{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,31]],"date-time":"2025-12-31T11:22:32Z","timestamp":1767180152994,"version":"build-2238731810"},"update-to":[{"DOI":"10.1371\/journal.pcbi.1013583","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2025,10,23]],"date-time":"2025-10-23T00:00:00Z","timestamp":1761177600000}}],"reference-count":70,"publisher":"Public Library of Science (PLoS)","issue":"10","license":[{"start":{"date-parts":[[2025,10,17]],"date-time":"2025-10-17T00:00:00Z","timestamp":1760659200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004837","name":"Ministerio de Ciencia e Innovaci\u00f3n","doi-asserted-by":"publisher","award":["PID2021-127311NB-I00"],"award-info":[{"award-number":["PID2021-127311NB-I00"]}],"id":[{"id":"10.13039\/501100004837","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004837","name":"Ministerio de Ciencia e Innovaci\u00f3n","doi-asserted-by":"publisher","award":["MICIN\/AEI\/10.13039\/501100011033\/FEDER"],"award-info":[{"award-number":["MICIN\/AEI\/10.13039\/501100011033\/FEDER"]}],"id":[{"id":"10.13039\/501100004837","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004837","name":"Ministerio de Ciencia e Innovaci\u00f3n","doi-asserted-by":"publisher","award":["Programme575 for Units of Excellence in R&D (project CEX2018-000792-M)"],"award-info":[{"award-number":["Programme575 for Units of Excellence in R&D (project CEX2018-000792-M)"]}],"id":[{"id":"10.13039\/501100004837","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003741","name":"Instituci\u00f3 Catalana de Recerca i Estudis Avan\u00e7ats","doi-asserted-by":"publisher","award":["Academia programme"],"award-info":[{"award-number":["Academia programme"]}],"id":[{"id":"10.13039\/501100003741","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>\n                    Alzheimer\u2019s disease encompasses multiple biological scales, spanning molecular factors, cells, tissues, and behavioral manifestations. The interplay among these scales in shaping the clinical phenotype is not yet fully comprehended. In particular, there is great interest in understanding the heterogeneity of the clinical aspects of AD in order to improve treatment and prevention, by targeting those aspects most susceptible to the disease. Here we employed a systems biology approach to address this issue, utilizing multilayer network analysis and deep phenotyping. This integrative analysis incorporated genomics, cerebrospinal fluid biomarkers, tau and amyloid beta (A\n                    <jats:italic>\u03b2<\/jats:italic>\n                    ) PET imaging, brain MRI data, risk factors, and clinical information (cognitive tests scores, Clinical Dementia Rating and clinical diagnosis) obtained through the ADNI collaboration. Multilayer networks were built based on mutual information between the elements of each layer and between layers. Boolean simulations allowed us to identify paths that transmit dynamic information across layers. The most prominent path for predicting variables in the cognitive phenotype layer included the PET radiotracer fluorodeoxyglucose (FDG) in the posterior cingulate. Combinations of different symptomatic variables, mainly related to mental health (depression, mood swings, drowsiness) and vascular features (hypertension, cardiovascular history), were also part of the paths explaining the average phenotype. Our results show that integrating the flow of information across biological scales reveals relevant paths for AD, which can be subsequently explored as potential biomarkers or therapeutic targets. In particular, our results point for paths related with brain hypometabolism as a key feature in AD.\n                  <\/jats:p>","DOI":"10.1371\/journal.pcbi.1013583","type":"journal-article","created":{"date-parts":[[2025,10,17]],"date-time":"2025-10-17T17:51:49Z","timestamp":1760723509000},"page":"e1013583","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Multiscale networks in Alzheimer\u2019s disease identify brain hypometabolism as central across biological scales"],"prefix":"10.1371","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-4611-3395","authenticated-orcid":true,"given":"Elena","family":"Lara-Simon","sequence":"first","affiliation":[]},{"given":"Juan 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Anat."