2025
Mechanism of EHMT2-mediated genomic imprinting associated with Prader-Willi syndrome
Wang S, Cheng Y, Lim J, Jang M, Forrest E, Kim Y, Donahue M, Jo S, Qiao S, Lee D, Hong J, Xiong Y, Jin J, Wang S, Jiang Y. Mechanism of EHMT2-mediated genomic imprinting associated with Prader-Willi syndrome. Nature Communications 2025, 16: 6125. PMID: 40610428, PMCID: PMC12229668, DOI: 10.1038/s41467-025-61156-8.Peer-Reviewed Original ResearchConceptsPWS-ICMaternal chromosomeImprinted domainExpression of paternally expressed genesPrader-Willi syndromeBipartite imprinting centerPaternally expressed genesHeterochromatin complexExpression of SNRPNImprinting centerPatient-derived cellsEHMT2 genesImprinted genesMaternal imprintingChromosomeMaternal deletionGenesPrader-WilliNoncoding RNAsEHMT2Imprint maintenanceEditing resultsPostnatal brainDerived cellsExpressionTargeted analysis of dyslexia-associated regions on chromosomes 6, 12 and 15 in large multigenerational cohorts
Chapman N, Navas P, Dorschner M, Mehaffey M, Wigg K, Price K, Naumova O, Kerr E, Guger S, Lovett M, Grigorenko E, Berninger V, Barr C, Wijsman E, Raskind W. Targeted analysis of dyslexia-associated regions on chromosomes 6, 12 and 15 in large multigenerational cohorts. PLOS ONE 2025, 20: e0324006. PMID: 40424442, PMCID: PMC12112411, DOI: 10.1371/journal.pone.0324006.Peer-Reviewed Original ResearchConceptsEvidence of associationLarge-scale sequencing studiesCis-acting regulatory regionsGenome-wide association studiesAggregating rare variantsRare exonic variantsDetected significant evidenceSingle nucleotide polymorphismsGenomic variationDeleterious variantsAssociated with reduced performanceAssociation studiesLarge-effectRegulatory elementsTranscriptional regulationRegulatory regionsQuantitative phenotypesCandidate genesExonic variantsChromosome 6Sequencing studiesSingle variantsCoding exonsMultiple traitsGenetic basis
2023
Beyond the Global Brain Differences: Intraindividual Variability Differences in 1q21.1 Distal and 15q11.2 BP1-BP2 Deletion Carriers
Boen R, Kaufmann T, van der Meer D, Frei O, Agartz I, Ames D, Andersson M, Armstrong N, Artiges E, Atkins J, Bauer J, Benedetti F, Boomsma D, Brodaty H, Brosch K, Buckner R, Cairns M, Calhoun V, Caspers S, Cichon S, Corvin A, Crespo-Facorro B, Dannlowski U, David F, de Geus E, de Zubicaray G, Desrivières S, Doherty J, Donohoe G, Ehrlich S, Eising E, Espeseth T, Fisher S, Forstner A, Fortaner-Uyà L, Frouin V, Fukunaga M, Ge T, Glahn D, Goltermann J, Grabe H, Green M, Groenewold N, Grotegerd D, Grøntvedt G, Hahn T, Hashimoto R, Hehir-Kwa J, Henskens F, Holmes A, Håberg A, Haavik J, Jacquemont S, Jansen A, Jockwitz C, Jönsson E, Kikuchi M, Kircher T, Kumar K, Le Hellard S, Leu C, Linden D, Liu J, Loughnan R, Mather K, McMahon K, McRae A, Medland S, Meinert S, Moreau C, Morris D, Mowry B, Mühleisen T, Nenadić I, Nöthen M, Nyberg L, Ophoff R, Owen M, Pantelis C, Paolini M, Paus T, Pausova Z, Persson K, Quidé Y, Marques T, Sachdev P, Sando S, Schall U, Scott R, Selbæk G, Shumskaya E, Silva A, Sisodiya S, Stein F, Stein D, Straube B, Streit F, Strike L, Teumer A, Teutenberg L, Thalamuthu A, Tooney P, Tordesillas-Gutierrez D, Trollor J, van ’t Ent D, van den Bree M, van Haren N, Vázquez-Bourgon J, Völzke H, Wen W, Wittfeld K, Ching C, Westlye L, Thompson P, Bearden C, Selmer K, Alnæs D, Andreassen O, Sønderby I, Group E. Beyond the Global Brain Differences: Intraindividual Variability Differences in 1q21.1 Distal and 15q11.2 