{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T06:34:44Z","timestamp":1791441284272,"version":"4.3.3"},"reference-count":51,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2020,7,22]],"date-time":"2020-07-22T00:00:00Z","timestamp":1595376000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Mucopolysaccharidosis type II is a lysosomal storage disorder caused by a deficiency of iduronate-2-sulfatase (IDS) and characterized by the accumulation of the primary storage substrate, glycosaminoglycans (GAGs). Understanding central nervous system (CNS) pathophysiology in neuronopathic MPS II (nMPS II) has been hindered by the lack of CNS biomarkers. Characterization of fluid biomarkers has been largely focused on evaluating GAGs in cerebrospinal fluid (CSF) and the periphery; however, GAG levels alone do not accurately reflect the broad cellular dysfunction in the brains of MPS II patients. We utilized a preclinical mouse model of MPS II, treated with a brain penetrant form of IDS (ETV:IDS) to establish the relationship between markers of primary storage and downstream pathway biomarkers in the brain and CSF. We extended the characterization of pathway and neurodegeneration biomarkers to nMPS II patient samples. In addition to the accumulation of CSF GAGs, nMPS II patients show elevated levels of lysosomal lipids, neurofilament light chain, and other biomarkers of neuronal damage and degeneration. Furthermore, we find that these biomarkers of downstream pathology are tightly correlated with heparan sulfate. Exploration of the responsiveness of not only CSF GAGs but also pathway and disease-relevant biomarkers during drug development will be crucial for monitoring disease progression, and the development of effective therapies for nMPS II.<\/jats:p>","DOI":"10.3390\/ijms21155188","type":"journal-article","created":{"date-parts":[[2020,7,23]],"date-time":"2020-07-23T10:14:06Z","timestamp":1595499246000},"page":"5188","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Characterization of Fluid Biomarkers Reveals Lysosome Dysfunction and Neurodegeneration in Neuronopathic MPS II Patients"],"prefix":"10.3390","volume":"21","author":[{"given":"Akhil","family":"Bhalla","sequence":"first","affiliation":[{"name":"Denali Therapeutics Inc., South San Francisco, CA 94080, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7947-2585","authenticated-orcid":false,"given":"Ritesh","family":"Ravi","sequence":"additional","affiliation":[{"name":"Denali Therapeutics Inc., South San Francisco, CA 94080, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng","family":"Fang","sequence":"additional","affiliation":[{"name":"Denali Therapeutics Inc., South San Francisco, CA 94080, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0313-0041","authenticated-orcid":false,"given":"Annie","family":"Arguello","sequence":"additional","affiliation":[{"name":"Denali Therapeutics Inc., South San Francisco, CA 94080, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonnet S.","family":"Davis","sequence":"additional","affiliation":[{"name":"Denali Therapeutics Inc., South San Francisco, CA 94080, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chi-Lu","family":"Chiu","sequence":"additional","affiliation":[{"name":"Denali Therapeutics Inc., South San Francisco, CA 94080, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica R.","family":"Blumenfeld","sequence":"additional","affiliation":[{"name":"Denali Therapeutics Inc., South San Francisco, CA 94080, USA"},{"name":"Department of Neuroscience, University of California, San Francisco, San Francisco, CA 94158, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hoang N.","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Denali Therapeutics Inc., South San Francisco, CA 94080, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy K.","family":"Earr","sequence":"additional","affiliation":[{"name":"Denali Therapeutics Inc., South San Francisco, CA 94080, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1054-2527","authenticated-orcid":false,"given":"Junhua","family":"Wang","sequence":"additional","affiliation":[{"name":"Denali Therapeutics Inc., South San Francisco, CA 94080, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6700-301X","authenticated-orcid":false,"given":"Giuseppe","family":"Astarita","sequence":"additional","affiliation":[{"name":"Denali Therapeutics Inc., South San Francisco, CA 94080, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuda","family":"Zhu","sequence":"additional","affiliation":[{"name":"Denali Therapeutics Inc., South San Francisco, CA 94080, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Damian","family":"Fiore","sequence":"additional","affiliation":[{"name":"Denali Therapeutics Inc., South San Francisco, CA 94080, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kimberly","family":"Scearce-Levie","sequence":"additional","affiliation":[{"name":"Denali Therapeutics Inc., South San Francisco, CA 94080, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dolores","family":"Diaz","sequence":"additional","affiliation":[{"name":"Denali Therapeutics Inc., South