},{"issue":"4","key":"pcbi.1013583.ref002","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1016\/j.jalz.2018.02.018","article-title":"NIA-AA research framework: toward a biological definition of Alzheimer\u2019s disease","volume":"14","author":"Jr Jack CR","year":"2018","journal-title":"Alzheimers Dement."},{"issue":"12","key":"pcbi.1013583.ref003","doi-asserted-by":"crossref","first-page":"3776","DOI":"10.1093\/brain\/awaa325","article-title":"Pathophysiological subtypes of Alzheimer\u2019s disease based on cerebrospinal fluid proteomics","volume":"143","author":"BM Tijms","year":"2020","journal-title":"Brain."},{"issue":"5","key":"pcbi.1013583.ref004","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1038\/s41591-021-01309-6","article-title":"Four distinct trajectories of tau deposition identified in Alzheimer\u2019s disease","volume":"27","author":"JW Vogel","year":"2021","journal-title":"Nat Med."},{"key":"pcbi.1013583.ref005","article-title":"Plasma p-tau231 and p-tau217 as state markers of amyloid-\u03b2 pathology in preclinical Alzheimer\u2019s disease","author":"M Mil\u00e0-Alom\u00e0","year":"2022","journal-title":"Nat Med."},{"issue":"1","key":"pcbi.1013583.ref006","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1186\/s13059-017-1215-1","article-title":"Multi-omics approaches to disease","volume":"18","author":"Y Hasin","year":"2017","journal-title":"Genome Biol."},{"issue":"1","key":"pcbi.1013583.ref007","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1038\/nrg2918","article-title":"Network medicine: a network-based approach to human disease","volume":"12","author":"A-L Barab\u00e1si","year":"2011","journal-title":"Nat Rev Genet."},{"key":"pcbi.1013583.ref008","doi-asserted-by":"crossref","first-page":"4212","DOI":"10.1038\/ncomms5212","article-title":"Human symptoms-disease network","volume":"5","author":"X Zhou","year":"2014","journal-title":"Nat 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multilayer networks","volume":"28","author":"B Avelar-Pereira","year":"2023","journal-title":"Mol Psychiatry."},{"issue":"4","key":"pcbi.1013583.ref013","doi-asserted-by":"crossref","DOI":"10.1016\/j.nic.2005.09.008","article-title":"The Alzheimer\u2019s disease neuroimaging initiative","volume":"15","author":"SG Mueller","year":"2005","journal-title":"Neuroimaging Clin N Am."},{"issue":"6","key":"pcbi.1013583.ref014","doi-asserted-by":"crossref","first-page":"871","DOI":"10.3390\/genes12060871","article-title":"TOMM40 RNA transcription in Alzheimer\u2019s disease brain and its implication in mitochondrial dysfunction","volume":"12","author":"E-G Lee","year":"2021","journal-title":"Genes (Basel)."},{"key":"pcbi.1013583.ref015","doi-asserted-by":"crossref","first-page":"260","DOI":"10.3389\/fnins.2018.00260","article-title":"Combining polygenic hazard score with volumetric MRI and cognitive measures improves prediction of progression from mild cognitive impairment to Alzheimer\u2019s disease","volume":"12","author":"K Kauppi","year":"2018","journal-title":"Front Neurosci."},{"issue":"3","key":"pcbi.1013583.ref016","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1002\/ana.25029","article-title":"Polygenic hazard scores in preclinical Alzheimer disease","volume":"82","author":"CH Tan","year":"2017","journal-title":"Ann Neurol."},{"issue":"11","key":"pcbi.1013583.ref017","doi-asserted-by":"crossref","DOI":"10.1212\/WNL.0000000000010256","article-title":"Multitracer model for staging cortical amyloid deposition using PET imaging","volume":"95","author":"LE Collij","year":"2020","journal-title":"Neurology."},{"issue":"1","key":"pcbi.1013583.ref018","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1186\/s13195-021-00880-x","article-title":"Tau-PET and in vivo Braak-staging as prognostic markers of future cognitive decline in cognitively normal to demented individuals","volume":"13","author":"D Biel","year":"2021","journal-title":"Alzheimers Res Ther."},{"issue":"7","key":"pcbi.1013583.ref019","doi-asserted-by":"crossref","first-page":"1207","DOI":"10.1016\/j.neurobiolaging.2009.07.002","article-title":"Associations between cognitive, functional, and FDG-PET measures of decline in AD and MCI","volume":"32","author":"SM Landau","year":"2011","journal-title":"Neurobiol Aging."},{"issue":"16","key":"pcbi.1013583.ref020","doi-asserted-by":"crossref","first-page":"1395","DOI":"10.1212\/WNL.0b013e3182166e96","article-title":"Alzheimer-signature MRI biomarker predicts AD dementia in cognitively normal adults","volume":"76","author":"BC Dickerson","year":"2011","journal-title":"Neurology."