2025
Establishing a Structured Hypospadias Biobank Cohort for Integrated Research: Methodology, Comprehensive Database Integration, and Phenotyping
Abbas T, Al-Shafai K, Jamil A, Mancha M, Azzah A, Arar S, Kumar S, Al Massih A, Mackeh R, Tomei S, Saraiva L. Establishing a Structured Hypospadias Biobank Cohort for Integrated Research: Methodology, Comprehensive Database Integration, and Phenotyping. Diagnostics 2025, 15: 561. PMID: 40075808, PMCID: PMC11898921, DOI: 10.3390/diagnostics15050561.Peer-Reviewed Original ResearchHypospadias severitySurgical outcomesEvidence-based surgical techniquesImprove long-term resultsPatient outcomesSeverity of hypospadiasTranslational researchGroup of patientsLong-term resultsFollow-up dataDiverse group of patientsLongitudinal follow-up dataPersonalized care strategiesPostoperative complicationsClinical presentationCongenital anomaliesImprove patient outcomesSurgical dataSurgical interventionBiobank cohortSurgical techniquePhenotypic spectrumClinical dataCongenital conditionHypospadias
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 diagnosisCaloric restriction reduces trabecular bone loss during aging and improves bone marrow adipocyte endocrine function in male mice
Rinne C, Soultoukis G, Oveisi M, Leer M, Schmidt-Bleek O, Burkhardt L, Bucher C, Moussa E, Makhlouf M, Duda G, Saraiva L, Schmidt-Bleek K, Schulz T. Caloric restriction reduces trabecular bone loss during aging and improves bone marrow adipocyte endocrine function in male mice. Frontiers In Endocrinology 2024, 15: 1394263. PMID: 38904042, PMCID: PMC11188307, DOI: 10.3389/fendo.2024.1394263.Peer-Reviewed Original ResearchConceptsBone marrow adipose tissueTrabecular bone lossAged miceCaloric restrictionBone lossEndocrine profileMale C57BL6J miceCardio-metabolic diseasesTime of CRAge-matched littermatesBiochemical lipid profilesAssess bone microstructureFree food accessC57BL6J miceBone healthYoung miceContext of agingMale miceDietary interventionNutritional interventionAnatomical localizationLipid profileAdipogenic gene expressionBone dysfunctionTrabecular bone structureConserved genes regulating human sex differentiation, gametogenesis and fertilization
Fakhro K, Awwad J, Garibova S, Saraiva L, Avella M. Conserved genes regulating human sex differentiation, gametogenesis and fertilization. Journal Of Translational Medicine 2024, 22: 473. PMID: 38764035, PMCID: PMC11103854, DOI: 10.1186/s12967-024-05162-2.Peer-Reviewed Original ResearchConceptsFertility phenotypesReproductive biologyMechanisms of gene functionNewly-discovered genesHuman reproductive biologyCharacterization of genesLoss-of-function mutationsFundamental reproductive processesNext-generation sequencingGenome editing technologyConserved genesFunctional genomicsGene functionFunctional characterizationConsanguineous populationsSex differentiationGenesReproductive tissuesMonogenic causeMolecular mechanismsHuman reproductive tissuesEditing technologyReproductive processesPhenotypeFertility disorders
2023
Identifying 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 1VariantsOlfactionFamilyCNGA2Short-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 phenotypeFunctional Characterization of Novel MC4R Variants Identified in Two Unrelated Patients with Morbid Obesity in Qatar
Mohammed I, Selvaraj S, Ahmed W, Al-Barazenji T, Hammad A, Dauleh H, Saraiva L, Al-Shafai M, Hussain K. Functional Characterization of Novel MC4R Variants Identified in Two Unrelated Patients with Morbid Obesity in Qatar. International Journal Of Molecular Sciences 2023, 24: 16361. PMID: 38003551, PMCID: PMC10671262, DOI: 10.3390/ijms242216361.Peer-Reviewed Original ResearchConceptsCREB signaling pathwaysHeterozygous variantsSignaling pathwayVariants associated with obesityIn silico prediction toolsEffects of allelic variationFunctional impactIn silico analysisMonogenic obesityDownstream signaling cascadesLigand binding activityGT1-7 cellsObesity-related genesIdentified variantsAllelic variationFunctional characterizationSilico analysisSanger sequencingPathogenic variantsActivation of PKALeptin-melanocortin pathwaySignaling cascadesMonogenic forms of obesityGenesIn vitro analysisGenome-Wide RNA Tomography in the Mouse Whole Olfactory Mucosa
Moussa E, Makhlouf M, Mathew L, Saraiva L. Genome-Wide RNA Tomography in the Mouse Whole Olfactory Mucosa. Methods In Molecular Biology 2023, 2710: 19-30. PMID: 37688721, DOI: 10.1007/978-1-0716-3425-7_2.Peer-Reviewed Original ResearchGenetic Variation and Sensory Perception of a Pediatric Formulation of Ibuprofen: Can a Medicine Taste Too Good for Some?