San Francisco, CA 94080, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather","family":"Cahan","sequence":"additional","affiliation":[{"name":"Denali Therapeutics Inc., South San Francisco, CA 94080, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0821-7509","authenticated-orcid":false,"given":"Matthew D.","family":"Troyer","sequence":"additional","affiliation":[{"name":"Denali Therapeutics Inc., South San Francisco, CA 94080, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4819-3908","authenticated-orcid":false,"given":"Jeffrey M.","family":"Harris","sequence":"additional","affiliation":[{"name":"Denali Therapeutics Inc., South San Francisco, CA 94080, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1530-6777","authenticated-orcid":false,"given":"Maria L.","family":"Escolar","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Children\u2019s Hospital of Pittsburgh, Pittsburgh, PA 15224, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,7,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Viana, G.M., Priestman, D.A., Platt, F.M., Khan, S., Tomatsu, S., and Pshezhetsky, A.V. (2020). Brain Pathology in Mucopolysaccharidoses (MPS) Patients with Neurological Forms. J. Clin. Med., 9.","DOI":"10.3390\/jcm9020396"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e377","DOI":"10.1542\/peds.2007-1350","article-title":"Recognition and diagnosis of mucopolysaccharidosis II (Hunter syndrome)","volume":"121","author":"Martin","year":"2008","journal-title":"Pediatrics"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"D\u2019Avanzo, F., Rigon, L., Zanetti, A., and Tomanin, R. (2020). Mucopolysaccharidosis Type II: One Hundred Years of Research, Diagnosis, and Treatment. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21041258"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1007\/8904_2013_289","article-title":"Enzyme Replacement Therapy in Mucopolysaccharidosis II Patients Under 1 Year of Age","volume":"14","author":"Lampe","year":"2014","journal-title":"JIMD Rep."},{"key":"ref_5","first-page":"103","article-title":"Levels of glycosaminoglycans in the cerebrospinal fluid of healthy young adults, surrogate-normal children, and Hunter syndrome patients with and without cognitive impairment","volume":"5","author":"Hendriksz","year":"2015","journal-title":"Mol. Genet. Metab. Rep."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Hendriksz, C., Muenzer, J., Burton, B., Pan, L., Wang, N., Naimy, H., Pano, A., and Barbier, A. (2015). A Cerebrospinal Fluid Collection Study in Pediatric and Adult Patients With Hunter Syndrome. J. Inborn Errors Metab. Screen., 1.","DOI":"10.1177\/2326409815595821"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1016\/j.semcdb.2004.03.002","article-title":"Secondary accumulation of gangliosides in lysosomal storage disorders","volume":"15","author":"Walkley","year":"2004","journal-title":"Semin. Cell Dev. Boil."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1016\/j.bbamcr.2008.11.014","article-title":"Secondary lipid accumulation in lysosomal disease","volume":"1793","author":"Walkley","year":"2009","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1399","DOI":"10.1111\/j.1471-4159.1980.tb11220.x","article-title":"Mucopolysaccharidosis Types IH, IS, II and IIIA: Glycosaminoglycans and Lipids of Isolated Brain Cells and Other Fractions from Autopsied Tissues","volume":"34","author":"Constantopoulos","year":"1980","journal-title":"J. Neurochem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1111\/jnc.13976","article-title":"Subregional brain distribution of simple and complex glycosphingolipids in the mucopolysaccharidosis type I (Hurler syndrome) mouse: Impact of diet","volume":"141","author":"Saville","year":"2017","journal-title":"J. Neurochem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1016\/j.ajhg.2009.07.011","article-title":"IDS crossing of the blood-brain barrier corrects CNS defects in MPSII mice","volume":"85","author":"Polito","year":"2009","journal-title":"Am. J. Hum. Genet."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Gleitz, H.F., Liao, A.Y., Cook, J.R., Rowlston, S.F., Forte, G.M., D\u2019Souza, Z., O\u2019Leary, C., Holley, R.J., and Bigger, B.W. (2018). Brain-targeted stem cell gene therapy corrects mucopolysaccharidosis type II via multiple mechanisms. EMBO Mol. Med., 10.","DOI":"10.15252\/emmm.201708730"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e35787","DOI":"10.1371\/journal.pone.0035787","article-title":"Neuropathology in mouse models of mucopolysaccharidosis type I, IIIA and IIIB","volume":"7","author":"Wilkinson","year":"2012","journal-title":"PLoS ONE"},{"key":"ref_14","first-page":"100455","article-title":"Biomarkers in patients with mucopolysaccharidosis type II and IV","volume":"19","author":"Fujitsuka","year":"2019","journal-title":"Mol. Genet. Metab. Rep."