BP1-BP2 Deletion Carriers. Biological Psychiatry 2023, 95: 147-160. PMID: 37661008, PMCID: PMC7615370, DOI: 10.1016/j.biopsych.2023.08.018.Peer-Reviewed Original ResearchMeSH KeywordsAbnormalities, MultipleBrainChromosome DeletionChromosomes, Human, Pair 15DNA Copy Number VariationsHumansMagnetic Resonance ImagingConceptsMedial visual cortexCortical surface areaBrain differencesCortical thicknessTemporal poleVisual cortexDeletion carriersGlobal brain measuresRegional brain differencesCopy number variantsSuperior temporal cortexSomatosensory cortexBrain valuesAltered neurodevelopmentAuditory cortexGlobal differencesRegional differencesTemporal cortexNumber variantsPosterior cingulateCortexBrain structuresBrain measuresStandardized differenceNoncarriers
2020
Congenital ichthyosis in Prader–Willi syndrome associated with maternal chromosome 15 uniparental disomy: Case report and review of autosomal recessive conditions unmasked by UPD
Muthusamy K, Macke E, Klee E, Tebben P, Hand J, Hasadsri L, Marcou C, Schimmenti L. Congenital ichthyosis in Prader–Willi syndrome associated with maternal chromosome 15 uniparental disomy: Case report and review of autosomal recessive conditions unmasked by UPD. American Journal Of Medical Genetics Part A 2020, 182: 2442-2449. PMID: 32815268, DOI: 10.1002/ajmg.a.61792.Peer-Reviewed Case Reports and Technical NotesMeSH KeywordsAdolescentAdultAngelman SyndromeChildChild, PreschoolChromosomes, Human, Pair 15Congenital AbnormalitiesFemaleGenes, RecessiveGenomic ImprintingHumansIchthyosisIn Situ Hybridization, FluorescenceInfantInfant, NewbornMaternal InheritancePrader-Willi SyndromeSphingosine N-AcyltransferaseUniparental DisomyYoung AdultConceptsPrader-Willi syndromeAutosomal recessive congenital ichthyosisAutosomal recessive conditionPrader-Willi syndrome/Angelman syndromeCeramide synthase 3Congenital ichthyosisUniparental disomyPathogenic variantsPaternal 15q11-q13 deletionComplex chromosomal rearrangementsCase of autosomal recessive congenital ichthyosisNovel pathogenic variantsDiagnosis of Prader-Willi syndromeRecessive conditionRecessive inherited diseaseAutosomal recessive inherited diseaseChromosomal rearrangementsGenetic mechanismsImprinting defectsMaternal UPD15Prader-WilliClinical courseUPD15Case reportClinical phenotypeDe novo Damaging Variants, Clinical Phenotypes and Post-Operative Outcomes in Congenital Heart Disease
Boskovski MT, Homsy J, Nathan M, Sleeper LA, Morton S, Manheimer KB, Tai A, Gorham J, Lewis M, Swartz M, Alfieris GM, Bacha EA, Karimi M, Meyer D, Nguyen K, Bernstein D, Romano-Adesman A, Porter GA, Goldmuntz E, Chung WK, Srivastava D, Kaltman JR, Tristani-Firouzi M, Lifton R, Roberts AE, Gaynor JW, Gelb BD, Kim R, Seidman JG, Brueckner M, Mayer JE, Newburger JW, Seidman CE. De novo Damaging Variants, Clinical Phenotypes and Post-Operative Outcomes in Congenital Heart Disease. Circulation Genomic And Precision Medicine 2020, 13: e002836-e002836. PMID: 32812804, PMCID: PMC7439931, DOI: 10.1161/circgen.119.002836.Peer-Reviewed Original ResearchConceptsWorse transplant-free survivalTransplant-free survivalExtra-cardiac anomaliesCongenital heart diseaseDe novo variantsHeart diseaseFinal extubationNovo variantsFirst operationPost-operative outcomesOpen heart surgeryPreoperative genetic testingRoutine clinical practiceDamaging variantsWhole-exome sequencingHeart transplantationAdverse outcomesSurgical dataPatientsClinical practiceCardiac repairClinical phenotypeDe novoGenetic testingGenetic abnormalities
