{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,21]],"date-time":"2026-02-21T01:25:09Z","timestamp":1771637109887,"version":"3.50.1"},"reference-count":36,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,11,3]],"date-time":"2021-11-03T00:00:00Z","timestamp":1635897600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,11,3]],"date-time":"2021-11-03T00:00:00Z","timestamp":1635897600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP20dm0107128"],"award-info":[{"award-number":["JP20dm0107128"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP20dm0207073"],"award-info":[{"award-number":["JP20dm0207073"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP21dk0207047"],"award-info":[{"award-number":["JP21dk0207047"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Transl Psychiatry"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Presenilin (PS) with a genetic mutation generates abundant \u03b2-amyloid protein (A\u03b2) 43. Senile plaques are formed by A\u03b243 in the cerebral parenchyma together with A\u03b242 at middle ages. These brains cause the early onset of Alzheimer\u2019s disease (AD), which is known as familial Alzheimer\u2019s disease (FAD). Based on the stepwise processing model of A\u03b2 generation by \u03b3-secretase, we reassessed the levels of A\u03b2s in the cerebrospinal fluid (CSF) of FAD participants. While low levels of A\u03b238, A\u03b240, and A\u03b242 were generated in the CSF of FAD participants, the levels of A\u03b243 were unchanged in some of them compared with other participants. We sought to investigate why the level of A\u03b243 was unchanged in FAD participants. These characteristics of A\u03b2 generation were observed in the \u03b3-secretase assay in vitro using cells, which express FAD mutations in PS1. A\u03b238 and A\u03b240 generation from their precursors, A\u03b242 and A\u03b243, was decreased in PS1 mutants compared with wild-type (WT) PS1, as observed in the CSF. Both the ratios of A\u03b238\/A\u03b242 and A\u03b240\/A\u03b243 in PS1 mutants were lower than those in the WT. However, the ratio of A\u03b243\/amyloid precursor protein intracellular domain (AICD) increased in the PS1 mutants in an onset age dependency, while other A\u03b2\/AICD ratios were decreased or unchanged. Importantly, liquid chromatography\u2013mass spectrometry found that the generation of A\u03b243 was stimulated from A\u03b248 in PS1 mutants. This result indicates that PS1 mutants switched the A\u03b243 generating line, which reflects the level of A\u03b243 in the CSF and forming senile plaques.<\/jats:p>","DOI":"10.1038\/s41398-021-01684-1","type":"journal-article","created":{"date-parts":[[2021,11,3]],"date-time":"2021-11-03T00:03:41Z","timestamp":1635897821000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Switched A\u03b243 generation in familial Alzheimer\u2019s disease with presenilin 1 mutation"],"prefix":"10.1038","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7011-6891","authenticated-orcid":false,"given":"Nobuto","family":"Kakuda","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mako","family":"Takami","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masayasu","family":"Okochi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2178-0769","authenticated-orcid":false,"given":"Kensaku","family":"Kasuga","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yasuo","family":"Ihara","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8828-8085","authenticated-orcid":false,"given":"Takeshi","family":"Ikeuchi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2021,11,3]]},"reference":[{"key":"1684_CR1","doi-asserted-by":"publisher","first-page":"664","DOI":"10.1086\/302553","volume":"65","author":"D Campion","year":"1999","unstructured":"Campion D, Dumanchin C, Hannequin D, Dubois B, Belliard S, Puel M, et al. Earlyonset autosomal dominant Alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum. Am J Hum Genet. 