/doi.org\/10.1097\/SLA.0b013e3182822c52 (2013).","journal-title":"Ann Surg"},{"key":"21591_CR8","doi-asserted-by":"publisher","first-page":"6639","DOI":"10.1038\/s41598-022-09933-z","volume":"12","author":"R Nazemian","year":"2022","unstructured":"Nazemian, R. et al. S-Nitrosylated hemoglobin predicts organ yield in neurologically-deceased human donors. Sci Rep 12, 6639. https:\/\/doi.org\/10.1038\/s41598-022-09933-z (2022).","journal-title":"Sci Rep"},{"key":"21591_CR9","doi-asserted-by":"publisher","first-page":"3203","DOI":"10.1073\/pnas.74.8.3203","volume":"74","author":"WP Arnold","year":"1977","unstructured":"Arnold, W. P., Mittal, C. K., Katsuki, S. & Murad, F. Nitric oxide activates guanylate cyclase and increases guanosine 3\u2032: 5\u2032-cyclic monophosphate levels in various tissue preparations. Proc. Natl. Acad. Sci. 74, 3203\u20133207 (1977).","journal-title":"Proc. Natl. Acad. Sci."},{"key":"21591_CR10","doi-asserted-by":"crossref","unstructured":"Denninger, J. W. & Marletta, M. A. Guanylate cyclase and the\u22c5 NO\/cGMP signaling pathway. Biochimica et Biophysica Acta (BBA)-Bioenergetics 1411, 334\u2013350 (1999).","DOI":"10.1016\/S0005-2728(99)00024-9"},{"key":"21591_CR11","doi-asserted-by":"publisher","first-page":"1331","DOI":"10.1089\/ars.2017.7403","volume":"30","author":"CT Stomberski","year":"2019","unstructured":"Stomberski, C. T., Hess, D. T. & Stamler, J. S. Protein S-nitrosylation: determinants of specificity and enzymatic regulation of S-nitrosothiol-based signaling. Antioxid. Redox Signal. 30, 1331\u20131351 (2019).","journal-title":"Antioxid. Redox Signal."},{"key":"21591_CR12","doi-asserted-by":"publisher","unstructured":"Zhou, H.-L. et al. An enzyme that selectively S-nitrosylates proteins to regulate insulin signaling. Cell 186, 5812\u20135825.e5821 (2023). https:\/\/doi.org\/10.1016\/j.cell.2023.11.009","DOI":"10.1016\/j.cell.2023.11.009"},{"key":"21591_CR13","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1161\/CIRCRESAHA.119.315626","volume":"126","author":"RT Premont","year":"2020","unstructured":"Premont, R. T., Reynolds, J. D., Zhang, R. & Stamler, J. S. Role of nitric oxide carried by hemoglobin in cardiovascular physiology: developments on a three-gas respiratory cycle. Circ. Res. 126, 129\u2013158 (2020).","journal-title":"Circ. Res."},{"key":"21591_CR14","doi-asserted-by":"publisher","unstructured":"Premont, R. T., Singel, D. J. & Stamler, J. S. The enzymatic function of the honorary enzyme: S-nitrosylation of hemoglobin in physiology and medicine. Molecular Aspects of Medicine 84, 101056 (2022). https:\/\/doi.org\/10.1016\/j.mam.2021.101056","DOI":"10.1016\/j.mam.2021.101056"},{"key":"21591_CR15","doi-asserted-by":"publisher","first-page":"601","DOI":"10.1177\/0310057X1804600611","volume":"46","author":"S Perez-Protto","year":"2018","unstructured":"Perez-Protto, S. et al. Peripheral tissue oxygenation and the number of organs transplanted per donor. Anaesth. Intensive Care 46, 601\u2013607 (2018).","journal-title":"Anaesth. Intensive Care"},{"key":"21591_CR16","doi-asserted-by":"crossref","unstructured":"Lyn H \u00e1Williams, D. S-Nitrosation and the reactions of S-nitroso compounds. Chemical Society Reviews 14, 171\u2013196 (1985).","DOI":"10.1039\/cs9851400171"},{"key":"21591_CR17","doi-asserted-by":"publisher","unstructured":"Patel, H. M. S. & Williams, D. L. H. Nitrosation by alkyl nitrites. Part 6. Thiolate nitrosation. Journal