2019
Epigenetic therapy of Prader–Willi syndrome
Kim Y, Wang SE, Jiang YH. Epigenetic therapy of Prader–Willi syndrome. Translational Research 2019, 208: 105-118. PMID: 30904443, PMCID: PMC6527448, DOI: 10.1016/j.trsl.2019.02.012.Peer-Reviewed Original ResearchConceptsPWS mouse modelEpigenetic-based therapiesMaternal chromosomesImprinted gene regulationEHMT2/G9aLysine 9 methyltransferasePatient-derived fibroblastsPrader-Willi syndromeGene regulationMethyltransferase SETDB1Epigenetic mechanismsSmall molecule librariesPWS genesHigh-content screeningSame genePerinatal lethalityEpigenetic therapyFusion proteinMolecular mechanismsG9a inhibitorChromosomesSNORD116 clusterGenesMolecular defectsPatient iPSC
2016
A method for integrating neuroimaging into genetic models of learning performance
Mehta CM, Gruen JR, Zhang H. A method for integrating neuroimaging into genetic models of learning performance. Genetic Epidemiology 2016, 41: 4-17. PMID: 27859682, PMCID: PMC5154929, DOI: 10.1002/gepi.22025.Peer-Reviewed Original ResearchReduced CYFIP1 in Human Neural Progenitors Results in Dysregulation of Schizophrenia and Epilepsy Gene Networks
Nebel RA, Zhao D, Pedrosa E, Kirschen J, Lachman HM, Zheng D, Abrahams BS. Reduced CYFIP1 in Human Neural Progenitors Results in Dysregulation of Schizophrenia and Epilepsy Gene Networks. PLOS ONE 2016, 11: e0148039. PMID: 26824476, PMCID: PMC4732616, DOI: 10.1371/journal.pone.0148039.Peer-Reviewed Original ResearchMeSH KeywordsAdaptor Proteins, Signal TransducingAdultBase SequenceChromosomes, Human, Pair 15EpilepsyGene Expression ProfilingGene Expression RegulationGene Knockdown TechniquesGene Regulatory NetworksGenetic LociHeterozygoteHumansMaleMiddle AgedMolecular Sequence DataNerve Tissue ProteinsNeural Stem CellsPrimary Cell CultureRiskSchizophreniaSequence DeletionConceptsEpilepsy genesRole of CYFIP1Novel disease candidatesHuman neural progenitorsEpilepsy riskSubset of DEGsPostsynaptic density genesNeuronal differentiationFMRP targetsGene networksNeural progenitorsSchizophreniaCytoskeletal remodelingRNA-seqDeletion carriersKnockdown experimentsVariable expressivityDisease genesProgenitors resultsDisease candidatesGenesCellular assaysCYFIP1DisordersDysregulation
2014
An Inherited Small Microdeletion at 15q13.3 in a Patient with Early- Onset Obsessive-Compulsive Disorder
Cappi C, Hounie A, Mariani D, Diniz J, Silva A, Reis V, Busso A, Silva A, Fidalgo F, Rogatto S, Miguel E, Krepischi A, Brentani H. An Inherited Small Microdeletion at 15q13.3 in a Patient with Early- Onset Obsessive-Compulsive Disorder. PLOS ONE 2014, 9: e110198. PMID: 25303678, PMCID: PMC4193873, DOI: 10.1371/journal.pone.0110198.Peer-Reviewed Original ResearchMeSH KeywordsAdolescentAge of OnsetCase-Control StudiesChildChild, PreschoolChromosome DeletionChromosomes, Human, Pair 15Comparative Genomic HybridizationDNA Copy Number VariationsFetal ProteinsForminsGenetic Predisposition to DiseaseGenome-Wide Association StudyHumansMaleMicrofilament ProteinsNuclear ProteinsObsessive-Compulsive DisorderConceptsObsessive-compulsive disorderOnset obsessive-compulsive disorderEarly-onset obsessive-compulsive disorderAttention deficit hyperactivity disorderArray-based comparative genomic hybridizationNeurodevelopmental psychiatric disordersDeficit hyperactivity disorderGlutamatergic involvementMale patientsGlutamatergic systemPsychiatric disordersHealthy individualsPatientsHyperactivity disorderGenetic riskComparative genomic hybridizationDisordersSmall microdeletionsChromosome 15q13.3Present studyGenomic hybridizationMicrodeletionCohort
