{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,2]],"date-time":"2025-11-02T10:30:06Z","timestamp":1762079406300,"version":"build-2065373602"},"reference-count":60,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2022,12,10]],"date-time":"2022-12-10T00:00:00Z","timestamp":1670630400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000049","name":"NIA","doi-asserted-by":"publisher","award":["R01 AG054048-01"],"award-info":[{"award-number":["R01 AG054048-01"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Blood-based biomarkers are needed for the early diagnosis of Alzheimer\u2019s disease (AD). We analyzed longitudinal human plasma samples from AD and control cases to identify biomarkers for the early diagnosis of AD. Plasma samples were grouped based on clinical diagnosis at the time of collection: AD, mild cognitive impairment (MCI), and pre-symptomatic (preMCI). Samples were analyzed by ELISA using a panel of reagents against nine different AD-related amyloid-\u03b2 (A\u03b2), tau, or TDP-43 variants. Receiver operating characteristic (ROC) curves of different biomarker panels for different diagnostic sample groups were determined. Analysis of all of the samples gave a sensitivity of 92% and specificity of 76% for the diagnosis of AD. Early-stage diagnosis of AD, utilizing only the preMCI and MCI samples, identified 88% of AD cases. Using sex-biased biomarker panels, early diagnosis of AD cases improved to 96%. Using the sex-biased panels, we also identified 6 of the 25 control group cases as being at high risk of AD, which is consistent with what is expected given the advanced age of the control cases. Specific AD-associated protein variants are effective blood-based biomarkers for the early diagnosis of AD. Notably, significant differences were observed in biomarker profiles for the early detection of male and female AD cases.<\/jats:p>","DOI":"10.3390\/ijms232415670","type":"journal-article","created":{"date-parts":[[2022,12,12]],"date-time":"2022-12-12T01:42:27Z","timestamp":1670809347000},"page":"15670","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Sex-Specific Multiparameter Blood Test for the Early Diagnosis of Alzheimer\u2019s Disease"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7481-6841","authenticated-orcid":false,"given":"Hyung Joon","family":"Cho","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, The University of Arizona College of Medicine\u2014Phoenix, Phoenix, AZ 85004, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Philip","family":"Schulz","sequence":"additional","affiliation":[{"name":"Chemical Engineering, School for Engineering of Matter, Transport and Energy, Arizona State University, Tempe, AZ 85287, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lalitha","family":"Venkataraman","sequence":"additional","affiliation":[{"name":"Center for Gene Therapy, Nationwide Children\u2019s Hospital, Columbus, OH 43205, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5784-2987","authenticated-orcid":false,"given":"Richard J.","family":"Caselli","sequence":"additional","affiliation":[{"name":"Department of Neurology, Mayo Clinic, Scottsdale, AZ 85259, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7301-230X","authenticated-orcid":false,"given":"Michael R.","family":"Sierks","sequence":"additional","affiliation":[{"name":"Chemical Engineering, School for Engineering of Matter, Transport and Energy, Arizona State University, Tempe, AZ 85287, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1186","DOI":"10.1002\/med.21434","article-title":"Drugs in Clinical Trials for Alzheimer\u2019s Disease: The Major Trends","volume":"37","author":"Bachurin","year":"2017","journal-title":"Med. Res. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"629","DOI":"10.4103\/0253-7613.194867","article-title":"Novel strategies for Alzheimer\u2019s disease treatment: An overview of anti-amyloid beta monoclonal antibodies","volume":"48","author":"Rygiel","year":"2016","journal-title":"Indian J. Pharmacol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1038\/nrneurol.2010.4","article-title":"Cerebrospinal fluid and plasma biomarkers in Alzheimer disease","volume":"6","author":"Blennow","year":"2010","journal-title":"Nat. Rev. Neurol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"493","DOI":"10.3109\/13547500903108423","article-title":"Proteomics-derived cerebrospinal fluid markers of autopsy-confirmed Alzheimer\u2019s disease","volume":"14","author":"Roher","year":"2009","journal-title":"Biomarkers"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1016\/j.exger.2009.09.008","article-title":"Biomarkers for Alzheimer\u2019s disease and other forms of dementia: Clinical needs, limitations and future aspects","volume":"45","author":"Winblad","year":"2010","journal-title":"Exp. Gerontol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1016\/j.pneurobio.2011.09.002","article-title":"Biomarkers of Parkinson\u2019s disease and Dementia with Lewy bodies","volume":"95","author":"Henchcliffe","year":"2011","journal-title":"Prog. Neurobiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1016\/j.cca.2021.05.011","article-title":"The