1999;65:664\u201370.","journal-title":"Am J Hum Genet."},{"key":"1684_CR2","doi-asserted-by":"publisher","first-page":"595","DOI":"10.15252\/emmm.201606210","volume":"8","author":"DJ Selkoe","year":"2016","unstructured":"Selkoe DJ, Hardy J. The amyloid hypothesis of Alzheimer\u2019s disease at 25 years. EMBO Mol Med. 2016;8:595\u2013608.","journal-title":"EMBO Mol Med."},{"key":"1684_CR3","doi-asserted-by":"publisher","first-page":"387","DOI":"10.1038\/34910","volume":"391","author":"B De Strooper","year":"1998","unstructured":"De Strooper B, Saftig P, Craessaerts K, Vanderstichele H, Guhde G, Annaert W, et al. Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein. Nature. 1998;391:387\u201390.","journal-title":"Nature."},{"key":"1684_CR4","doi-asserted-by":"publisher","first-page":"741","DOI":"10.1152\/physrev.2001.81.2.741","volume":"81","author":"DJ Selkoe","year":"2001","unstructured":"Selkoe DJ. Alzheimer\u2019s disease: genes, proteins, and therapy. Physiol Rev. 2001;81:741\u201366.","journal-title":"Physiol Rev."},{"key":"1684_CR5","doi-asserted-by":"publisher","first-page":"438","DOI":"10.1038\/nature01506","volume":"422","author":"N Takasugi","year":"2003","unstructured":"Takasugi N, Tomita T, Hayashi I, Tsuruoka M, Niimura M, Takahashi Y, et al. The role of presenilin cofactors in the gamma-secretase complex. Nature. 2003;422:438\u201341.","journal-title":"Nature."},{"key":"1684_CR6","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-020-02249-0","author":"D Sepulveda-Falla","year":"2020","unstructured":"Sepulveda-Falla D, Chavez-Gutierrez L, Portelius E, V\u00e9lez JI, Dujardin S, Barrera-Ocampo A, et al. A multifactorial model of pathology for age of onset heterogeneity in familial Alzheimer\u2019s disease. Acta Neuropathol. 2020. https:\/\/doi.org\/10.1007\/s00401-020-02249-0","journal-title":"Acta Neuropathol."},{"key":"1684_CR7","doi-asserted-by":"publisher","first-page":"1005","DOI":"10.1016\/S0896-6273(00)80230-5","volume":"17","author":"DR Borchelt","year":"1996","unstructured":"Borchelt DR, Thinakaran G, Eckman CB, Lee MK, Davenport F, Ratovitsky T, et al. Familial Alzheimer\u2019s disease-linked presenilin 1 variants elevate Abeta1-42\/1-40 ratio in vitro and in vivo. Neuron. 1996;17:1005\u201313.","journal-title":"Neuron."},{"key":"1684_CR8","doi-asserted-by":"publisher","first-page":"710","DOI":"10.1038\/383710a0","volume":"383","author":"K Duff","year":"1996","unstructured":"Duff K, Eckman C, Zehr C, Yu X, Prada CM, Perez-tur J, et al. Increased amyloid-beta42(43) in brains of mice expressing mutant presenilin 1. Nature. 1996;383:710\u20133.","journal-title":"Nature."},{"key":"1684_CR9","doi-asserted-by":"publisher","first-page":"864","DOI":"10.1038\/nm0896-864","volume":"2","author":"D Scheuner","year":"1996","unstructured":"Scheuner D, Eckman C, Jensen M, Song X, Citron M, Suzuki N, et al. Secreted amyloid beta-protein similar to that in the senile plaques of Alzheimer\u2019s disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer\u2019s disease. Nat Med. 1996;2:864\u201370.","journal-title":"Nat Med"},{"key":"1684_CR10","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1016\/S0304-3940(99)00187-1","volume":"265","author":"O Murayama","year":"1999","unstructured":"Murayama O, Tomita T, Nihonmatsu N, Murayama M, Sun X, Honda T, et al. Enhancement of amyloid beta 42 secretion by 28 different presenilin 1 mutations of familial Alzheimer\u2019s disease. Neurosci Lett. 1999;265:61\u20133.","journal-title":"Neurosci Lett."},{"key":"1684_CR11","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1016\/0896-6273(94)90458-8","volume":"13","author":"T Iwatsubo","year":"1994","unstructured":"Iwatsubo T, Odaka A, Suzuki N, Mizusawa H, Nukina N, Ihara Y. Visualization of A\u03b242(43) and A\u03b240 in senile plaque with end-specific A\u03b2 monoclonals: evidence that an initially deposited forms is A\u03b242(43). Neuron. 