},{"key":"pcbi.1013583.ref021","doi-asserted-by":"crossref","first-page":"802","DOI":"10.1016\/j.nicl.2016.05.017","article-title":"A large-scale comparison of cortical thickness and volume methods for measuring Alzheimer\u2019s disease severity","volume":"11","author":"CG Schwarz","year":"2016","journal-title":"Neuroimage Clin."},{"key":"pcbi.1013583.ref022","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1097\/00002093-199700112-00003","article-title":"Development of cognitive instruments for use in clinical trials of antidementia drugs","volume":"11","author":"RC Mohs","year":"1997","journal-title":"Alzheimer Disease & Associated Disorders."},{"issue":"3","key":"pcbi.1013583.ref023","first-page":"189","article-title":"\u201cMini-mental state\u201d. A practical method for grading the cognitive state of patients for the clinician","volume":"12","author":"MF Folstein","year":"1975","journal-title":"J Psychiatr Res."},{"issue":"11","key":"pcbi.1013583.ref024","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":"JC Morris","year":"1993","journal-title":"Neurology."},{"issue":"7","key":"pcbi.1013583.ref025","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1007\/BF02339212","article-title":"Hachinski\u2019s ischemic score and the diagnosis of vascular dementia: a review","volume":"14","author":"L Pantoni","year":"1993","journal-title":"Ital J Neurol Sci."},{"key":"pcbi.1013583.ref026","unstructured":"Shannon CE, Weaver W. The mathematical theory of communication. Urbana: University of Illinois Press; 1998."},{"key":"pcbi.1013583.ref027","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1007\/BF01025996","article-title":"Mutual information functions versus correlation functions","volume":"60","author":"W Li","year":"1990","journal-title":"J Stat Phys."},{"key":"pcbi.1013583.ref028","doi-asserted-by":"crossref","first-page":"066138","DOI":"10.1103\/PhysRevE.69.066138","article-title":"Estimating mutual information","volume":"69","author":"A Kraskov","year":"2004","journal-title":"Phys Rev E Stat Nonlin Soft Matter Phys."},{"issue":"85","key":"pcbi.1013583.ref029","first-page":"2825","article-title":"Scikit-learn: machine learning in python","volume":"12","author":"F Pedregosa","year":"2011","journal-title":"Journal of Machine Learning Research."},{"key":"pcbi.1013583.ref030","unstructured":"Newman M. Networks. Oxford University Press; 2010. https:\/\/academic.oup.com\/book\/27303.2023"},{"issue":"12","key":"pcbi.1013583.ref031","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pcbi.1002297","article-title":"Information routing driven by background chatter in a signaling network","volume":"7","author":"N Domedel-Puig","year":"2011","journal-title":"PLoS Comput Biol."},{"key":"pcbi.1013583.ref032","unstructured":"Lasher CD. Edge swap graph; 2011 -2012. GitHub Gist. https:\/\/gist.github.com\/gotgenes\/2770023."},{"issue":"3","key":"pcbi.1013583.ref033","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1038\/s41583-019-0132-6","article-title":"Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease","volume":"20","author":"DA Butterfield","year":"2019","journal-title":"Nat Rev Neurosci."},{"issue":"16","key":"pcbi.1013583.ref034","doi-asserted-by":"crossref","first-page":"1188","DOI":"10.1089\/ars.2019.7763","article-title":"Central and peripheral metabolic defects contribute to the pathogenesis of Alzheimer\u2019s disease: targeting mitochondria for diagnosis and prevention","volume":"32","author":"Y Peng","year":"2020","journal-title":"Antioxid Redox Signal."},{"issue":"11","key":"pcbi.1013583.ref035","doi-asserted-by":"crossref","first-page":"1474","DOI":"10.15252\/embj.201695810","article-title":"Brain metabolism in health, aging, and neurodegeneration","volume":"36","author":"S Camandola","year":"2017","journal-title":"The EMBO Journal."},{"key":"pcbi.1013583.ref036","doi-asserted-by":"crossref","first-page":"670","DOI":"10.3389\/fnins.2020.00670","article-title":"Down syndrome is a metabolic disease: altered insulin signaling mediates peripheral and brain dysfunctions","volume":"14","author":"M Dierssen","year":"2020","journal-title":"Front Neurosci."},{"key":"pcbi.1013583.ref037","doi-asserted-by":"crossref","first-page":"1003721","DOI":"10.3389\/fnagi.2022.1003721","article-title":"Redox signaling and metabolism in Alzheimer\u2019s disease","volume":"14","author":"MI Holubiec","year":"2022","journal-title":"Front Aging Neurosci."