of the Chemical Society, Perkin Transactions 2, 37\u201342 (1990). https:\/\/doi.org\/10.1039\/P29900000037","DOI":"10.1039\/P29900000037"},{"key":"21591_CR18","doi-asserted-by":"publisher","unstructured":"Moya, M. P. et al. <i>S<\/i>-nitrosothiol repletion by an inhaled gas regulates pulmonary function. Proceedings of the National Academy of Sciences 98, 5792\u20135797 (2001). https:\/\/doi.org\/10.1073\/pnas.091109498","DOI":"10.1073\/pnas.091109498"},{"key":"21591_CR19","doi-asserted-by":"publisher","first-page":"711","DOI":"10.1038\/nm718","volume":"8","author":"TJ McMahon","year":"2002","unstructured":"McMahon, T. J. et al. Nitric oxide in the human respiratory cycle. Nat. Med. 8, 711\u2013717. https:\/\/doi.org\/10.1038\/nm718 (2002).","journal-title":"Nat. Med."},{"key":"21591_CR20","doi-asserted-by":"publisher","unstructured":"Reynolds, J. D. et al. S-nitrosylation therapy to improve oxygen delivery of banked blood. Proceedings of the National Academy of Sciences 110, 11529\u201311534 (2013). https:\/\/doi.org\/10.1073\/pnas.1306489110","DOI":"10.1073\/pnas.1306489110"},{"key":"21591_CR21","doi-asserted-by":"publisher","first-page":"3786","DOI":"10.1021\/ja01111a054","volume":"75","author":"AM Fairlie Jr","year":"1953","unstructured":"Fairlie, A. M. Jr., Carberry, J. J. & Treacy, J. C. A Study of the Kinetics of the Reaction between Nitrogen Dioxide and Alcohols. J. Am. Chem. Soc. 75, 3786\u20133789. https:\/\/doi.org\/10.1021\/ja01111a054 (1953).","journal-title":"J. Am. Chem. Soc."},{"key":"21591_CR22","doi-asserted-by":"publisher","first-page":"1780","DOI":"10.1021\/ja01590a002","volume":"78","author":"JB Levy","year":"1956","unstructured":"Levy, J. B. The Thermal Decomposition of Ethyl Nitrite 1,2. J. Am. Chem. Soc. 78, 1780\u20131783. https:\/\/doi.org\/10.1021\/ja01590a002 (1956).","journal-title":"J. Am. Chem. Soc."},{"key":"21591_CR23","doi-asserted-by":"publisher","unstructured":"Reynolds, J. D. et al. Pharmacologic Targeting of Red Blood Cells to Improve Tissue Oxygenation. Clinical Pharmacology & Therapeutics 104, 553\u2013563 (2018). https:\/\/doi.org\/10.1002\/cpt.979","DOI":"10.1002\/cpt.979"},{"key":"21591_CR24","doi-asserted-by":"publisher","first-page":"e610","DOI":"10.1097\/sla.0000000000003702","volume":"274","author":"L Zhu","year":"2021","unstructured":"Zhu, L. et al. A Novel Method to Improve Perfusion of Ex Vivo Pumped Human Kidneys. Ann Surg 274, e610\u2013e615. https:\/\/doi.org\/10.1097\/sla.0000000000003702 (2021).","journal-title":"Ann Surg"},{"key":"21591_CR25","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1101\/gad.12.2.149","volume":"12","author":"NV Iyer","year":"1998","unstructured":"Iyer, N. V. et al. Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1 alpha. Genes Dev. 12, 149\u2013162. https:\/\/doi.org\/10.1101\/gad.12.2.149 (1998).","journal-title":"Genes Dev."},{"issue":"88","key":"21591_CR26","doi-asserted-by":"publisher","first-page":"1474","DOI":"10.1152\/jappl.2000.88.4.1474","volume":"1985","author":"GL Semenza","year":"2000","unstructured":"Semenza, G. L. HIF-1: mediator of physiological and pathophysiological responses to hypoxia. J Appl Physiol 1985(88), 1474\u20131480. https:\/\/doi.org\/10.1152\/jappl.2000.88.4.1474 (2000).","journal-title":"J Appl Physiol"},{"key":"21591_CR27","doi-asserted-by":"publisher","first-page":"14801","DOI":"10.1073\/pnas.0506957102","volume":"102","author":"TJ McMahon","year":"2005","unstructured":"McMahon, T. J. et al. A nitric oxide processing defect of red blood cells created by hypoxia: deficiency of S-nitrosohemoglobin in pulmonary hypertension. Proc Natl Acad Sci U S A 102, 14801\u201314806. https:\/\/doi.org\/10.1073\/pnas.0506957102 (2005).","journal-title":"Proc Natl Acad Sci U S A"},{"key":"21591_CR28","doi-asserted-by":"publisher","first-page":"17058","DOI":"10.1073\/pnas.0707958104","volume":"104","author":"JD Reynolds","year":"2007","unstructured":"Reynolds, J. D. et al. S-nitrosohemoglobin deficiency: a mechanism for loss of physiological activity in banked blood. Proc Natl Acad Sci U S A 104, 17058\u201317062. https:\/\/doi.org\/10.1073\/pnas.0707958104 (2007).","journal-title":"Proc Natl Acad Sci U S A"},{"key":"21591_CR29","doi-asserted-by":"publisher","first-page":"2531","DOI":"10.1073\/pnas.0409876102","volume":"102","author":"JR Pawloski","year":"2005","unstructured":"Pawloski, J. R., Hess, D. T. & Stamler, J. S. Impaired vasodilation by red blood cells in sickle cell disease. Proc Natl Acad Sci U S A 102, 2531\u20132536. https:\/\/doi.org\/10.1073\/pnas.0409876102 (2005).","journal-title":"Proc Natl Acad Sci U S A"},{"key":"21591_CR30","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2220769120","volume":"120","author":"JD Reynolds","year":"2023","unstructured":"Reynolds, J. D. et al. Control of tissue oxygenation by S-nitrosohemoglobin in human subjects. Proc Natl Acad Sci U S A 120, e2220769120. https:\/\/doi.org\/10.1073\/pnas.2220769120 (2023).","journal-title":"Proc Natl Acad Sci U S A"},{"key":"21591_CR31","doi-asserted-by":"publisher","first-page":"4654","DOI":"10.1172\/JCI90425","volume":"126","author":"R Zhang","year":"2016","unstructured":"Zhang, R., Hess, D. T., Reynolds, J. D. & Stamler, J. S. Hemoglobin S-nitrosylation plays an essential role in cardioprotection. J. Clin. Investig. 126, 4654\u20134658. https:\/\/doi.org\/10.1172\/JCI90425 (2016).","journal-title":"J. Clin. Investig."},{"key":"21591_CR32","doi-asserted-by":"publisher","first-page":"852","DOI":"10.1111\/j.1537-2995.2011.03097.x","volume":"51","author":"JD Reynolds","year":"2011","unstructured":"Reynolds, J. D., Hess, D. T. & Stamler, J. S. The transfusion problem: role of aberrant S-nitrosylation. Transfusion 51, 852\u2013858. https:\/\/doi.org\/10.1111\/j.1537-2995.2011.03097.x (2011).","journal-title":"Transfusion"},{"key":"21591_CR33","doi-asserted-by":"publisher","first-page":"237","DOI":"10.1111\/cts.12530","volume":"11","author":"F Matto","year":"2018","unstructured":"Matto, F. et al. S-Nitrosohemoglobin Levels and Patient Outcome After Transfusion During Pediatric Bypass Surgery. Clin Transl Sci 11, 237\u2013243. https:\/\/doi.org\/10.1111\/cts.12530 (2018).","journal-title":"Clin Transl Sci"},{"key":"21591_CR34","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1111\/j.1752-8062.2009.00154.x","volume":"2","author":"K Shimazutsu","year":"2009","unstructured":"Shimazutsu, K. et al. Inclusion of a nitric oxide congener in the insufflation gas repletes S-nitrosohemoglobin and stabilizes physiologic status during prolonged carbon dioxide pneumoperitoneum. Clin Transl Sci 2, 405\u2013412. https:\/\/doi.org\/10.1111\/j.1752-8062.2009.00154.x (2009).","journal-title":"Clin Transl Sci"},{"key":"21591_CR35","doi-asserted-by":"publisher","first-page":"2425","DOI":"10.1097\/ms9.0000000000001880","volume":"86","author":"A Moyal","year":"2024","unstructured":"Moyal, A. et