{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T02:05:52Z","timestamp":1787796352044,"version":"build-2784847793"},"reference-count":58,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2019,3,18]],"date-time":"2019-03-18T00:00:00Z","timestamp":1552867200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2019,3,18]],"date-time":"2019-03-18T00:00:00Z","timestamp":1552867200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["NRF-2017R1A2B4003890"],"award-info":[{"award-number":["NRF-2017R1A2B4003890"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["NRF-2017R1A2B4003890"],"award-info":[{"award-number":["NRF-2017R1A2B4003890"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["NRF-2017R1A2B4003890"],"award-info":[{"award-number":["NRF-2017R1A2B4003890"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["NRF-2017R1A2B4003890"],"award-info":[{"award-number":["NRF-2017R1A2B4003890"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Green Cross Corporation, Republic of Korea"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Hantavax is an inactivated vaccine for hemorrhagic fever with renal syndrome (HFRS). The immunogenic responses have not been elucidated yet. Here we conducted a cohort study in which 20 healthy subjects were administered four doses of Hantavax during 13-months period. Pre- and post- vaccinated peripheral blood mononuclear cells (PBMCs) and sera were analysed by transcriptomic and metabolomic profilings, respectively. Based on neutralizing antibody titers, subjects were subsequently classified into three groups; non responders (NRs), low responders (LRs) and high responders (HRs). Post vaccination differentially expressed genes (DEGs) associated with innate immunity and cytokine pathways were highly upregulated. DEG analysis revealed a significant induction of CD69 expression in the HRs. High resolution metabolomics (HRM) analysis showed that correlated to the antibody response, cholesteryl nitrolinoleate, octanoyl-carnitine, tyrosine, ubiquinone-9, and benzoate were significantly elevated in HRs, while chenodeoxycholic acid and methyl palmitate were upregulated in NRs and LRs, compared with HRs. Additionally, gene-metabolite interaction revealed upregulated gene-metabolite couplings in, folate biosynthesis, nicotinate and nicotinamide, arachidonic acid, thiamine and pyrimidine metabolism in a dose dependent manner in HR group. Collectively, our data provide new insight into the underlying mechanisms of the Hantavax-mediated immunogenicity in humans.<\/jats:p>","DOI":"10.1038\/s41598-019-41205-1","type":"journal-article","created":{"date-parts":[[2019,3,19]],"date-time":"2019-03-19T18:46:13Z","timestamp":1553021173000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["A Systems Vaccinology Approach Reveals the Mechanisms of Immunogenic Responses to Hantavax Vaccination in Humans"],"prefix":"10.1038","volume":"9","author":[{"given":"Adnan","family":"Khan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ok Sarah","family":"Shin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinhyuk","family":"Na","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jae Kwan","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rak-Kyun","family":"Seong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Man-Seong","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji Yun","family":"Noh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joon Young","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hee Jin","family":"Cheong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4348-2217","authenticated-orcid":false,"given":"Youngja Hwang","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4546-3880","authenticated-orcid":false,"given":"Woo Joo","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,3,18]]},"reference":[{"key":"41205_CR1","doi-asserted-by":"publisher","first-page":"116","DOI":"10.1038\/ni.1688","volume":"10","author":"TD Querec","year":"2009","unstructured":"Querec, T. D. et al. Systems biology approach predicts immunogenicity of the yellow fever vaccine in humans. Nat Immunol 10, 116\u2013125, https:\/\/doi.org\/10.1038\/ni.1688 (2009).","journal-title":"Nat Immunol"},{"key":"41205_CR2","doi-asserted-by":"publisher","first-page":"5294","DOI":"10.1016\/j.vaccine.2015.03.072","volume":"33","author":"T Hagan","year":"2015","unstructured":"Hagan, T., Nakaya, H. I., Subramaniam, S. & Pulendran, B. Systems vaccinology: Enabling rational vaccine design with systems biological approaches. Vaccine 33, 5294\u20135301, https:\/\/doi.org\/10.1016\/j.vaccine.2015.03.072 (2015).","journal-title":"Vaccine"},{"key":"41205_CR3","doi-asserted-by":"publisher","first-page":"2425","DOI":"10.1073\/pnas.1621489114","volume":"114","author":"D Kazmin","year":"2017","unstructured":"Kazmin, D. et al. Systems analysis of protective immune responses to RTS,S malaria vaccination in humans. Proc Natl Acad Sci USA 114, 2425\u20132430, https:\/\/doi.org\/10.1073\/pnas.1621489114 (2017).","journal-title":"Proc Natl Acad Sci USA"},{"key":"41205_CR4","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1097\/COH.0b013e32834dc37b","volume":"7","author":"HI Nakaya","year":"2012","unstructured":"Nakaya, H. I. & Pulendran, B. Systems vaccinology: its promise and challenge for HIV vaccine development. Curr Opin. HIV AIDS 7, 24\u201331, https:\/\/doi.org\/10.1097\/COH.0b013e32834dc37b (2012).","journal-title":"HIV AIDS"},{"key":"41205_CR5","doi-asserted-by":"publisher","first-page":"551","DOI":"10.1016\/j.coi.2013.09.014","volume":"25","author":"M Mooney","year":"2013","unstructured":"Mooney, M., McWeeney, S., Canderan, G. & Sekaly, R. P. A systems framework for vaccine design. Curr Opin Immunol 25, 551\u2013555 (2013).","journal-title":"Curr Opin Immunol"},{"key":"41205_CR6","doi-asserted-by":"publisher","first-page":"5241","DOI":"10.1016\/j.vaccine.2015.05.098","volume":"33","author":"DE Zak","year":"2015","unstructured":"Zak, D. E. & Aderem, A. Systems integration of innate and adaptive immunity. Vaccine 33, 5241\u20135248, https:\/\/doi.org\/10.1016\/j.vaccine.2015.05.098 (2015).","journal-title":"Vaccine"},{"key":"41205_CR7","doi-asserted-by":"publisher","first-page":"118","DOI":"10.1038\/ni.2787","volume":"15","author":"BA Kidd","year":"2014","unstructured":"Kidd, B. A., Peters, L. A., Schadt, E. E. & Dudley, J. T. Unifying immunology with informatics and multiscale biology. Nat Immunol 15, 118\u2013127, https:\/\/doi.org\/10.1038\/ni.2787 (2014).","journal-title":"Nat Immunol"},{"key":"41205_CR8","doi-asserted-by":"publisher","DOI":"10.1038\/srep16512","volume":"5","author":"SJ Park","year":"2015","unstructured":"Park, S. J. et al. Dynamic changes in host gene expression associated with H5N8 avian influenza virus infection in mice. Sci Rep 5, 16512, https:\/\/doi.org\/10.1038\/srep16512 (2015).","journal-title":"Sci Rep"},{"key":"41205_CR9","doi-asserted-by":"publisher","first-page":"862","DOI":"10.1016\/j.cell.2017.04.026","volume":"169","author":"S Li","year":"2017","unstructured":"Li, S. et al. Metabolic Phenotypes of Response to Vaccination in Humans. Cell 169, 862\u2013877 e817, https:\/\/doi.org\/10.1016\/j.cell.2017.04.026 (2017).","journal-title":"Cell"},{"key":"41205_CR10","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1016\/j.virusres.2013.12.038","volume":"187","author":"R Yanagihara","year":"2014","unstructured":"Yanagihara, R., Gu, S. H., Arai, S., Kang, H. J. & Song, J. W. Hantaviruses: rediscovery and new beginnings. Virus Res 187, 6\u201314, https:\/\/doi.org\/10.1016\/j.virusres.2013.12.038 (2014).","journal-title":"Virus Res"},{"key":"41205_CR11","doi-asserted-by":"publisher","first-page":"128","DOI":"10.1016\/j.jcv.2014.08.033","volume":"64","author":"DH