2013
LOH in the HLA Class I Region at 6p21 Is Associated with Shorter Survival in Newly Diagnosed Adult Glioblastoma
Yeung JT, Hamilton RL, Ohnishi K, Ikeura M, Potter DM, Nikiforova MN, Ferrone S, Jakacki RI, Pollack IF, Okada H. LOH in the HLA Class I Region at 6p21 Is Associated with Shorter Survival in Newly Diagnosed Adult Glioblastoma. Clinical Cancer Research 2013, 19: 1816-1826. PMID: 23401227, PMCID: PMC3618546, DOI: 10.1158/1078-0432.ccr-12-2861.Peer-Reviewed Original ResearchConceptsHLA class IT cell infiltrationHLA class IILoss of heterozygosityHLA class IIIClass IOverall survivalAdult glioblastomaClass IIIHLA class I expressionHuman leukocyte antigen (HLA) class IClass IIEfficacy of immunotherapyShorter overall survivalCytotoxic T cellsClass I expressionAntigen class ICross-sectional analysisAdult patientsShorter survivalImmunohistochemical evaluationT cellsHLA class I regionI expressionDownregulated expression
2011
A balanced t(10;15) translocation in a male patient with developmental language disorder
Ercan-Sencicek AG, Wright N, Sanders SJ, Oakman N, Valdes L, Bakkaloglu B, Doyle N, Yrigollen CM, Morgan TM, Grigorenko EL. A balanced t(10;15) translocation in a male patient with developmental language disorder. European Journal Of Medical Genetics 2011, 55: 128-131. PMID: 22266071, PMCID: PMC3322462, DOI: 10.1016/j.ejmg.2011.12.005.Peer-Reviewed Case Reports and Technical NotesConceptsLanguage disordersDevelopmental language disorderMale patientsMale childrenCytogenetic findingsPhysical abnormalitiesDisordersChildren's parentsSitu hybridization analysisSample of individualsFurther evidenceDe novoClone mappingPatientsHybridization analysisTranslocationENTPD1AbnormalitiesBreakpointsMicroduplications in an autism multiplex family narrow the region of susceptibility for developmental disorders on 15q24 and implicate 7p21
Cukier H, Salyakina D, Blankstein S, Robinson J, Sacharow S, Ma D, Wright H, Abramson R, Menon R, Williams S, Haines J, Cuccaro M, Gilbert J, Pericak‐Vance M. Microduplications in an autism multiplex family narrow the region of susceptibility for developmental disorders on 15q24 and implicate 7p21. American Journal Of Medical Genetics Part B Neuropsychiatric Genetics 2011, 156: 493-501. PMID: 21480499, PMCID: PMC5490366, DOI: 10.1002/ajmg.b.31188.Peer-Reviewed Original ResearchAn Application of the Elastic Net for an Endophenotype Analysis
Palejev D, Hwang W, Landi N, Eastman M, Frost SJ, Fulbright RK, Kidd JR, Kidd KK, Mason GF, Mencl WE, Yrigollen C, Pugh KR, Grigorenko EL. An Application of the Elastic Net for an Endophenotype Analysis. Behavior Genetics 2011, 41: 120-124. PMID: 21229297, PMCID: PMC3613288, DOI: 10.1007/s10519-011-9443-8.Peer-Reviewed Original Research
2010
Multiple Independent Loci at Chromosome 15q25.1 Affect Smoking Quantity: a Meta-Analysis and Comparison with Lung Cancer and COPD