PrecivityAD\u2122 test: Accurate and reliable LC-MS\/MS assays for quantifying plasma amyloid beta 40 and 42 and apolipoprotein E proteotype for the assessment of brain amyloidosis","volume":"519","author":"Kirmess","year":"2021","journal-title":"Clin. Chim. Acta"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1016\/j.neuron.2010.04.029","article-title":"Deleterious effects of amyloid beta oligomers acting as an extracellular scaffold for mGluR5","volume":"66","author":"Renner","year":"2010","journal-title":"Neuron"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"14234","DOI":"10.1523\/JNEUROSCI.1523-15.2015","article-title":"Internalized tau oligomers cause neurodegeneration by inducing accumulation of pathogenic tau in human neurons derived from induced pluripotent stem cells","volume":"35","author":"Usenovic","year":"2015","journal-title":"J. Neurosci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1038\/ncb1901","article-title":"Transmission and spreading of tauopathy in transgenic mouse brain","volume":"11","author":"Clavaguera","year":"2009","journal-title":"Nat. Cell Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1038\/nrn2786","article-title":"Prion-like mechanisms in neurodegenerative diseases","volume":"11","author":"Frost","year":"2010","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1038\/nature12481","article-title":"Self-propagation of pathogenic protein aggregates in neurodegenerative diseases","volume":"501","author":"Jucker","year":"2013","journal-title":"Nature"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3539","DOI":"10.1111\/j.1742-4658.2011.08256.x","article-title":"TDP-43: The relationship between protein aggregation and neurodegeneration in amyotrophic lateral sclerosis and frontotemporal lobar degeneration","volume":"278","author":"Baloh","year":"2011","journal-title":"FEBS J."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1097\/NEN.0b013e31817713b5","article-title":"Concomitant TAR-DNA-binding protein 43 pathology is present in Alzheimer disease and corticobasal degeneration but not in other tauopathies","volume":"67","author":"Uryu","year":"2008","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1007\/s00401-007-0323-5","article-title":"TDP-43 immunoreactivity in neurodegenerative disorders: Disease versus mechanism specificity","volume":"115","author":"Dickson","year":"2008","journal-title":"Acta Neuropathol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1002\/ana.21154","article-title":"TDP-43 immunoreactivity in hippocampal sclerosis and Alzheimer\u2019s disease","volume":"61","author":"Lin","year":"2007","journal-title":"Ann. Neurol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1007\/s00401-022-02444-1","article-title":"Frequency of LATE neuropathologic change across the spectrum of Alzheimer\u2019s disease neuropathology: Combined data from 13 community-based or population-based autopsy cohorts","volume":"144","author":"Nelson","year":"2022","journal-title":"Acta Neuropathol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"20329","DOI":"10.1074\/jbc.M109.010264","article-title":"TDP-43 is intrinsically aggregation-prone, and amyotrophic lateral sclerosis-linked mutations accelerate aggregation and increase toxicity","volume":"284","author":"Johnson","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1093\/protein\/gzl036","article-title":"Isolating recombinant antibodies against specific protein morphologies using atomic force microscopy and phage display technologies","volume":"19","author":"Barkhordarian","year":"2006","journal-title":"Protein Eng. Des. Sel."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1132","DOI":"10.1016\/j.jmb.2007.02.089","article-title":"Isolation of a human single chain antibody fragment against oligomeric \u03b1-synuclein that inhibits aggregation and prevents \u03b1-synuclein induced toxicity","volume":"368","author":"Emadi","year":"2007","journal-title":"J. Mol. Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"11048","DOI":"10.1074\/jbc.M806559200","article-title":"Detecting morphologically distinct oligomeric forms of \u03b1-synuclein","volume":"284","author":"Emadi","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2871","DOI":"10.1021\/bi036281f","article-title":"Inhibiting aggregation of \u03b1-synuclein with human single chain antibody fragments","volume":"43","author":"Emadi","year":"2004","journal-title":"Biochemistry"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1023","DOI":"10.1016\/j.ymthe.2004.08.019","article-title":"A human single-chain Fv intrabody blocks aberrant cellular effects of overexpressed \u03b1-synuclein","volume":"10","author":"Zhou","year":"2004","journal-title":"Mol. Ther."