1994;13:45\u201353.","journal-title":"Neuron."},{"key":"1684_CR12","doi-asserted-by":"publisher","first-page":"294","DOI":"10.1002\/ana.410370305","volume":"37","author":"T Iwatsubo","year":"1995","unstructured":"Iwatsubo T, Mann DM, Odaka A, Suzuki N, Ihara Y. Amyloid beta protein (Abeta) deposition: Abeta 42(43) precedes A beta 40 in Down syndrome. Ann Neurol. 1995;37:294\u20139.","journal-title":"Ann Neurol"},{"key":"1684_CR13","doi-asserted-by":"publisher","first-page":"697","DOI":"10.1111\/j.1471-4159.2009.06170.x","volume":"110","author":"H Welander","year":"2009","unstructured":"Welander H, Fr\u00e5nberg J, Graff C, Sundstr\u00f6m E, Winblad B, Tjernberg LO. Abeta43 is more frequent than Abeta40 in amyloid plaque cores from Alzheimer disease brains. J Neurochem. 2009;110:697\u2013706.","journal-title":"J Neurochem."},{"key":"1684_CR14","doi-asserted-by":"publisher","first-page":"e55847","DOI":"10.1371\/journal.pone.0055847","volume":"8","author":"A Sandebring","year":"2013","unstructured":"Sandebring A, Welander H, Winblad B, Graff C, Tjernberg LO. The pathogenic A\u03b243 is enriched in familial and sporadic Alzheimer disease. PLoS ONE. 2013;8:e55847.","journal-title":"PLoS ONE."},{"key":"1684_CR15","doi-asserted-by":"publisher","first-page":"19070","DOI":"10.1074\/jbc.M501130200","volume":"280","author":"Y Nakaya","year":"2005","unstructured":"Nakaya Y, Yamane T, Shiraishi H, Wang HQ, Matsubara E, Sato T, et al. Random mutagenesis of presenilin-1 identifies novel mutants exclusively generating long amyloid beta-peptides. J Biol Chem. 2005;280:19070\u20137.","journal-title":"J Biol Chem."},{"key":"1684_CR16","doi-asserted-by":"crossref","unstructured":"Saito T, Suemoto T, Brouwers N, Sleegers K, Funamoto S, Mihira N, et al. Potent amyloidgenecity and pathogenecity of A\u03b243 Nat Neurosci. 2011;14:1023\u201332.","DOI":"10.1038\/nn.2858"},{"key":"1684_CR17","doi-asserted-by":"publisher","first-page":"1702","DOI":"10.1212\/01.WNL.0000143060.98164.1A","volume":"63","author":"AK Godbolt","year":"2004","unstructured":"Godbolt AK, Beck JA, Collinge J, Garrard P, Warren JD, Fox NC, et al. A presenilin 1 R278I mutation presenting with language impairment. Neurology. 2004;63:1702\u20134.","journal-title":"Neurology."},{"key":"1684_CR18","doi-asserted-by":"publisher","first-page":"13042","DOI":"10.1523\/JNEUROSCI.2362-09.2009","volume":"29","author":"M Takami","year":"2009","unstructured":"Takami M, Nagashima Y, Sano Y, Ishihara S, Morishima-Kawashima M, Funamoto S, et al. \u03b3-Secretase: successive tripeptide and tetrapeptide release from the transmembrane domain of \u03b2-carboxyl terminal fragment. J Neurosci. 2009;29:13042\u201352.","journal-title":"J Neurosci."},{"key":"1684_CR19","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1016\/j.celrep.2012.11.028","volume":"3","author":"M Okochi","year":"2013","unstructured":"Okochi M, Tagami S, Yanagida K, Takami M, Kodama TS, Mori K, et al. \u03b3-secretase modulators and presenilin 1 mutants act differently on presenilin\/\u03b3-secretase function to cleave A\u03b242 and A\u03b243. Cell Rep. 2013;3:42\u201351.","journal-title":"Cell Rep."},{"key":"1684_CR20","doi-asserted-by":"publisher","first-page":"5109","DOI":"10.1074\/jbc.M113.510131","volume":"289","author":"N Matsumura","year":"2014","unstructured":"Matsumura N, Takami M, Okochi M, Wada-Kakuda S, Fujiwara H, Tagami S, et al. \u03b3-Secretase associated with lipid rafts: multiple interactive pathways in the stepwise processing of \u03b2-carboxyl-terminal fragment. J Biol Chem. 2014;289:5109\u201321.","journal-title":"J Biol Chem"},{"key":"1684_CR21","doi-asserted-by":"publisher","first-page":"344","DOI":"10.1002\/emmm.201200214","volume":"4","author":"N Kakuda","year":"2012","unstructured":"Kakuda N, Shoji M, Arai H, Furukawa K, Ikeuchi T, Akazawa K, et al. Altered \u03b3-secretase activity in mild cognitive impairment and Alzheimer\u2019s disease. EMBO Mol Med. 2012;4:344\u201352.","journal-title":"EMBO Mol Med"},{"key":"1684_CR22","doi-asserted-by":"publisher","first-page":"1101","DOI":"10.1016\/j.neurobiolaging.2012.08.017","volume":"34","author":"N Kakuda","year":"2013","unstructured":"Kakuda N, Akazawa K, Hatsuta H, Murayama S, Ihara Y. Japanese Alzheimer\u2019s Disease Neuroimaging Initiative. Suspected limited efficacy of \u03b3-secretase modulators. Neurobiol Aging. 