Kruger","year":"2015","unstructured":"Kruger, D. H., Figueiredo, L. T., Song, J. W. & Klempa, B. Hantaviruses\u2013globally emerging pathogens. J Clin Virol 64, 128\u2013136, https:\/\/doi.org\/10.1016\/j.jcv.2014.08.033 (2015).","journal-title":"J Clin Virol"},{"key":"41205_CR12","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3389\/fcimb.2016.00001","volume":"6","author":"H Jiang","year":"2016","unstructured":"Jiang, H., Du, H., Wang, L. M., Wang, P. Z. & Bai, X. F. Hemorrhagic Fever with Renal Syndrome: Pathogenesis and Clinical Picture. Front Cell Infect Microbiol 6, 1, https:\/\/doi.org\/10.3389\/fcimb.2016.00001 (2016).","journal-title":"Front Cell Infect Microbiol"},{"key":"41205_CR13","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1016\/j.jcv.2013.06.027","volume":"58","author":"JY Noh","year":"2013","unstructured":"Noh, J. Y. et al. Clinical and molecular epidemiological features of hemorrhagic fever with renal syndrome in Korea over a 10-year period. J Clin Virol 58, 11\u201317, https:\/\/doi.org\/10.1016\/j.jcv.2013.06.027 (2013).","journal-title":"J Clin Virol"},{"key":"41205_CR14","doi-asserted-by":"publisher","first-page":"1289","DOI":"10.1016\/j.vaccine.2016.01.031","volume":"34","author":"JY Song","year":"2016","unstructured":"Song, J. Y. et al. Long-term immunogenicity and safety of inactivated Hantaan virus vaccine (Hantavax\u2122) in healthy adults. Vaccine 34, 1289\u20131295, https:\/\/doi.org\/10.1016\/j.vaccine.2016.01.031 (2016).","journal-title":"Vaccine"},{"key":"41205_CR15","doi-asserted-by":"publisher","first-page":"1289","DOI":"10.1016\/j.vaccine.2016.01.031","volume":"34","author":"JY Song","year":"2016","unstructured":"Song, J. Y. et al. Long-term immunogenicity and safety of inactivated Hantaan virus vaccine (Hantavax) in healthy adults. Vaccine 34, 1289\u20131295, https:\/\/doi.org\/10.1016\/j.vaccine.2016.01.031 (2016).","journal-title":"Vaccine"},{"key":"41205_CR16","doi-asserted-by":"publisher","DOI":"10.1186\/s12859-018-2053-1","volume":"19","author":"PST Russo","year":"2018","unstructured":"Russo, P. S. T. et al. CEMiTool: a Bioconductor package for performing comprehensive modular co-expression analyses. BMC Bioinformatics 19, 56, https:\/\/doi.org\/10.1186\/s12859-018-2053-1 (2018).","journal-title":"BMC Bioinformatics"},{"key":"41205_CR17","doi-asserted-by":"publisher","first-page":"3043","DOI":"10.1093\/bioinformatics\/bti476","volume":"21","author":"AK Smilde","year":"2005","unstructured":"Smilde, A. K. et al. ANOVA-simultaneous component analysis (ASCA): a new tool for analyzing designed metabolomics data. Bioinformatics 21, 3043\u20133048, https:\/\/doi.org\/10.1093\/bioinformatics\/bti476 (2005).","journal-title":"Bioinformatics"},{"key":"41205_CR18","doi-asserted-by":"publisher","first-page":"1792","DOI":"10.1093\/bioinformatics\/btm251","volume":"23","author":"MJ Nueda","year":"2007","unstructured":"Nueda, M. J. et al. Discovering gene expression patterns in time course microarray experiments by ANOVA-SCA. Bioinformatics 23, 1792\u20131800, https:\/\/doi.org\/10.1093\/bioinformatics\/btm251 (2007).","journal-title":"Bioinformatics"},{"key":"41205_CR19","doi-asserted-by":"publisher","first-page":"408","DOI":"10.1111\/eci.12609","volume":"46","author":"B Waagsbo","year":"2016","unstructured":"Waagsbo, B. et al. Low levels of short- and medium-chain acylcarnitines in HIV-infected patients. Eur J Clin Invest 46, 408\u2013417, https:\/\/doi.org\/10.1111\/eci.12609 (2016).","journal-title":"Eur J Clin Invest"},{"key":"41205_CR20","doi-asserted-by":"publisher","first-page":"460","DOI":"10.1089\/rej.2013.1459","volume":"16","author":"K Fukami","year":"2013","unstructured":"Fukami, K. et al. Potential Inhibitory Effects of l-Carnitine Supplementation on Tissue Advanced Glycation End Products in Patients with Hemodialysis. Rejuvenation Research 16, 460\u2013466, https:\/\/doi.org\/10.1089\/rej.2013.1459 (2013).","journal-title":"Rejuvenation