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"6959","DOI":"10.1021\/bi049933o","article-title":"Single chain variable fragments against \u03b2-Amyloid (A\u03b2) can inhibit A\u03b2 aggregation and prevent A\u03b2-induced neurotoxicity","volume":"43","author":"Liu","year":"2004","journal-title":"Biochemistry"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"11532","DOI":"10.1021\/bi060601o","article-title":"Single chain Fv antibodies against the 25\u201335 A\u03b2 fragment inhibit aggregation and toxicity of A\u03b242","volume":"45","author":"Zameer","year":"2006","journal-title":"Biochemistry"},{"key":"ref_26","first-page":"e52584","article-title":"Novel atomic force microscopy based biopanning for isolation of morphology specific reagents against TDP-43 variants in amyotrophic lateral sclerosis","volume":"96","author":"Williams","year":"2015","journal-title":"J. Vis. Exp."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Williams, S.M., Khan, G., Harris, B.T., Ravits, J., and Sierks, M.R. (2017). TDP-43 protein variants as biomarkers in amyotrophic lateral sclerosis. BMC Neurosci., 18.","DOI":"10.1186\/s12868-017-0334-7"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1016\/j.jmb.2008.09.068","article-title":"Anti-oligomeric A\u03b2 single-chain variable domain antibody blocks A\u03b2-induced toxicity against human neuroblastoma cells","volume":"384","author":"Zameer","year":"2008","journal-title":"J. Mol. Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1320","DOI":"10.1016\/j.neurobiolaging.2010.09.020","article-title":"Nanobody specific for oligomeric beta-amyloid stabilizes nontoxic form","volume":"33","author":"Kasturirangan","year":"2012","journal-title":"Neurobiol. Aging"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1002\/btpr.1698","article-title":"Isolation and characterization of antibody fragments selective for specific protein morphologies from nanogram antigen samples","volume":"29","author":"Kasturirangan","year":"2013","journal-title":"Biotechnol. Prog."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1342","DOI":"10.1016\/j.neurobiolaging.2014.12.002","article-title":"Isolation and characterization of antibody fragments selective for toxic oligomeric tau","volume":"36","author":"Tian","year":"2015","journal-title":"Neurobiol. Aging."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.neurobiolaging.2020.04.014","article-title":"Isolation and characterization of antibody fragment selective for human Alzheimer\u2019s disease brain-derived tau variants","volume":"94","author":"Venkataraman","year":"2020","journal-title":"Neurobiol. Aging"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"23","DOI":"10.3233\/JAD-161116","article-title":"Blood-based oligomeric and other protein variant biomarkers to facilitate pre-symptomatic diagnosis and staging of Alzheimer\u2019s disease","volume":"58","author":"Williams","year":"2017","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1111\/ejn.13056","article-title":"Oligomeric \u03b1-synuclein and \u03b2-amyloid variants as potential biomarkers for Parkinson\u2019s and Alzheimer\u2019s diseases","volume":"43","author":"Williams","year":"2016","journal-title":"Eur. J. Neurosci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1038\/nature25456","article-title":"High performance plasma amyloid-beta biomarkers for Alzheimer\u2019s disease","volume":"554","author":"Nakamura","year":"2018","journal-title":"Nature"},{"key":"ref_36","unstructured":"(2022, October 20). Facts and Figures. Available online: https:\/\/www.alz.org\/alzheimers-dementia\/facts-figures."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1001\/jamaneurol.2021.5216","article-title":"Prevalence estimates of amyloid abnormality across the Alzheimer Disease Clinical Spectrum","volume":"79","author":"Jansen","year":"2022","journal-title":"JAMA Neurol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1924","DOI":"10.1001\/jama.2015.4668","article-title":"Prevalence of cerebral amyloid pathology in persons without dementia: A meta-analysis","volume":"313","author":"Jansen","year":"2015","journal-title":"JAMA"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1001\/jamaneurol.2019.4749","article-title":"Characterization of Alzheimer disease biomarker discrepancies using cerebrospinal fluid phosphorylated tau and AV1451 positron emission tomography","volume":"77","author":"Meyer","year":"2020","journal-title":"JAMA Neurol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"e12069","DOI":"10.1002\/trc2.12069","article-title":"The pathway to secondary prevention of Alzheimer\u2019s disease","volume":"6","author":"McDade","year":"2020","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1131","DOI":"10.1007\/s11606-018-4377-y","article-title":"Underdiagnosis of Dementia: An observational study of patterns in diagnosis and awareness in US older adults","volume":"33","author":"Amjad","year":"2018","journal-title":"J. Gen. Intern. Med."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"e210169","DOI":"10.1001\/jamanetworkopen.2021.0169","article-title":"Sex differences in cognitive decline among US adults","volume":"4","author":"Levine","year":"2021","journal-title":"JAMA Netw. Open"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1038\/nrn2168","article-title":"Intracellular amyloid-\u03b2 in Alzheimer\u2019s disease","volume":"8","author":"LaFerla","year":"2007","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1016\/j.nlm.2011.08.003","article-title":"The A\u03b2 oligomer hypothesis for synapse failure and memory loss in Alzheimer\u2019s disease","volume":"96","author":"Ferreira","year":"2011","journal-title":"Neurobiol. Learn. Mem."