Featured Publications
Short-term consumption of highly processed diets varying in macronutrient content impair the sense of smell and brain metabolism in mice
Makhlouf M, Souza D, Kurian S, Bellaver B, Ellis H, Kuboki A, Al-Naama A, Hasnah R, Venturin G, da Costa J, Venugopal N, Manoel D, Mennella J, Reisert J, Tordoff M, Zimmer E, Saraiva L. Short-term consumption of highly processed diets varying in macronutrient content impair the sense of smell and brain metabolism in mice. Molecular Metabolism 2023, 79: 101837. PMID: 37977411, PMCID: PMC10724696, DOI: 10.1016/j.molmet.2023.101837.Peer-Reviewed Original ResearchConceptsMacronutrient contentIncrease food safetyGrain-based dietShort-term consumptionElectro-olfactogramFood safetyProcessed dietsFood processingBrain regionsBrain metabolismOdor-guided behaviorStandard chow dietShort-term intakeDietGlucose metabolism imagingHigh-fat dietFoodResponses to odorantsBrain glucose metabolismOlfactory mucosaModern dietFood consumptionChow dietChronic consumptionMetabolic phenotypeIdentifying candidate genes underlying isolated congenital anosmia
Kamarck M, Trimmer C, Murphy N, Gregory K, Manoel D, Logan D, Saraiva L, Mainland J. Identifying candidate genes underlying isolated congenital anosmia. Clinical Genetics 2023, 105: 376-385. PMID: 38148624, PMCID: PMC10932857, DOI: 10.1111/cge.14470.Peer-Reviewed Original ResearchConceptsIsolated congenital anosmiaWhole-exome sequencingCongenital anosmiaGene candidate listsLoss-of-function variantsSpectrum of genetic alterationsOlfactory transduction pathwayZinc ion bindingDeleterious variantsExome sequencingTransduction pathwaysGenetic alterationsOlfactory signalsNon-syndromicOlfactory functionAssociated with olfactionQuality of lifeGenesAnosmiaIon bindingEstimated 1VariantsOlfactionFamilyCNGA2Investigation of Genetic Causes in Patients with Congenital Heart Disease in Qatar: Findings from the Sidra Cardiac Registry
Okashah S, Vasudeva D, Jerbi A, Khodjet-El-khil H, Al-Shafai M, Syed N, Kambouris M, Udassi S, Saraiva L, Al-Saloos H, Udassi J, Al-Shafai K. Investigation of Genetic Causes in Patients with Congenital Heart Disease in Qatar: Findings from the Sidra Cardiac Registry. Genes 2022, 13: 1369. PMID: 36011280, PMCID: PMC9407366, DOI: 10.3390/genes13081369.Peer-Reviewed Original ResearchConceptsCongenital heart diseaseWhole-exome sequencingGenetic etiology of congenital heart diseaseAmerican College of Medical GeneticsPotential genetic variantsPotential causative variantsPathogenesis of congenital heart diseaseChromosomal abnormalitiesCardiac RegistryEtiology of congenital heart diseaseResults of genetic testingDevelopment of congenital heart diseaseCausative variantsHeart diseaseIdentified variantsMedical geneticsExome sequencingExome analysisGenetic variantsGenetic causeGenetic etiologyCHD phenotypesFunctional studiesGenetic defectsPotential variantsA 3D transcriptomics atlas of the mouse nose sheds light on the anatomical logic of smell
Ruiz Tejada Segura M, Abou Moussa E, Garabello E, Nakahara T, Makhlouf M, Mathew L, Wang L, Valle F, Huang S, Mainland J, Caselle M, Osella M, Lorenz S, Reisert J, Logan D, Malnic B, Scialdone A, Saraiva L. A 3D transcriptomics atlas of the mouse nose sheds light on the anatomical logic of smell. Cell Reports 2022, 38: 110547. PMID: 35320714, PMCID: PMC8995392, DOI: 10.1016/j.celrep.2022.110547.Peer-Reviewed Original ResearchClinical, Genetic and Functional Characterization of a Novel AVPR2 Missense Mutation in a Woman with X-Linked Recessive Nephrogenic Diabetes Insipidus