Research"},{"key":"41205_CR21","doi-asserted-by":"publisher","first-page":"1840","DOI":"10.1002\/hep.510290617","volume":"29","author":"P Podevin","year":"1999","unstructured":"Podevin, P. et al. Bile acids modulate the interferon signalling pathway. Hepatology 29, 1840\u20131847, https:\/\/doi.org\/10.1002\/hep.510290617 (1999).","journal-title":"Hepatology"},{"key":"41205_CR22","doi-asserted-by":"publisher","first-page":"302","DOI":"10.1002\/jbt.20150","volume":"20","author":"S Sarkar","year":"2006","unstructured":"Sarkar, S., Khan, M. F., Kaphalia, B. S. & Ansari, G. A. Methyl palmitate inhibits lipopolysaccharide-stimulated phagocytic activity of rat peritoneal macrophages. J Biochem Mol Toxicol 20, 302\u2013308, https:\/\/doi.org\/10.1002\/jbt.20150 (2006).","journal-title":"J Biochem Mol Toxicol"},{"key":"41205_CR23","doi-asserted-by":"publisher","first-page":"939","DOI":"10.1152\/ajplegacy.1964.206.5.939","volume":"206","author":"NR Diluzio","year":"1964","unstructured":"Diluzio, N. R. & Wooles, W. R. Depression of phagocytic activity and immune response by methyl palmitate. Am J Physiol 206, 939\u2013943 (1964).","journal-title":"Am J Physiol"},{"key":"41205_CR24","doi-asserted-by":"publisher","first-page":"343","DOI":"10.1016\/j.coviro.2013.04.007","volume":"3","author":"D Falzarano","year":"2013","unstructured":"Falzarano, D. & Feldmann, H. Vaccines for Viral Hemorrhagic Fevers \u2013 Progress and Shortcomings. Current opinion in virology 3, 343\u2013351, https:\/\/doi.org\/10.1016\/j.coviro.2013.04.007 (2013).","journal-title":"Current opinion in virology"},{"key":"41205_CR25","doi-asserted-by":"publisher","first-page":"237","DOI":"10.1017\/s000711450769936x","volume":"98","author":"P Li","year":"2007","unstructured":"Li, P., Yin, Y.-L., Li, D., Woo Kim, S. & Wu, G. Amino acids and immune function. British Journal of Nutrition 98, 237\u2013252, https:\/\/doi.org\/10.1017\/s000711450769936x (2007).","journal-title":"British Journal of Nutrition"},{"key":"41205_CR26","doi-asserted-by":"publisher","first-page":"351","DOI":"10.1002\/biof.5520090235","volume":"9","author":"B Barbieri","year":"1999","unstructured":"Barbieri, B., Lund, B., Lundstrom, B. & Scaglione, F. Coenzyme Q10 administration increases antibody titer in hepatitis B vaccinated volunteers\u2013a single blind placebo-controlled and randomized clinical study. Biofactors 9, 351\u2013357 (1999).","journal-title":"Biofactors"},{"key":"41205_CR27","doi-asserted-by":"publisher","first-page":"331","DOI":"10.1111\/j.1744-313X.2011.01012.x","volume":"38","author":"W Cheng","year":"2011","unstructured":"Cheng, W. et al. Coenzyme Q plays opposing roles on bacteria\/fungi and viruses in Drosophila innate immunity. Int J Immunogenet 38, 331\u2013337, https:\/\/doi.org\/10.1111\/j.1744-313X.2011.01012.x (2011).","journal-title":"Int J Immunogenet"},{"key":"41205_CR28","doi-asserted-by":"publisher","first-page":"1692","DOI":"10.1002\/eji.1830240735","volume":"24","author":"AG Santis","year":"1994","unstructured":"Santis, A. G., Lopez-Cabrera, M., Hamann, J., Strauss, M. & Sanchez-Madrid, F. Structure of the gene coding for the human early lymphocyte activation antigen CD69: a C-type lectin receptor evolutionarily related with the gene families of natural killer cell-specific receptors. Eur J Immunol 24, 1692\u20131697, https:\/\/doi.org\/10.1002\/eji.1830240735 (1994).","journal-title":"Eur J Immunol"},{"key":"41205_CR29","doi-asserted-by":"publisher","first-page":"537","DOI":"10.1084\/jem.178.2.537","volume":"178","author":"M Lopez-Cabrera","year":"1993","unstructured":"Lopez-Cabrera, M. et al. Molecular cloning, expression, and chromosomal localization of the human earliest lymphocyte activation antigen AIM\/CD69, a new member of the C-type animal lectin superfamily of signal-transmitting receptors. J Exp Med 178, 537\u2013547 (1993).","journal-title":"J Exp