2013;34:1101\u201314.","journal-title":"Neurobiol Aging."},{"key":"1684_CR23","doi-asserted-by":"publisher","first-page":"1323","DOI":"10.1016\/j.ajpath.2020.02.009","volume":"190","author":"N Kakuda","year":"2020","unstructured":"Kakuda N, Yamaguchi H, Akazawa K, Hata S, Suzuki T, Hatsuta H, et al. \u03b3-Secretase activity is associated with Braak senile plaque stages. Am J Pathol. 2020;190:1323\u201331.","journal-title":"Am J Pathol."},{"key":"1684_CR24","doi-asserted-by":"publisher","first-page":"14776","DOI":"10.1074\/jbc.M513453200","volume":"281","author":"N Kakuda","year":"2006","unstructured":"Kakuda N, Funamoto S, Yagishita S, Takami M, Osawa S, Dohmae N, et al. Equimolar production of amyloid beta-protein and amyloid precursor protein intracellular domain from beta-carboxyl-terminal fragment by gamma-secretase. J Biol Chem. 2006;281:14776\u201386.","journal-title":"J Biol Chem."},{"key":"1684_CR25","doi-asserted-by":"publisher","first-page":"3952","DOI":"10.1021\/bi0521846","volume":"45","author":"S Yagishita","year":"2006","unstructured":"Yagishita S, Morishima-Kawashima M, Tanimura Y, Ishiura S, Ihara Y. DAPT-induced intracellular accumulations of longer amyloid beta-proteins: further implications for the mechanism of intramembrane cleavage by gamma-secretase. Biochemistry. 2006;45:3952\u201360.","journal-title":"Biochemistry."},{"key":"1684_CR26","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1002\/emmm.200900026","volume":"1","author":"K Yanagida","year":"2009","unstructured":"Yanagida K, Okochi M, Tagami S, Nakayama T, Kodama TS, Nishitomi K, et al. The 28-amino acid form of an APLP1-derived Abeta-like peptide is a surrogate marker for Abeta42 production in the central nervous system. EMBO Mol Med. 2009;1:223\u201335.","journal-title":"EMBO Mol Med."},{"key":"1684_CR27","doi-asserted-by":"publisher","first-page":"13977","DOI":"10.1021\/bi034904j","volume":"47","author":"S Wada","year":"2003","unstructured":"Wada S, Morishima-Kawashima M, Qi Y, Misonou H, Shimada Y, Ohno-Iwashita Y, et al. Gamma-secretase activity is present in rafts but is not cholesterol-dependent. Biochemistry. 2003;47:13977\u201386.","journal-title":"Biochemistry."},{"key":"1684_CR28","doi-asserted-by":"publisher","first-page":"2261","DOI":"10.1038\/emboj.2012.79","volume":"31","author":"L Ch\u00e1vez-Guti\u00e9rrez","year":"2012","unstructured":"Ch\u00e1vez-Guti\u00e9rrez L, Bammens L, Benilova I, Vandersteen A, Benurwar M, Borgers M, et al. The mechanism of \u03b3-Secretase dysfunction in familial Alzheimer disease. EMBO J. 2012;31:2261\u201374.","journal-title":"EMBO J"},{"key":"1684_CR29","doi-asserted-by":"publisher","first-page":"6959","DOI":"10.1073\/pnas.96.12.6959","volume":"96","author":"W Song","year":"1999","unstructured":"Song W, Nadeau P, Yuan M, Yang X, Shen J, Yankner BA. Proteolytic release and nuclear translocation of Notch-1 are induced by presenilin-1 and impaired by pathogenic presenilin-1 mutations. Proc Natl Acad Sci USA. 1999;96:6959\u201363.","journal-title":"Proc Natl Acad Sci USA."},{"key":"1684_CR30","doi-asserted-by":"publisher","first-page":"732","DOI":"10.1111\/j.1471-4159.2005.03578.x","volume":"96","author":"M Bentahir","year":"2006","unstructured":"Bentahir M, Nyabi O, Verhamme J, Tolia A, Horr\u00e9 K, Wiltfang J, et al. Presenilin clinical mutations can affect gamma-secretase activity by different mechanisms. J Neurochem. 