Selvaraj S, Rodrigues D, Krishnamoorthy N, Fakhro K, Saraiva L, Lemos M. Clinical, Genetic and Functional Characterization of a Novel AVPR2 Missense Mutation in a Woman with X-Linked Recessive Nephrogenic Diabetes Insipidus. Journal Of Personalized Medicine 2022, 12: 118. PMID: 35055433, PMCID: PMC8779739, DOI: 10.3390/jpm12010118.Peer-Reviewed Original ResearchNephrogenic diabetes insipidusX-linked recessive nephrogenic diabetes insipidusRecessive nephrogenic diabetes insipidusMissense mutationsAquaporin-2Diabetes insipidusIn silico protein modelingCongenital nephrogenic diabetes insipidusArginine vasopressin receptor 2Plasma membrane localizationVolumes of dilute urineAverage urinary outputAVPR2</i> geneDownstream intracellular signaling pathwaysHeterozygous missense mutationX-linked recessive inheritanceVasopressin receptor 2Intracellular signaling pathwaysHuman cellular modelsResponse to water deprivationX chromosomePhenotypic effectsGenetic analysisTransmembrane domainMembrane localizationCongenital iRHOM2 deficiency causes ADAM17 dysfunction and environmentally directed immunodysregulatory disease
Kubo S, Fritz J, Raquer-McKay H, Kataria R, Vujkovic-Cvijin I, Al-Shaibi A, Yao Y, Zheng L, Zou J, Waldman A, Jing X, Farley T, Park A, Oler A, Charles A, Makhlouf M, AbouMoussa E, Hasnah R, Saraiva L, Ganesan S, Al-Subaiey A, Matthews H, Flano E, Lee H, Freeman A, Sefer A, Sayar E, Çakır E, Karakoc-Aydiner E, Baris S, Belkaid Y, Ozen A, Lo B, Lenardo M. Congenital iRHOM2 deficiency causes ADAM17 dysfunction and environmentally directed immunodysregulatory disease. Nature Immunology 2021, 23: 75-85. PMID: 34937930, PMCID: PMC11060421, DOI: 10.1038/s41590-021-01093-y.Peer-Reviewed Original ResearchMeSH KeywordsA549 CellsADAM17 ProteinAnimalsCarrier ProteinsChildChild, PreschoolCitrobacter rodentiumColitisCytokinesEnterobacteriaceae InfectionsFemaleHEK293 CellsHumansInfant, NewbornMacrophagesMaleMiceMice, Inbred C57BLMutationPrimary Immunodeficiency DiseasesPseudomonas aeruginosaPseudomonas InfectionsSignal TransductionConceptsIRhom2 deficiencyLoss-of-function mutationsLocal microbial environmentLoss of iRhom2Diverse clinical phenotypesRecurrent respiratory infectionsWild-type miceRelease of cytokinesTumor necrosis factorHemorrhagic colitisCitrobacter rodentiumADAM17 metalloproteinaseFecal microbiotaSuperfamily membersRecurrent infectionsRecurrent pneumoniaTumor necrosisLung involvementColonic involvementHuman immunodeficiencyInflammatory colitisMicrobial environmentOral speciesPseudomonas aeruginosaColitis patientsInherited human c-Rel deficiency disrupts myeloid and lymphoid immunity to multiple infectious agents
Lévy R, Langlais D, Béziat V, Rapaport F, Rao G, Lazarov T, Bourgey M, Zhou Y, Briand C, Moriya K, Ailal F, Avery D, Markle J, Lim A, Ogishi M, Yang R, Pelham S, Emam M, Migaud M, Deswarte C, Habib T, Saraiva L, Moussa E, Guennoun A, Boisson B, Belkaya S, Martinez-Barricarte R, Rosain J, Belkadi A, Breton S, Payne K, Benhsaien I, Plebani A, Lougaris V, Di Santo J, Neven B, Abel L, S. C, Bousfiha A, Marr N, Bustamante J, Liu K, Gros P, Geissmann F, Tangye S, Casanova J, Puel A. Inherited human c-Rel deficiency disrupts myeloid and lymphoid immunity to multiple infectious agents. Journal Of Clinical Investigation 2021, 131: e150143. PMID: 34623332, PMCID: PMC8409595, DOI: 10.1172/jci150143.Peer-Reviewed Original ResearchConceptsCD4+ T cellsMemory CD4+ T cellsC-Rel deficiencyT cellsMyeloid cellsLymphoid cellsB cellsC-RelMultiple infectious agentsNaive CD4+ T cellsCD8+ T cellsAntigen-presenting cell functionConventional DC1sFrequency of NKMemory B cellsNaive T cellsNaive B cellsFunctional deficitsReduced IL-2 productionProduction of Th1Infectious agentsIL-23 productionIL-2 productionInduction of CD86 expressionB cell survivalDeconstructing the mouse olfactory percept through an ethological atlas