},{"issue":"11","key":"pcbi.1013583.ref038","doi-asserted-by":"crossref","first-page":"951","DOI":"10.1016\/S1474-4422(20)30314-8","article-title":"Amyloid-PET and 18F-FDG-PET in the diagnostic investigation of Alzheimer\u2019s disease and other dementias","volume":"19","author":"G Ch\u00e9telat","year":"2020","journal-title":"Lancet Neurol."},{"issue":"1","key":"pcbi.1013583.ref039","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1002\/ana.410420114","article-title":"Metabolic reduction in the posterior cingulate cortex in very early Alzheimer\u2019s disease","volume":"42","author":"S Minoshima","year":"1997","journal-title":"Ann Neurol."},{"issue":"13","key":"pcbi.1013583.ref040","doi-asserted-by":"crossref","first-page":"1194","DOI":"10.1212\/WNL.0b013e31828970c2","article-title":"Cognitive reserve associated with FDG-PET in preclinical Alzheimer disease","volume":"80","author":"M Ewers","year":"2013","journal-title":"Neurology."},{"key":"pcbi.1013583.ref041","first-page":"3105","article-title":"Examination of the relationship between PiB-PET and FDG-PET in Alzheimer\u2019s disease using random forest and two-sample t-test","volume":"61","author":"Y Tsubaki","year":"2020","journal-title":"Journal of Nuclear Medicine."},{"issue":"4","key":"pcbi.1013583.ref042","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1007\/s40336-013-0029-8","article-title":"FDG PET and cognitive symptoms of dementia","volume":"1","author":"D Perani","year":"2013","journal-title":"Clin Transl Imaging."},{"issue":"6711","key":"pcbi.1013583.ref043","doi-asserted-by":"crossref","DOI":"10.1126\/science.abm6131","article-title":"Restoring hippocampal glucose metabolism rescues cognition across Alzheimer\u2019s disease pathologies","volume":"385","author":"PS Minhas","year":"2024","journal-title":"Science."},{"issue":"2","key":"pcbi.1013583.ref044","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1007\/s00401-011-0821-3","article-title":"Clinicopathological correlates of behavioral and psychological symptoms of dementia","volume":"122","author":"MF Casanova","year":"2011","journal-title":"Acta Neuropathol."},{"issue":"4","key":"pcbi.1013583.ref045","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1176\/jnp.9.4.556","article-title":"Major and minor depression in Alzheimer\u2019s disease: prevalence and impact","volume":"9","year":"1997","journal-title":"JNP."},{"issue":"2","key":"pcbi.1013583.ref046","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1021\/acs.jproteome.3c00289","article-title":"Shared proteins and pathways of cardiovascular and cognitive diseases: relation to vascular cognitive impairment","volume":"23","author":"ME Zeylan","year":"2024","journal-title":"J Proteome Res."},{"issue":"7","key":"pcbi.1013583.ref047","doi-asserted-by":"crossref","first-page":"888","DOI":"10.1016\/j.jacc.2020.12.027","article-title":"Subclinical atherosclerosis and brain metabolism in middle-aged individuals","volume":"77","author":"M Cortes-Canteli","year":"2021","journal-title":"Journal of the American College of Cardiology."},{"issue":"9","key":"pcbi.1013583.ref048","doi-asserted-by":"crossref","DOI":"10.1016\/S2666-7568(23)00134-4","article-title":"Longitudinal interplay between subclinical atherosclerosis, cardiovascular risk factors, and cerebral glucose metabolism in midlife: results from the PESA prospective cohort study","volume":"4","author":"C Trist\u00e3o-Pereira","year":"2023","journal-title":"Lancet Healthy Longev."},{"key":"pcbi.1013583.ref049","doi-asserted-by":"crossref","first-page":"5","DOI":"10.3389\/fcvm.2020.00005","article-title":"Hypertension and the risk of dementia","volume":"7","author":"C Sierra","year":"2020","journal-title":"Front Cardiovasc Med."},{"issue":"12","key":"pcbi.1013583.ref050","doi-asserted-by":"crossref","first-page":"2866","DOI":"10.1007\/s00259-020-04758-2","article-title":"Regional [18F]flortaucipir PET is more closely associated with disease severity than CSF p-tau in Alzheimer\u2019s disease","volume":"47","author":"EE Wolters","year":"2020","journal-title":"Eur J Nucl Med Mol Imaging."},{"key":"pcbi.1013583.ref051","doi-asserted-by":"crossref","first-page":"101544","DOI":"10.1016\/j.arr.2021.101544","article-title":"Biomarkers used in Alzheimer\u2019s disease diagnosis, treatment, and prevention","volume":"74","author":"YAR Mahaman","year":"2022","journal-title":"Ageing Res Rev."