Mennella J, Kan M, Lowenthal E, Saraiva L, Mainland J, Himes B, Pepino M. Genetic Variation and Sensory Perception of a Pediatric Formulation of Ibuprofen: Can a Medicine Taste Too Good for Some? International Journal Of Molecular Sciences 2023, 24: 13050. PMID: 37685855, PMCID: PMC10487938, DOI: 10.3390/ijms241713050.Peer-Reviewed Original ResearchConceptsGenetic ancestryEuropean genetic ancestryTaste receptor genesIndependent of ancestryAfrican genetic ancestryGenetic variationFormulations of ibuprofenEpigenetic factorsAncestryReceptor geneDouble-blind cohort studyUrge to coughPerception of palatabilityRisk of accidental ingestionPersonality variationCohort studyPediatric formulationsSensory phenotypesThroat sensationChemesthetic sensationsMedicinal tasteTingling sensationPanelistsAdult panelistsDiverse populations
2022
The Neanderthal inside us
Saraiva L. The Neanderthal inside us. Nature Reviews Genetics 2022, 24: 142-142. PMID: 36471017, DOI: 10.1038/s41576-022-00561-x.Peer-Reviewed Original ResearchThe quality of energy- and macronutrient-balanced diets regulates host susceptibility to influenza in mice
Cootes T, Bhattacharyya N, Huang S, Daniel L, Bell-Anderson K, Stifter S, Chew T, Solon-Biet S, Saraiva L, Cai Y, Chen X, Simpson S, Feng C. The quality of energy- and macronutrient-balanced diets regulates host susceptibility to influenza in mice. Cell Reports 2022, 41: 111638. PMID: 36384123, DOI: 10.1016/j.celrep.2022.111638.Peer-Reviewed Original ResearchConceptsGrain-based chow dietOutcome of host-pathogen interactionsSusceptibility to influenzaHost resistance to infectionInterferon (IFN)-gHost-pathogen interactionsMortality to infectionDiet compositionInfluenza infectionResistance to infectionHost phenotypeChow dietInfection susceptibilityHost defenseImpact of diet compositionExtrinsic signalsMiceLaboratory rodent dietHeightened susceptibilityInfectionAdaptive homeostasisAIN93GRodent dietIndividual macronutrientsInfluenzaInvestigation 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 variantsOdor blocking of stress hormone responses
Lee E, Saraiva L, Hanchate N, Ye X, Asher G, Ho J, Buck L. Odor blocking of stress hormone responses. Scientific Reports 2022, 12: 8773. PMID: 35610316, PMCID: PMC9130126, DOI: 10.1038/s41598-022-12663-x.Peer-Reviewed Original ResearchConceptsCorticotropin-releasing hormone neuronsBed nucleus of the stria terminalisOdor blockingHypothalamic corticotropin-releasing hormone neuronsInhibitory neuronsInhibition of excitatory neuronsBlood stress hormonesStress-induced increaseActivity of inhibitory neuronsActivate inhibitory neuronsHypothalamic ventromedial nucleusStress hormone responsesBed nucleusStria terminalisTransmit stress signalsPredator odorSocial confrontationVentromedial nucleusStress hormonesHormone neuronsAllay stressPhysical restraintExcitatory neuronsOdorHormonal responsesA Novel FGFR1 Missense Mutation in a Portuguese Family with Congenital Hypogonadotropic Hypogonadism
Fadiga L, Lavrador M, Vicente N, Barros L, Gonçalves C, Al-Naama A, Saraiva L, Lemos M. A Novel FGFR1 Missense Mutation in a Portuguese Family with Congenital Hypogonadotropic Hypogonadism. International Journal Of Molecular Sciences 2022, 23: 4423. PMID: 35457241, PMCID: PMC9026826, DOI: 10.3390/ijms23084423.Peer-Reviewed Original ResearchConceptsCongenital hypogonadotropic hypogonadismMissense mutationsFibroblast growth factor receptor 1Sequence-based prediction methodsPathogenesis of CHHFailure of pubertal developmentIdentified missense mutationsFibroblast growth factor receptor 1 geneHypogonadotropic hypogonadismWhole-exome sequencingNormosmic congenital hypogonadotropic hypogonadismHeterozygous missense mutationExome sequencingGenetic studiesGrowth factor receptor 1Mutation spectrumFibroblast growth factor receptor 1 proteinIncomplete penetranceGonadotropin-releasing hormoneReproductive endocrine disordersAffected siblingsAmino acidsMutationsGenetic defectsGenesA 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 localization
2021
Congenital 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 patientsSysInflam HuDB, a Web Resource for Mining Human Blood Cells Transcriptomic Data Associated with Systemic Inflammatory Responses to Sepsis
Toufiq M, Huang S, Boughorbel S, Alfaki M, Rinchai D, Saraiva L, Chaussabel D, Garand M. SysInflam HuDB, a Web Resource for Mining Human Blood Cells Transcriptomic Data Associated with Systemic Inflammatory Responses to Sepsis. The Journal Of Immunology 2021, 207: 2195-2202. PMID: 34663591, PMCID: PMC8525868, DOI: 10.4049/jimmunol.2100697.Peer-Reviewed Original ResearchConceptsPublic transcriptome dataGene expression changesTranscriptome dataTranscriptomic datasetsBlood transcriptome datasetsSystemic inflammatory response to sepsisDisease susceptibilityResponse to infectionBlood gene signaturesExpression changesClinical metadataHost inflammatory responseInflammatory responseSystemic infectionDysregulated host inflammatory responseInflammatory response to sepsisGene signatureSystemic inflammatory responseMechanistic discoveriesSystemic inflammatory diseaseResponse to sepsisHeterogeneous diseaseWeb-based interfaceSepsis biomarkersInflammatory diseasesInherited human c-Rel deficiency disrupts myeloid and lymphoid immunity to multiple infectious agents
LĂ©vy R, Langlais D, BĂ©ziat 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 survival
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