Manoel D, Makhlouf M, Arayata C, Sathappan A, Da'as S, Abdelrahman D, Selvaraj S, Hasnah R, Mainland J, Gerkin R, Saraiva L. Deconstructing the mouse olfactory percept through an ethological atlas. Current Biology 2021, 31: 2809-2818.e3. PMID: 33957076, PMCID: PMC8282700, DOI: 10.1016/j.cub.2021.04.020.Peer-Reviewed Original ResearchConceptsOlfactory perceptionMouse behaviorStudy of olfactory perceptionOdor perceptionBehavioral responsesPhysicochemical properties of odorantsHuman odor perceptionProperties of odorantsOdor identityOlfactory behaviorTarget odorOdorOdor concentrationPerceptionMiceBehaviorNon-humanResponseMultiple concentrationsDifferential regulation of the immune system in a brain-liver-fats organ network during short-term fasting
Huang S, Makhlouf M, AbouMoussa E, Segura M, Mathew L, Wang K, Leung M, Chaussabel D, Logan D, Scialdone A, Garand M, Saraiva L. Differential regulation of the immune system in a brain-liver-fats organ network during short-term fasting. Molecular Metabolism 2020, 40: 101038. PMID: 32526449, PMCID: PMC7339127, DOI: 10.1016/j.molmet.2020.101038.Peer-Reviewed Original ResearchConceptsShort-term fastingGene Ontology enrichment analysisOntology enrichment analysisReactome pathway analysisInnate immune signalingCombination of multivariate analysisImmune systemPriming of adaptive immunityChronic immunological disordersTranscriptional dynamicsGene setsGene OntologyWhite adipose tissueAdipose tissueProtein dataRNA sequencingBrown adipose tissueExpression analysisEnrichment analysisImmune signalingProfiles of miceDifferential regulationBiological pathwaysPathway analysisMolecular mechanismsA transcriptomic atlas of mammalian olfactory mucosae reveals an evolutionary influence on food odor detection in humans
Saraiva L, Riveros-McKay F, Mezzavilla M, Abou-Moussa E, Arayata C, Makhlouf M, Trimmer C, Ibarra-Soria X, Khan M, Van Gerven L, Jorissen M, Gibbs M, O'Flynn C, McGrane S, Mombaerts P, Marioni J, Mainland J, Logan D. A transcriptomic atlas of mammalian olfactory mucosae reveals an evolutionary influence on food odor detection in humans. Science Advances 2019, 5: eaax0396. PMID: 31392275, PMCID: PMC6669018, DOI: 10.1126/sciadv.aax0396.Peer-Reviewed Original ResearchConceptsOlfactory sensory neuronsChemosensory receptor gene familiesSpecies-specific adaptationsOlfactory sensory neurons subtypesCanonical olfactory receptorsReceptor gene familyOlfactory mucosa samplesMammalian olfactory mucosaGene familyEcological nichesMammalian evolutionTranscriptomic atlasAnalyzed speciesEvolutionary dynamicsRNA sequencingMammalian olfactory systemEvolutionary influencesOlfactory mucosaHomologous subtypesSensory neuronsOlfactory receptorsMucosa samplesOlfactory systemSubtypesMammalian olfactionAdipocyte Accumulation in the Bone Marrow during Obesity and Aging Impairs Stem Cell-Based Hematopoietic and Bone Regeneration
Ambrosi T, Scialdone A, Graja A, Gohlke S, Jank A, Bocian C, Woelk L, Fan H, Logan D, Schürmann A, Saraiva L, Schulz T. Adipocyte Accumulation in the Bone Marrow during Obesity and Aging Impairs Stem Cell-Based Hematopoietic and Bone Regeneration. Cell Stem Cell 2017, 20: 771-784.e6. PMID: 28330582, PMCID: PMC5459794, DOI: 10.1016/j.stem.2017.02.009.Peer-Reviewed Original ResearchConceptsStem cell-basedHematopoietic regenerationAdipocyte accumulationStem cell-like characteristicsCell-like characteristicsBone resident cellsDipeptidyl peptidase-4Bone marrow cavityCompetitive repopulationLethal irradiationHematopoietic nicheBone marrowCell-basedPeptidase-4Osteogenic lineageAged animalsBone healingDiabetes therapyAdipocyte lineageBoneMarrow cavityAge-dependentMolecular identityObesityAdipogenic lineagesCombinatorial effects of odorants on mouse behavior