Med"},{"key":"41205_CR30","doi-asserted-by":"publisher","first-page":"946","DOI":"10.1002\/eji.201646837","volume":"47","author":"D Cibrian","year":"2017","unstructured":"Cibrian, D. & Sanchez-Madrid, F. CD69: from activation marker to metabolic gatekeeper. Eur J Immunol 47, 946\u2013953, https:\/\/doi.org\/10.1002\/eji.201646837 (2017).","journal-title":"Eur J Immunol"},{"key":"41205_CR31","doi-asserted-by":"publisher","first-page":"237","DOI":"10.1017\/s000711450769936x","volume":"98","author":"P Li","year":"2007","unstructured":"Li, P., Yin, Y. L., Li, D., Kim, S. W. & Wu, G. Amino acids and immune function. Br J Nutr 98, 237\u2013252, https:\/\/doi.org\/10.1017\/s000711450769936x (2007).","journal-title":"Br J Nutr"},{"key":"41205_CR32","doi-asserted-by":"publisher","first-page":"415","DOI":"10.1385\/cbb:41:3:415","volume":"41","author":"W Shi","year":"2004","unstructured":"Shi, W., Meininger, C. J., Haynes, T. E., Hatakeyama, K. & Wu, G. Regulation of tetrahydrobiopterin synthesis and bioavailability in endothelial cells. Cell Biochem Biophys 41, 415\u2013434, https:\/\/doi.org\/10.1385\/cbb:41:3:415 (2004).","journal-title":"Cell Biochem Biophys"},{"key":"41205_CR33","doi-asserted-by":"publisher","first-page":"1129","DOI":"10.1172\/jci113427","volume":"81","author":"DL Granger","year":"1988","unstructured":"Granger, D. L., Hibbs, J. B. Jr., Perfect, J. R. & Durack, D. T. Specific amino acid (L-arginine) requirement for the microbiostatic activity of murine macrophages. J Clin Invest 81, 1129\u20131136, https:\/\/doi.org\/10.1172\/jci113427 (1988).","journal-title":"J Clin Invest"},{"key":"41205_CR34","doi-asserted-by":"publisher","first-page":"495","DOI":"10.3892\/ijmm_00000156","volume":"23","author":"T Naito","year":"2009","unstructured":"Naito, T. et al. Antiviral effect of arginine against herpes simplex virus type 1. Int J Mol Med 23, 495\u2013499 (2009).","journal-title":"Int J Mol Med"},{"key":"41205_CR35","doi-asserted-by":"publisher","first-page":"641","DOI":"10.1038\/nri1668","volume":"5","author":"V Bronte","year":"2005","unstructured":"Bronte, V. & Zanovello, P. Regulation of immune responses by L-arginine metabolism. Nat Rev Immunol 5, 641\u2013654, https:\/\/doi.org\/10.1038\/nri1668 (2005).","journal-title":"Nat Rev Immunol"},{"key":"41205_CR36","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1042\/bj20080701","volume":"417","author":"AM Ferreira","year":"2009","unstructured":"Ferreira, A. M. et al. Macrophage activation induces formation of the anti-inflammatory lipid cholesteryl-nitrolinoleate. Biochemical Journal 417, 223\u2013234, https:\/\/doi.org\/10.1042\/bj20080701 (2009).","journal-title":"Biochemical Journal"},{"key":"41205_CR37","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1038\/icb.2013.85","volume":"92","author":"M Pittelli","year":"2014","unstructured":"Pittelli, M. et al. Nicotinamide phosphoribosyltransferase (NAMPT) activity is essential for survival of resting lymphocytes. Immunol Cell Biol 92, 191\u2013199, https:\/\/doi.org\/10.1038\/icb.2013.85 (2014).","journal-title":"Immunol Cell Biol"},{"key":"41205_CR38","doi-asserted-by":"publisher","first-page":"e97378","DOI":"10.1371\/journal.pone.0097378","volume":"9","author":"G Venter","year":"2014","unstructured":"Venter, G. et al. NAMPT-mediated salvage synthesis of NAD\u2009+\u2009controls morphofunctional changes of macrophages. PLoS One 9, e97378, https:\/\/doi.org\/10.1371\/journal.pone.0097378 (2014).","journal-title":"PLoS One"},{"key":"41205_CR39","doi-asserted-by":"publisher","first-page":"212","DOI":"10.1177\/1753425910361989","volume":"17","author":"A Grahnert","year":"2011","unstructured":"Grahnert, A., Klein, C., Schilling, E., Wehrhahn, J. & Hauschildt, S. Review: NAD\u2009+\u2009: a modulator of immune functions. Innate Immun 17, 212\u2013233, https:\/\/doi.org\/10.1177\/1753425910361989 (2011).","journal-title":"Innate