Saccone NL, Culverhouse RC, Schwantes-An TH, Cannon DS, Chen X, Cichon S, Giegling I, Han S, Han Y, Keskitalo-Vuokko K, Kong X, Landi MT, Z. J, Short SE, Stephens SH, Stevens VL, Sun L, Wang Y, Wenzlaff AS, Aggen SH, Breslau N, Broderick P, Chatterjee N, Chen J, Heath AC, Heliövaara M, Hoft NR, Hunter DJ, Jensen MK, Martin NG, Montgomery GW, Niu T, Payne TJ, Peltonen L, Pergadia ML, Rice JP, Sherva R, Spitz MR, Sun J, Wang JC, Weiss RB, Wheeler W, Witt SH, Yang BZ, Caporaso NE, Ehringer MA, Eisen T, Gapstur SM, Gelernter J, Houlston R, Kaprio J, Kendler KS, Kraft P, Leppert MF, Li MD, Madden PA, Nöthen MM, Pillai S, Rietschel M, Rujescu D, Schwartz A, Amos CI, Bierut LJ. Multiple Independent Loci at Chromosome 15q25.1 Affect Smoking Quantity: a Meta-Analysis and Comparison with Lung Cancer and COPD. PLOS Genetics 2010, 6: e1001053. PMID: 20700436, PMCID: PMC2916847, DOI: 10.1371/journal.pgen.1001053.Peer-Reviewed Original ResearchConceptsChronic obstructive pulmonary diseaseLung cancerNicotine dependenceSmoking behaviorSmoking quantityObstructive pulmonary diseaseSmoking-related diseasesLung cancer casesPulmonary diseaseNicotinic receptor subunit geneCOPD casesIndependent associationLung tissueCancer casesReceptor subunit genesMeta-analysisSignificant associationSmokingRs16969968CancerSmoking phenotypesGenetic association findingsSNP rs16969968MRNA levelsCHRNA5-CHRNA3Variation in Nicotinic Acetylcholine Receptor Genes is Associated with Multiple Substance Dependence Phenotypes
Sherva R, Kranzler HR, Yu Y, Logue MW, Poling J, Arias AJ, Anton RF, Oslin D, Farrer LA, Gelernter J. Variation in Nicotinic Acetylcholine Receptor Genes is Associated with Multiple Substance Dependence Phenotypes. Neuropsychopharmacology 2010, 35: 1921-1931. PMID: 20485328, PMCID: PMC3055642, DOI: 10.1038/npp.2010.64.Peer-Reviewed Original ResearchMeSH KeywordsAdultBlack or African AmericanChromosomes, Human, Pair 15Family HealthFemaleGene FrequencyGenetic Predisposition to DiseaseGenome-Wide Association StudyGenotypeHumansLinkage DisequilibriumMaleMiddle AgedPhenotypePolymorphism, Single NucleotideReceptors, NicotinicSubstance-Related DisordersWhite PeopleConceptsGene clusterAssociation studiesNicotinic receptor gene clusterNicotinic acetylcholine receptor genesAcetylcholine receptor genesReceptor gene clusterStrongest association signalSubstance dependence phenotypesAssociation signalsImportance of variationChromosome 15q25.1Opposite risk allelePermutation-based correctionDependence phenotypesReplication setReceptor geneMultiple polymorphismsSNPs
2008
Congenital fibrosarcoma with a novel complex 3-way translocation t(12;15;19) and unusual histologic features
Mariño-Enríquez A, Li P, Samuelson J, Rossi MR, Reyes-Múgica M. Congenital fibrosarcoma with a novel complex 3-way translocation t(12;15;19) and unusual histologic features. Human Pathology 2008, 39: 1844-1848. PMID: 18657299, DOI: 10.1016/j.humpath.2008.04.013.Peer-Reviewed Original ResearchMeSH KeywordsBiomarkers, TumorChromosomes, Human, Pair 12Chromosomes, Human, Pair 15Chromosomes, Human, Pair 19Combined Modality TherapyFibrosarcomaGene RearrangementHumansInfantMaleProto-Oncogene Proteins c-etsReceptor, trkCRepressor ProteinsRetroperitoneal NeoplasmsTomography, X-Ray ComputedTranslocation, GeneticTreatment OutcomeConceptsCongenital fibrosarcomaInflammatory myofibroblastic tumorUnusual histologic featuresGenotype/phenotype correlationGenotype-phenotype correlationMyofibroblastic tumorHistologic featuresMesenchymal tumorsTherapeutic armamentariumIntermediate malignancyTrisomy 8TumorsFibrosarcomaRefined diagnosisDiagnosisUltrastructural featuresMolecular diagnosisPhenotype correlationNovel findingsFusion signalCytogenetic analysisGenomic analysis of the chromosome 15q11-q13 Prader-Willi syndrome region and characterization of transcripts for GOLGA8E and WHCD1L1 from the proximal breakpoint region