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1608","DOI":"10.1016\/j.bbadis.2016.05.021","article-title":"Oxidative and nitrative stress and pro-inflammatory cytokines in Mucopolysaccharidosis type II patients: Effect of long-term enzyme replacement therapy and relation with glycosaminoglycan accumulation","volume":"1862","author":"Jacques","year":"2016","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"38305","DOI":"10.1038\/srep38305","article-title":"Elevated cerebral spinal fluid biomarkers in children with mucopolysaccharidosis I-H","volume":"6","author":"Raymond","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"728","DOI":"10.1038\/jhg.2013.92","article-title":"High-dose enzyme replacement therapy attenuates cerebroventriculomegaly in a mouse model of mucopolysaccharidosis type II","volume":"58","author":"Ahn","year":"2013","journal-title":"J. Hum. Genet."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1007\/s00401-007-0325-3","article-title":"Mechanisms of neurodegeneration in mucopolysaccharidoses II and IIIB: Analysis of human brain tissue","volume":"115","author":"Hamano","year":"2008","journal-title":"Acta Neuropathol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1186\/s12987-017-0073-2","article-title":"Correlation of CSF flow using phase-contrast MRI with ventriculomegaly and CSF opening pressure in mucopolysaccharidoses","volume":"14","author":"Corte","year":"2017","journal-title":"Fluids Barriers CNS"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Huang, F., Zhu, Y., Hsiao-Nakamoto, J., Tang, X., Dugas, J.C., Moscovitch-Lopatin, M., Glass, J.D., Brown, R.H., Ladha, S.S., and Lacomis, D. (2020). Longitudinal biomarkers in amyotrophic lateral sclerosis. Ann. Clin. Transl. Neurol.","DOI":"10.1002\/acn3.51078"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.neuron.2016.05.018","article-title":"Neurofilament Light Chain in Blood and CSF as Marker of Disease Progression in Mouse Models and in Neurodegenerative Diseases","volume":"91","author":"Bacioglu","year":"2016","journal-title":"Neuron"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1002\/ana.25276","article-title":"Neurofilament light: A candidate biomarker of presymptomatic amyotrophic lateral sclerosis and phenoconversion","volume":"84","author":"Benatar","year":"2018","journal-title":"Ann. Neurol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1037","DOI":"10.3389\/fneur.2018.01037","article-title":"CSF Neurofilament Light Chain Levels in Primary Progressive MS: Signs of Axonal Neurodegeneration","volume":"9","author":"Pawlitzki","year":"2018","journal-title":"Front. Neurol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1002\/ana.22247","article-title":"Axonal damage in relapsing multiple sclerosis is markedly reduced by natalizumab","volume":"69","author":"Gunnarsson","year":"2011","journal-title":"Ann. Neurol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2129","DOI":"10.1007\/s00415-019-09389-8","article-title":"NFL is a marker of treatment response in children with SMA treated with nusinersen","volume":"266","author":"Olsson","year":"2019","journal-title":"J. Neurol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2437","DOI":"10.1002\/acn3.50942","article-title":"Neurofilament light is a treatment-responsive biomarker in CLN2 disease","volume":"6","author":"Ru","year":"2019","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.ymgme.2017.10.007","article-title":"Treatment of brain disease in the mucopolysaccharidoses","volume":"122s","author":"Scarpa","year":"2017","journal-title":"Mol. Genet. Metab."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Parini, R., and Deodato, F. (2020). Intravenous Enzyme Replacement Therapy in Mucopolysaccharidoses: Clinical Effectiveness and Limitations. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21082975"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1038\/gim.2015.36","article-title":"A phase I\/II study of intrathecal idursulfase-IT in children with severe mucopolysaccharidosis II","volume":"18","author":"Muenzer","year":"2016","journal-title":"Genet. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1016\/j.ymthe.2018.12.005","article-title":"Iduronate-2-Sulfatase with Anti-human Transferrin Receptor Antibody for Neuropathic Mucopolysaccharidosis II: A Phase 1\/2 Trial","volume":"27","author":"Okuyama","year":"2019","journal-title":"Mol. Ther."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"eaay1163","DOI":"10.1126\/scitranslmed.aay1163","article-title":"Brain delivery and activity of a lysosomal enzyme using a blood-brain barrier transport vehicle in mice","volume":"12","author":"Ullman","year":"2020","journal-title":"Sci. Transl. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1111\/j.1651-2227.2002.tb03118.x","article-title":"Enzyme replacement therapy in mucopolysaccharidosis type II (Hunter syndrome): A preliminary report","volume":"91","author":"Muenzer","year":"2002","journal-title":"Acta Paediatr. Suppl."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"eaay1359","DOI":"10.1126\/scitranslmed.aay1359","article-title":"Brain delivery of therapeutic proteins using an Fc fragment blood-brain barrier transport vehicle in mice and monkeys","volume":"12","author":"Kariolis","year":"2020","journal-title":"Sci. Transl. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1111\/jnc.14632","article-title":"The role of innate immunity in mucopolysaccharide diseases","volume":"148","author":"Parker","year":"2019","journal-title":"J. Neurochem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"825","DOI":"10.4155\/bio-2018-0025","article-title":"A novel LC-MS\/MS assay to quantify dermatan sulfate in cerebrospinal fluid as a biomarker for mucopolysaccharidosis II","volume":"10","author":"Pan","year":"2018","journal-title":"Bioanalysis"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"e4294","DOI":"10.1002\/bmc.4294","article-title":"Development and validation of an LC-MS\/MS Method for the quantitation of heparan sulfate in human urine","volume":"32","author":"Wang","year":"2018","journal-title":"Biomed. Chromatogr."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1053\/j.seminhematol.2009.10.008","article-title":"Transplant outcomes in mucopolysaccharidoses","volume":"47","author":"Prasad","year":"2010","journal-title":"Semin. Hematol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/S0022-3476(96)70202-0","article-title":"Bone marrow transplantation in Hunter syndrome","volume":"129","author":"McKinnis","year":"1996","journal-title":"J. Pediatr."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1423","DOI":"10.1038\/gim.2018.29","article-title":"Long-term outcomes of systemic therapies for Hurler syndrome: An international multicenter comparison","volume":"20","author":"Eisengart","year":"2018","journal-title":"Genet. Med."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1795","DOI":"10.1016\/j.bbmt.2017.06.020","article-title":"Hematopoietic Stem Cell Transplantation for Patients with Mucopolysaccharidosis II","volume":"23","author":"Kubaski","year":"2017","journal-title":"Biol. Blood Marrow Transplant."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1080\/01621459.1972.10481279","article-title":"Constructing Confidence Sets Using Rank Statistics","volume":"67","author":"Bauer","year":"1972","journal-title":"J. Am. Stat. Assoc."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1594","DOI":"10.1007\/s11064-010-0337-6","article-title":"Biological Function of the Cellular Lipid BMP\u2014BMP as a Key Activator for Cholesterol Sorting and Membrane Digestion","volume":"36","author":"Gallala","year":"2011","journal-title":"Neurochem. Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1002\/iub.477","article-title":"Metabolic pathways and intracellular trafficking of gangliosides","volume":"63","author":"Daniotti","year":"2011","journal-title":"IUBMB Life"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1016\/j.bbamcr.2008.09.020","article-title":"Principles of lysosomal membrane degradation: Cellular topology and biochemistry of lysosomal lipid degradation","volume":"1793","author":"Schulze","year":"2009","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1191","DOI":"10.1016\/j.ajem.2015.05.023","article-title":"Serum ubiquitin C-terminal hydrolase L1 as a biomarker for traumatic brain injury: A systematic review and meta-analysis","volume":"33","author":"Li","year":"2015","journal-title":"Am. J. Emerg. Med."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1111\/jnc.13399","article-title":"Glial fibrillar acidic protein in the cerebrospinal fluid of Alzheimer\u2019s disease, dementia with Lewy bodies, and frontotemporal lobar degeneration","volume":"136","author":"Ishiki","year":"2016","journal-title":"J. Neurochem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1136\/jnnp-2019-321954","article-title":"Plasma glial fibrillary acidic protein is raised in progranulin-associated frontotemporal dementia","volume":"91","author":"Heller","year":"2020","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1007\/s12031-019-01411-y","article-title":"Targeted Multiple Reaction Monitoring Analysis of CSF Identifies UCHL1 and GPNMB as Candidate Biomarkers for ALS","volume":"69","author":"Zhu","year":"2019","journal-title":"J. Mol. Neurosci."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"963","DOI":"10.2307\/2529876","article-title":"Random-Effects Models for Longitudinal Data","volume":"38","author":"Laird","year":"1982","journal-title":"Biometrics"},{"key":"ref_50","first-page":"1","article-title":"The R Core Team nlme: Linear and Nonlinear Mixed Effects Models","volume":"3","author":"Pinheiro","year":"2010","journal-title":"R Package Nlme Vers."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1111\/j.2517-6161.1995.tb02031.x","article-title":"Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing","volume":"57","author":"Benjamini","year":"1995","journal-title":"J. R. Stat. Soc. Ser. B Methodol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/15\/5188\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:50:44Z","timestamp":1760176244000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/15\/5188"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,7,22]]},"references-count":51,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2020,8]]}},"alternative-id":["ijms21155188"],"URL":"https:\/\/doi.org\/10.3390\/ijms21155188","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,7,22]]}}}