Saraiva L, Kondoh K, Ye X, Yoon K, Hernandez M, Buck L. Combinatorial effects of odorants on mouse behavior. Proceedings Of The National Academy Of Sciences Of The United States Of America 2016, 113: e3300-e3306. PMID: 27208093, PMCID: PMC4988607, DOI: 10.1073/pnas.1605973113.Peer-Reviewed Original ResearchConceptsTrace amine-associated receptorsOdor aversionBehavioral effectsInstinctive behavioral responsesBinary odor mixturesEffects of odorsOdorant receptorsAversive responsesPredator odorMouse behaviorOdor stimuliOdor mixturesOdor responsesOdor perceptionReceptor antagonismBehavioral responsesOdor detectionSingle receptorSensory inputInstinctive behaviorAversionOdorStereotyped natureReceptor inputMouse noseHierarchical deconstruction of mouse olfactory sensory neurons: from whole mucosa to single-cell RNA-seq
Saraiva L, Ibarra-Soria X, Khan M, Omura M, Scialdone A, Mombaerts P, Marioni J, Logan D. Hierarchical deconstruction of mouse olfactory sensory neurons: from whole mucosa to single-cell RNA-seq. Scientific Reports 2015, 5: 18178. PMID: 26670777, PMCID: PMC4680959, DOI: 10.1038/srep18178.Peer-Reviewed Original ResearchConceptsMature olfactory sensory neuronsOlfactory sensory neuronsRNA-seqOR genesGene expressionSingle-cell RNA-seqIntact OR genesOlfactory receptorsCell typesSingle-nucleotide polymorphismsOR-expressing OSNsOR gene expressionIntact olfactory receptorsNeuron-one receptor ruleCrude tissue samplesMonoallelic expressionNeuronal cell typesMouse olfactory mucosaMultiple cell typesChemosensory tissuesGenesCellular heterogeneityOlfactory mucosaSensory neuronsNon-neuronalHigh-throughput spatial mapping of single-cell RNA-seq data to tissue of origin
Achim K, Pettit J, Saraiva L, Gavriouchkina D, Larsson T, Arendt D, Marioni J. High-throughput spatial mapping of single-cell RNA-seq data to tissue of origin. Nature Biotechnology 2015, 33: 503-509. PMID: 25867922, DOI: 10.1038/nbt.3209.Peer-Reviewed Original ResearchHigh-affinity olfactory receptor for the death-associated odor cadaverine
Hussain A, Saraiva L, Ferrero D, Ahuja G, Krishna V, Liberles S, Korsching S. High-affinity olfactory receptor for the death-associated odor cadaverine. Proceedings Of The National Academy Of Sciences Of The United States Of America 2013, 110: 19579-19584. PMID: 24218586, PMCID: PMC3845148, DOI: 10.1073/pnas.1318596110.Peer-Reviewed Original ResearchConceptsInnate behaviorsOlfactory receptorsSocial cuesOlfactory sensory neuronsNeural circuitsDetect cadaverineCarrion smellsVertebrate olfactionSensory neuronsAmino acids ornithinePhysiologically relevant sourceReceptorsConcomitant activationMolecular basisConcentration of cadaverineTAAR13cNeuronsSpeciesCuesOlfactionBehaviorSmellCadaverineA Large-Scale Analysis of Odor Coding in the Olfactory Epithelium
Nara K, Saraiva L, Ye X, Buck L. A Large-Scale Analysis of Odor Coding in the Olfactory Epithelium. Journal Of Neuroscience 2011, 31: 9179-9191. PMID: 21697369, PMCID: PMC3758579, DOI: 10.1523/jneurosci.1282-11.2011.Peer-Reviewed Original ResearchConceptsOlfactory sensory neuronsOdor qualityOdor recognitionMouse olfactory sensory neuronsOdorant receptorsEncode odor identityExpressed odorant receptorOdor identityOdor codingOlfactory epitheliumSensory neuronsPerceived odorMultiple odorantsSensory inputInnate behaviorsOdorLarge-scale analysisOR genesMiceCombinatorial codePositive Darwinian selection and the birth of an olfactory receptor clade in teleosts