Immun"},{"key":"41205_CR40","first-page":"43","volume":"15","author":"A Dhur","year":"1991","unstructured":"Dhur, A., Galan, P. & Hercberg, S. Folate status and the immune system. Prog Food Nutr Sci 15, 43\u201360 (1991).","journal-title":"Prog Food Nutr Sci"},{"key":"41205_CR41","doi-asserted-by":"publisher","first-page":"127","DOI":"10.4168\/aair.2010.2.2.127","volume":"2","author":"KY Oh","year":"2010","unstructured":"Oh, K. Y. et al. Association Between Serum IgE Levels and the CTLA4\u2009+\u200949A\/G and FCER1B -654C\/T Polymorphisms in Korean Children With Asthma. Allergy Asthma Immunol Res 2, 127\u2013133, https:\/\/doi.org\/10.4168\/aair.2010.2.2.127 (2010).","journal-title":"Allergy Asthma Immunol Res"},{"key":"41205_CR42","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1038\/icb.2015.48","volume":"94","author":"L Eon Kuek","year":"2016","unstructured":"Eon Kuek, L., Leffler, M., Mackay, G. A. & Hulett, M. D. The MS4A family: counting past 1, 2 and 3. Immunol Cell Biol 94, 11\u201323, https:\/\/doi.org\/10.1038\/icb.2015.48 (2016).","journal-title":"Immunol Cell Biol"},{"key":"41205_CR43","doi-asserted-by":"publisher","first-page":"821","DOI":"10.1021\/bi401618y","volume":"53","author":"S Manzetti","year":"2014","unstructured":"Manzetti, S., Zhang, J. & van der Spoel, D. Thiamin function, metabolism, uptake, and transport. Biochemistry 53, 821\u2013835, https:\/\/doi.org\/10.1021\/bi401618y (2014).","journal-title":"Biochemistry"},{"key":"41205_CR44","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1177\/014860719902300124","volume":"23","author":"J Khan","year":"1999","unstructured":"Khan, J. et al. Alanyl-glutamine-supplemented parenteral nutrition increases luminal mucus gel and decreases permeability in the rat small intestine. JPEN J Parenter Enteral Nutr 23, 24\u201331, https:\/\/doi.org\/10.1177\/014860719902300124 (1999).","journal-title":"JPEN J Parenter Enteral Nutr"},{"key":"41205_CR45","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1016\/0261-5614(92)90029-P","volume":"11","author":"MS Ardawi","year":"1992","unstructured":"Ardawi, M. S. Effect of glutamine-supplemented total parenteral nutrition on the small bowel of septic rats. Clin Nutr 11, 207\u2013215 (1992).","journal-title":"Clin Nutr"},{"key":"41205_CR46","doi-asserted-by":"publisher","first-page":"202784","DOI":"10.1155\/2014\/202784","volume":"2014","author":"V Sharma","year":"2014","unstructured":"Sharma, V., Chitranshi, N. & Agarwal, A. K. Significance and biological importance of pyrimidine in the microbial world. Int J Med Chem 2014, 202784, https:\/\/doi.org\/10.1155\/2014\/202784 (2014).","journal-title":"Int J Med Chem"},{"key":"41205_CR47","doi-asserted-by":"publisher","first-page":"e34145","DOI":"10.1371\/journal.pone.0034145","volume":"7","author":"K Stiasny","year":"2012","unstructured":"Stiasny, K., Aberle, J. H., Keller, M., Grubeck-Loebenstein, B. & Heinz, F. X. Age Affects Quantity but Not Quality of Antibody Responses after Vaccination with an Inactivated Flavivirus Vaccine against Tick-Borne Encephalitis. Plos One 7, e34145, https:\/\/doi.org\/10.1371\/journal.pone.0034145 (2012).","journal-title":"Plos One"},{"key":"41205_CR48","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1093\/nar\/30.1.207","volume":"30","author":"R Edgar","year":"2002","unstructured":"Edgar, R., Domrachev, M. & Lash, A. E. Gene Expression Omnibus: NCBI gene expression and hybridization array data repository. Nucleic Acids Res 30, 207\u2013210 (2002).","journal-title":"Nucleic Acids Res"},{"key":"41205_CR49","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":"41205_CR50","doi-asserted-by":"publisher","first-page":"511","DOI":"10.1038\/nbt.1621","volume":"28","author":"C Trapnell","year":"2010","unstructured":"Trapnell, C. et al. Transcript assembly and quantification by RNA-Seq reveals unannotated transcripts and isoform switching during cell