al. Renal dysfunction in adults following cardiopulmonary bypass is linked to declines in S-nitroso hemoglobin: a case series. Annals of Medicine and Surgery 86, 2425\u20132431. https:\/\/doi.org\/10.1097\/ms9.0000000000001880 (2024).","journal-title":"Annals of Medicine and Surgery"},{"key":"21591_CR36","doi-asserted-by":"publisher","unstructured":"Reynolds James, D. et al. Pharmacologic Targeting of Red Blood Cells to Improve Tissue Oxygenation. Clinical Pharmacology & Therapeutics 0 https:\/\/doi.org\/10.1002\/cpt.979","DOI":"10.1002\/cpt.979"},{"key":"21591_CR37","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.1000412","volume":"8","author":"C Kilkenny","year":"2010","unstructured":"Kilkenny, C., Browne, W. J., Cuthill, I. C., Emerson, M. & Altman, D. G. Improving Bioscience Research Reporting: The ARRIVE Guidelines for Reporting Animal Research. PLoS Biol. 8, e1000412. https:\/\/doi.org\/10.1371\/journal.pbio.1000412 (2010).","journal-title":"PLoS Biol."},{"key":"21591_CR38","doi-asserted-by":"crossref","unstructured":"Levey, A. S. et al. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med 130, 461\u2013470 (1999).","DOI":"10.7326\/0003-4819-130-6-199903160-00002"},{"key":"21591_CR39","doi-asserted-by":"publisher","first-page":"2157","DOI":"10.1073\/pnas.0611191104","volume":"104","author":"A Hausladen","year":"2007","unstructured":"Hausladen, A. et al. Assessment of nitric oxide signals by triiodide chemiluminescence. Proc Natl Acad Sci U S A 104, 2157\u20132162. https:\/\/doi.org\/10.1073\/pnas.0611191104 (2007).","journal-title":"Proc Natl Acad Sci U S A"},{"key":"21591_CR40","doi-asserted-by":"publisher","unstructured":"Liu, T. et al. Artifacts Introduced by Sample Handling in Chemiluminescence Assays of Nitric Oxide Metabolites. Antioxidants (Basel) 12 (2023). https:\/\/doi.org\/10.3390\/antiox12091672","DOI":"10.3390\/antiox12091672"},{"key":"21591_CR41","doi-asserted-by":"publisher","first-page":"676","DOI":"10.1038\/nmeth.2019","volume":"9","author":"J Schindelin","year":"2012","unstructured":"Schindelin, J. et al. Fiji: an open-source platform for biological-image analysis. Nat. Methods 9, 676\u2013682. https:\/\/doi.org\/10.1038\/nmeth.2019 (2012).","journal-title":"Nat. Methods"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-21591-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-21591-5","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-21591-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,4]],"date-time":"2025-11-04T18:29:47Z","timestamp":1762280987000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-21591-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,4]]},"references-count":41,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["21591"],"URL":"https:\/\/doi.org\/10.1038\/s41598-025-21591-5","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,4]]},"assertion":[{"value":"27 February 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 September 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 November 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Drs. Reynolds and Stamler hold patents related to renitrosylation some of may be licensed for commercial development. Their institutions are aware of these conflicts and appropriate management plans are in place. None of the other authors have relevant conflicts to disclose.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"38539"}}