Hussain A, Saraiva L, Korsching S. Positive Darwinian selection and the birth of an olfactory receptor clade in teleosts. Proceedings Of The National Academy Of Sciences Of The United States Of America 2009, 106: 4313-4318. PMID: 19237578, PMCID: PMC2657432, DOI: 10.1073/pnas.0803229106.Peer-Reviewed Original ResearchConceptsTrace amine-associated receptorsTAAR genesIntron gainGene familyClass IIIBony fishesOlfactory receptor neuronsPositive Darwinian selectionLocal positive selectionOlfactory receptor gene familyClass III genesOlfactory receptorsOlfactory receptor familyReceptor gene familyOlfactory epitheliumLigand-binding motifsFish genesTeleost lineageReceptor neuronsJawless vertebratesVertebrate evolutionIII genesPositive selectionDarwinian selectionEvolutionary dynamicsA novel olfactory receptor gene family in teleost fish
Saraiva L, Korsching S. A novel olfactory receptor gene family in teleost fish. Genome Research 2007, 17: 1448-1457. PMID: 17717047, PMCID: PMC1987349, DOI: 10.1101/gr.6553207.Peer-Reviewed Original ResearchConceptsOra genesGene pairsMulti-exon structureSpecies-specific expansionOlfactory receptor gene familyV1R-like genesOlfactory receptor familyReceptor gene familySpeciation eventsTeleost lineagePhylogenetic treePhylogenetic analysisGene familyGene regulationGene repertoireGene functionOlfactory epithelium of zebrafishTeleost familiesTeleost speciesOrthologsTeleost fishGenesNegative selectionTeleostFish species
2024
Functional Evaluation of a Novel Homozygous ADCY3 Variant Causing Childhood Obesity
Mohammed I, Selvaraj S, Ahmed W, Al-Barazenji T, Dauleh H, Love D, Saraiva L, Hussain K. Functional Evaluation of a Novel Homozygous ADCY3 Variant Causing Childhood Obesity. International Journal Of Molecular Sciences 2024, 25: 11815. PMID: 39519366, PMCID: PMC11547096, DOI: 10.3390/ijms252111815.Peer-Reviewed Original ResearchAdenylate cyclase 3Early-onset obesityRegulating various downstream signaling pathwaysIn silico functional characterizationHomozygous nonsense variant c.Homozygous loss-of-function variantsIn silico functional analysisLoss-of-function variantsReceptor loss of functionNonsense variant c.Impaired enzymatic activityGene panel sequencingATP to cAMPIn silico validationDownstream signaling pathwaysGain-of-function variantsPrimary cilia of neuronsIn vitroInsulin resistanceLoss of functionTransmembrane proteinsFunctional characterizationPrimary ciliaNovel p.Variant c.Genetic architecture of congenital hypogonadotropic hypogonadism: insights from analysis of a Portuguese cohort
Carriço J, Gonçalves C, Al-Naama A, Syed N, Aragüés J, Bastos M, Fonseca F, Borges T, Pereira B, Pignatelli D, Carvalho D, Cunha F, Saavedra A, Rodrigues E, Saraiva J, Ruas L, Vicente N, Martins J, De Sousa Lages A, Oliveira M, Castro-Correia C, Melo M, Martins R, Couto J, Moreno C, Martins D, Oliveira P, Martins T, Martins S, Marques O, Meireles C, Garrão A, Nogueira C, Baptista C, Gama-de-Sousa S, Amaral C, Martinho M, Limbert C, Barros L, Vieira I, Sabino T, Saraiva L, Lemos M. Genetic architecture of congenital hypogonadotropic hypogonadism: insights from analysis of a Portuguese cohort. Human Reproduction Open 2024, 2024: hoae053. PMID: 39308770, PMCID: PMC11415827, DOI: 10.1093/hropen/hoae053.Peer-Reviewed Original ResearchCongenital hypogonadotropic hypogonadismPathogenic variantsGenetic causeRare sequence variantsCopy number variantsWhole-exome sequencingGenetically heterogeneous disorderPathogenic germline variantsGenetic architectureVariant interpretationOligogenic inheritanceSequence variantsGenetic screeningGenetic analysisPortuguese patientsNon-codingGenetic heterogeneityNovel variantsGermline variantsVUS variantsMutation spectrumAnalysed genesProportion of patientsGenesGenetic diagnosis