2006;96:732\u201342.","journal-title":"J Neurochem"},{"key":"1684_CR31","doi-asserted-by":"publisher","first-page":"22350","DOI":"10.1074\/jbc.M110.116962","volume":"285","author":"EA Heilig","year":"2010","unstructured":"Heilig EA, Xia W, Shen J, Kelleher RJ 3rd. A presenilin-1 mutation identified in familial Alzheimer disease with cotton wool plaques causes a nearly complete loss of gamma-secretase activity. J Biol Chem. 2010;285:22350\u20139.","journal-title":"J Biol Chem."},{"key":"1684_CR32","doi-asserted-by":"publisher","first-page":"686","DOI":"10.1002\/humu.20336","volume":"27","author":"S Kumar-Singh","year":"2006","unstructured":"Kumar-Singh S, Theuns J, Van Broeck B, Pirici D, Vennekens K, Corsmit E, et al. Mean age-of-onset of familial alzheimer disease caused by presenilin mutations correlates with both increased Abeta42 and decreased Abeta40. Hum Mutat. 2006;27:686\u201395.","journal-title":"Hum Mutat"},{"key":"1684_CR33","doi-asserted-by":"publisher","first-page":"35235","DOI":"10.1074\/jbc.C100357200","volume":"276","author":"Y Gu","year":"2001","unstructured":"Gu Y, Misonou H, Sato T, Dohmae N, Takio K, Ihara Y. Distinct intramembrane cleavage of the beta-amyloid precursor protein family resembling gamma-secretase-like cleavage of Notch. J Biol Chem. 2001;276:35235\u20138.","journal-title":"J Biol Chem."},{"key":"1684_CR34","doi-asserted-by":"publisher","first-page":"24294","DOI":"10.1074\/jbc.M211161200","volume":"278","author":"T Sato","year":"2003","unstructured":"Sato T, Dohmae N, Qi Y, Kakuda N, Misonou H, Mitsumori R, et al. Potential link between amyloid beta-protein 42 and C-terminal fragment gamma 49\u201399 of beta-amyloid precursor protein. J Biol Chem. 2003;278:24294\u2013301.","journal-title":"J Biol Chem"},{"key":"1684_CR35","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1016\/j.neuron.2005.06.030","volume":"47","author":"E McGowan","year":"2005","unstructured":"McGowan E, Pickford F, Kim J, Onstead L, Eriksen J, Yu C, et al. Abeta42 is essential for parenchymal and vascular amyloid deposition in mice. Neuron. 2005;47:191\u20139.","journal-title":"Neuron."},{"key":"1684_CR36","doi-asserted-by":"publisher","first-page":"627","DOI":"10.1523\/JNEUROSCI.4849-06.2007","volume":"27","author":"J Kim","year":"2007","unstructured":"Kim J, Onstead L, Randle S, Price R, Smithson L, Zwizinski C, et al. Abeta40 inhibits amyloid deposition in vivo. J Neurosci. 2007;27:627\u201333.","journal-title":"J Neurosci."}],"container-title":["Translational Psychiatry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41398-021-01684-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41398-021-01684-1","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41398-021-01684-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,1]],"date-time":"2022-12-01T15:27:11Z","timestamp":1669908431000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41398-021-01684-1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,3]]},"references-count":36,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["1684"],"URL":"https:\/\/doi.org\/10.1038\/s41398-021-01684-1","relation":{},"ISSN":["2158-3188"],"issn-type":[{"value":"2158-3188","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,3]]},"assertion":[{"value":"19 June 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 October 2021","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 October 2021","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 November 2021","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Ethics permission was granted by the ethical committee of Doshisha University and we obtained written informed consent from the patient\u2019s family for the use of samples for medical research.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"The authors declare no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"558"}}