differentiation. Nat Biotechnol 28, 511\u2013515, https:\/\/doi.org\/10.1038\/nbt.1621 (2010).","journal-title":"Nat Biotechnol"},{"key":"41205_CR51","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":"41205_CR52","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-14-219","volume":"14","author":"J Sun","year":"2013","unstructured":"Sun, J., Nishiyama, T., Shimizu, K. & Kadota, K. TCC: an R package for comparing tag count data with robust normalization strategies. BMC Bioinformatics 14, 219, https:\/\/doi.org\/10.1186\/1471-2105-14-219 (2013).","journal-title":"BMC Bioinformatics"},{"key":"41205_CR53","doi-asserted-by":"publisher","first-page":"D480","DOI":"10.1093\/nar\/gkm882","volume":"36","author":"M Kanehisa","year":"2008","unstructured":"Kanehisa, M. et al. KEGG for linking genomes to life and the environment. Nucleic Acids Res 36, D480\u2013484, https:\/\/doi.org\/10.1093\/nar\/gkm882 (2008).","journal-title":"Nucleic Acids Res"},{"key":"41205_CR54","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1038\/nprot.2008.211","volume":"4","author":"W Huang da","year":"2009","unstructured":"Huang da, W., Sherman, B. T. & Lempicki, R. A. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc 4, 44\u201357, https:\/\/doi.org\/10.1038\/nprot.2008.211 (2009).","journal-title":"Nat Protoc"},{"key":"41205_CR55","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-14-128","volume":"14","author":"EY Chen","year":"2013","unstructured":"Chen, E. Y. et al. Enrichr: interactive and collaborative HTML5 gene list enrichment analysis tool. BMC Bioinformatics 14, 128, https:\/\/doi.org\/10.1186\/1471-2105-14-128 (2013).","journal-title":"BMC Bioinformatics"},{"key":"41205_CR56","doi-asserted-by":"publisher","first-page":"371","DOI":"10.1093\/toxsci\/kfx189","volume":"160","author":"A Khan","year":"2017","unstructured":"Khan, A. et al. Elevated Metabolites of Steroidogenesis and Amino Acid Metabolism in Preadolescent Female Children With High Urinary Bisphenol A Levels: A High-Resolution Metabolomics Study. Toxicol Sci 160, 371\u2013385, https:\/\/doi.org\/10.1093\/toxsci\/kfx189 (2017).","journal-title":"Toxicol Sci"},{"key":"41205_CR57","doi-asserted-by":"publisher","first-page":"1109","DOI":"10.1039\/c6mb00732e","volume":"13","author":"Y Lee","year":"2017","unstructured":"Lee, Y., Khan, A., Hong, S., Jee, S. H. & Park, Y. H. A metabolomic study on high-risk stroke patients determines low levels of serum lysine metabolites: a retrospective cohort study. Mol Biosyst 13, 1109\u20131120, https:\/\/doi.org\/10.1039\/c6mb00732e (2017).","journal-title":"Mol Biosyst"},{"key":"41205_CR58","doi-asserted-by":"publisher","DOI":"10.1186\/s12936-015-0651-1","volume":"14","author":"YH Park","year":"2015","unstructured":"Park, Y. H. et al. High-resolution metabolomics to discover potential parasite-specific biomarkers in a Plasmodium falciparum erythrocytic stage culture system. Malar J 14, 122, https:\/\/doi.org\/10.1186\/s12936-015-0651-1 (2015).","journal-title":"Malar J"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-41205-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-41205-1","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-41205-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,17]],"date-time":"2022-12-17T07:50:07Z","timestamp":1671263407000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-41205-1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,3,18]]},"references-count":58,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2019,12]]}},"alternative-id":["41205"],"URL":"https:\/\/doi.org\/10.1038\/s41598-019-41205-1","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,3,18]]},"assertion":[{"value":"17 July 2018","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 February 2019","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 March 2019","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"4760"}}