Jiang YH, Wauki K, Liu Q, Bressler J, Pan Y, Kashork CD, Shaffer LG, Beaudet AL. Genomic analysis of the chromosome 15q11-q13 Prader-Willi syndrome region and characterization of transcripts for GOLGA8E and WHCD1L1 from the proximal breakpoint region. BMC Genomics 2008, 9: 50. PMID: 18226259, PMCID: PMC2268926, DOI: 10.1186/1471-2164-9-50.Peer-Reviewed Original ResearchMeSH KeywordsAlternative SplicingAngelman SyndromeAnimalsAutoantigensChromosome BreakageChromosome DeletionChromosomes, Human, Pair 15Conserved SequenceContig MappingCpG IslandsDNA MethylationElectrophoresis, Gel, Pulsed-FieldExonsGenomic ImprintingGenomicsHumansIntronsMiceOpen Reading FramesPrader-Willi SyndromeRNA, MessengerTranscription, GeneticWiskott-Aldrich Syndrome Protein FamilyConceptsLow-copy repeatsHuman genomeAllele-specific expression patternsProtein-coding genesHuman genome sequenceComplex chromosomal regionsCoiled-coil proteinsUCSC Genome BrowserCharacterization of transcriptsPolymorphic regionSequence-based physical mapProximal breakpoint regionCultured human cellsExtensive sequence analysisCopy number variationsGenomic orientationGene organizationNovel genesCentromeric deletion breakpointGenome sequenceSubfamily proteinsGenome browserGenomic analysisPhysical mapExact protein
2005
Ordered‐subset analysis of savant skills in autism for 15q11‐q13
Ma D, Jaworski J, Menold M, Donnelly S, Abramson R, Wright H, Delong G, Gilbert J, Pericak‐Vance M, Cuccaro M. Ordered‐subset analysis of savant skills in autism for 15q11‐q13. American Journal Of Medical Genetics Part B Neuropsychiatric Genetics 2005, 135B: 38-41. PMID: 15756693, DOI: 10.1002/ajmg.b.30166.Peer-Reviewed Original ResearchMeSH KeywordsAdolescentAdultAutistic DisorderChildChild, PreschoolChromosome MappingChromosomes, Human, Pair 15Family HealthFemaleGenetic LinkageGenotypeHumansLod ScoreMaleMicrosatellite Repeats
2004
A mixed epigenetic/genetic model for oligogenic inheritance of autism with a limited role for UBE3A
Jiang Y, Sahoo T, Michaelis RC, Bercovich D, Bressler J, Kashork CD, Liu Q, Shaffer LG, Schroer RJ, Stockton DW, Spielman RS, Stevenson RE, Beaudet AL. A mixed epigenetic/genetic model for oligogenic inheritance of autism with a limited role for UBE3A. American Journal Of Medical Genetics Part A 2004, 131A: 1-10. PMID: 15389703, DOI: 10.1002/ajmg.a.30297.Peer-Reviewed Original ResearchMeSH KeywordsAllelesAutistic DisorderBlotting, SouthernBlotting, WesternBrainChromosome AberrationsChromosomes, Human, Pair 15Deoxyribonuclease BamHIDeoxyribonuclease HpaIIDNADNA MethylationFemaleGene DuplicationHumansIn Situ Hybridization, FluorescenceMaleModels, GeneticMutationPedigreeUbiquitin-Protein LigasesConceptsOligogenic inheritanceComplex disease traitsGenome-wide studiesAbnormal DNA methylationE6-AP proteinDe novoGenetic modelsRole of UBE3AUbiquitin ligaseDNA methylationEpigenetic abnormalitiesDisease traitsAutism brainPaternal duplicationChromosome 15qUBE3AGenetic contributionRegion downstreamGenesOligogenic modelInheritanceProteinNovoLigaseBrain samples
2003
Prenatal origin of childhood acute myeloid leukemias harboring chromosomal rearrangements t(15;17) and inv(16)
McHale CM, Wiemels JL, Zhang L, Ma X, Buffler PA, Feusner J, Matthay K, Dahl G, Smith MT. Prenatal origin of childhood acute myeloid leukemias harboring chromosomal rearrangements t(15;17) and inv(16). Blood 2003, 101: 4640-4641. PMID: 12756163, DOI: 10.1182/blood-2003-01-0313.Peer-Reviewed Original Research
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