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"260787","DOI":"10.1155\/2013\/260787","article-title":"Trimeric tau is toxic to human neuronal cells at low nanomolar concentrations","volume":"2013","author":"Tian","year":"2013","journal-title":"Int. J. Cell Biol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1016\/j.celrep.2014.02.031","article-title":"Detection of misfolded A\u03b2 oligomers for sensitive biochemical diagnosis of Alzheimer\u2019s disease","volume":"7","author":"Salvadores","year":"2014","journal-title":"Cell Rep."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/j.jalz.2012.11.005","article-title":"New ELISAs with high specificity for soluble oligomers of amyloid \u03b2-protein detect natural A\u03b2 oligomers in human brain but not CSF","volume":"9","author":"Yang","year":"2013","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1007\/s00401-014-1269-z","article-title":"TDP-43 is a key player in the clinical features associated with Alzheimer\u2019s disease","volume":"127","author":"Josephs","year":"2014","journal-title":"Acta Neuropathol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"4824","DOI":"10.1038\/ncomms5824","article-title":"Full-length TDP-43 forms toxic amyloid oligomers that are present in frontotemporal lobar dementia-TDP patients","volume":"5","author":"Fang","year":"2014","journal-title":"Nat. Commun."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Venkataraman, L., He, P., Khan, G., Harris, B.T., and Sierks, M.R. (2020). Isolation and characterization of antibody fragments selective for human FTD brain derived TDP-43 variants. BMC Neurosci., 21.","DOI":"10.1186\/s12868-020-00586-0"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/0022-3956(75)90026-6","article-title":"\u201cMini-mental state\u201d. A practical method for grading the cognitive state of patients for the clinician","volume":"12","author":"Folstein","year":"1975","journal-title":"J. Psychiatr. Res."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1136\/jnnp.23.1.56","article-title":"A rating scale for depression","volume":"23","author":"Hamilton","year":"1960","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_53","unstructured":"Lezak, M., Howieson, D., and Loring, D. (2004). Neuropsychological Assessment, Oxford University Press. [4th ed.]."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"2412","DOI":"10.1212\/WNL.43.11.2412-a","article-title":"The Clinical Dementia Rating (CDR): Current version and scoring rules","volume":"43","author":"Morris","year":"1993","journal-title":"Neurology"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1016\/j.jalz.2011.03.008","article-title":"The diagnosis of mild cognitive impairment due to Alzheimer\u2019s disease: Recommendations from the National Institute on Aging-Alzheimer\u2019s Association workgroups on diagnostic guidelines for Alzheimer\u2019s disease","volume":"7","author":"Albert","year":"2011","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1016\/j.jalz.2011.03.005","article-title":"The diagnosis of dementia due to Alzheimer\u2019s disease: Recommendations from the National Institute on Aging-Alzheimer\u2019s Association workgroups on diagnostic guidelines for Alzheimer\u2019s disease","volume":"7","author":"McKhann","year":"2011","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1002\/btpr.1987","article-title":"A sensitive phage-based capture ELISA for sub-femtomolar detection of protein variants directly from biological samples","volume":"31","author":"Williams","year":"2015","journal-title":"Biotechnol. Prog."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"171","DOI":"10.2225\/vol9-issue2-fulltext-6","article-title":"Improved affinity selection using phage display technology and off-rate based selection","volume":"9","author":"Yuan","year":"2006","journal-title":"Electron. J. Biotechnol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1212\/WNL.0000000000006322","article-title":"CNS disease-related protein variants as blood-based biomarkers in traumatic brain injury","volume":"91","author":"Williams","year":"2018","journal-title":"Neurology"},{"key":"ref_60","unstructured":"R Core Team (2022, June 22). R: A Language and Environment for Statistical Computing. Available online: https:\/\/www.R-project.org\/."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/24\/15670\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:37:44Z","timestamp":1760146664000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/24\/15670"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,10]]},"references-count":60,"journal-issue":{"issue":"24","published-online":{"date-parts":[[2022,12]]}},"alternative-id":["ijms232415670"],"URL":"https:\/\/doi.org\/10.3390\/ijms232415670","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2022,12,10]]}}}