},{"issue":"2","key":"pcbi.1013583.ref052","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1038\/s41593-021-00999-y","article-title":"Large-scale deep multi-layer analysis of Alzheimer\u2019s disease brain reveals strong proteomic disease-related changes not observed at the RNA level","volume":"25","author":"ECB Johnson","year":"2022","journal-title":"Nat Neurosci."},{"issue":"10","key":"pcbi.1013583.ref053","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1186\/s13073-014-0082-6","article-title":"Modules, networks and systems medicine for understanding disease and aiding diagnosis","volume":"6","author":"M Gustafsson","year":"2014","journal-title":"Genome Med."},{"issue":"34","key":"pcbi.1013583.ref054","doi-asserted-by":"crossref","first-page":"12741","DOI":"10.1073\/pnas.0605457103","article-title":"Identification of inflammatory gene modules based on variations of human endothelial cell responses to oxidized lipids","volume":"103","author":"PS Gargalovic","year":"2006","journal-title":"Proc Natl Acad Sci U S A."},{"key":"pcbi.1013583.ref055","doi-asserted-by":"crossref","first-page":"104023","DOI":"10.1016\/j.compbiomed.2020.104023","article-title":"Prioritizing disease biomarkers using functional module based network analysis: a multilayer consensus driven scheme","volume":"126","author":"M Jha","year":"2020","journal-title":"Comput Biol Med."},{"key":"pcbi.1013583.ref056","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1186\/1752-0509-7-32","article-title":"Construction and analysis of the protein-protein interaction network related to essential hypertension","volume":"7","author":"J Ran","year":"2013","journal-title":"BMC Syst Biol."},{"key":"pcbi.1013583.ref057","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1016\/j.plrev.2017.11.003","article-title":"Network science of biological systems at different scales: A review","volume":"24","author":"M Gosak","year":"2018","journal-title":"Phys Life Rev."},{"key":"pcbi.1013583.ref058","first-page":"1880","article-title":"HCNM: heterogeneous correlation network model for multi-level integrative study of multi-omics data for cancer subtype prediction","volume":"2021","author":"RR Vangimalla","year":"2021","journal-title":"Annu Int Conf IEEE Eng Med Biol Soc."},{"issue":"1","key":"pcbi.1013583.ref059","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1093\/bioinformatics\/btab580","article-title":"A cross-level information transmission network for hierarchical omics data integration and phenotype prediction from a new genotype","volume":"38","author":"D He","year":"2021","journal-title":"Bioinformatics."},{"issue":"534","key":"pcbi.1013583.ref060","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1080\/01621459.2020.1775611","article-title":"Bayesian structure learning in multi-layered genomic networks","volume":"116","author":"MJ Ha","year":"2021","journal-title":"J Am Stat Assoc."},{"key":"pcbi.1013583.ref061","doi-asserted-by":"crossref","first-page":"1159","DOI":"10.3389\/fonc.2020.01159","article-title":"A cancer gene module mining method based on bio-network of multi-omics gene groups","volume":"10","author":"C Wang","year":"2020","journal-title":"Front Oncol."},{"issue":"3","key":"pcbi.1013583.ref062","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1038\/s41571-019-0273-6","article-title":"A systems approach to clinical oncology uses deep phenotyping to deliver personalized care","volume":"17","author":"JT Yurkovich","year":"2020","journal-title":"Nat Rev Clin Oncol."},{"issue":"1","key":"pcbi.1013583.ref063","doi-asserted-by":"crossref","DOI":"10.1186\/s41044-020-00046-0","article-title":"Multilayer networks: aspects, implementations, and application in biomedicine","volume":"5","author":"Z Hammoud","year":"2020","journal-title":"Big Data Anal."},{"issue":"11","key":"pcbi.1013583.ref064","doi-asserted-by":"crossref","first-page":"1555","DOI":"10.3390\/ph16111555","article-title":"Construction of an exudative age-related macular degeneration diagnostic and therapeutic molecular network using multi-layer network analysis, a fuzzy logic model, and deep learning techniques: are retinal and brain neurodegenerative disorders related?","volume":"16","author":"H Latifi-Navid","year":"2023","journal-title":"Pharmaceuticals (Basel)."},{"key":"pcbi.1013583.ref065","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1016\/j.plrev.2017.11.003","article-title":"Network science of biological systems at different scales: A 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