2023
4E-BP1 expression in embryonic postmitotic neurons mitigates mTORC1-induced cortical malformations and behavioral seizure severity but does not prevent epilepsy in mice
Nguyen L, Sharma M, Bordey A. 4E-BP1 expression in embryonic postmitotic neurons mitigates mTORC1-induced cortical malformations and behavioral seizure severity but does not prevent epilepsy in mice. Frontiers In Neuroscience 2023, 17: 1257056. PMID: 37680968, PMCID: PMC10480503, DOI: 10.3389/fnins.2023.1257056.Peer-Reviewed Original ResearchBehavioral seizure severityCortical malformationsSeizure frequencySeizure severityRadial gliaLayer 2/3 pyramidal neuronsCortical layer 2/3 pyramidal neuronsFocal cortical malformationsBehavioral seizuresNeuronal hypertrophyIntractable seizuresPyramidal neuronsSeizure activityRapamycin complex 1 (mTORC1) pathwayEctopic neuronsSeizure preventionMigratory neuronsWhite matterSeizuresNeuronsMalformationsMechanistic targetRecent evidenceSeverityEpilepsyCalcineurin-inhibitor free immunosuppression after lung transplantation – a single center case-control study in 51 patients converted to Mechanistic Target of Rapamycin (mTOR) inhibitors
Gottlieb J, Fischer B, Schupp J, Golpon H. Calcineurin-inhibitor free immunosuppression after lung transplantation – a single center case-control study in 51 patients converted to Mechanistic Target of Rapamycin (mTOR) inhibitors. PLOS ONE 2023, 18: e0284653. PMID: 37200246, PMCID: PMC10194991, DOI: 10.1371/journal.pone.0284653.Peer-Reviewed Original ResearchConceptsCNI-free immunosuppressionCalcineurin inhibitor-free immunosuppressionMTOR inhibitorsFree immunosuppressionLung transplantationImproved survivalRapamycin inhibitorsNeurological diseasesSingle-center case-control studyCenter case-control studyCNI-free regimenCurative treatment optionGlomerular filtration rateMajority of patientsNon-malignant indicationsSignificant functional improvementCase-control studyMechanistic targetAcute rejectionLTx patientsNeurological complicationsAdult patientsMedian durationSingle centerTreatment options
2022
Cutting Edge: mTORC2 Regulates CD8+ Effector and Memory T Cell Differentiation through Serum and Glucocorticoid Kinase 1.
Patel C, Heikamp E, Xu W, Sun I, Oh M, Sun I, Wen J, Tam A, Blosser R, Powell J. Cutting Edge: mTORC2 Regulates CD8+ Effector and Memory T Cell Differentiation through Serum and Glucocorticoid Kinase 1. The Journal Of Immunology 2022, 209: 2287-2291. PMID: 36469844, PMCID: PMC10065985, DOI: 10.4049/jimmunol.2100669.Peer-Reviewed Original ResearchConceptsT cell differentiationT cellsMemory T cell differentiationMemory precursor phenotypeMemory T cellsEfficacy of vaccinesGlucocorticoid-regulated kinase 1Mechanistic targetRapamycin complex 2 (mTORC2) signalingT cell metabolismT cells resultsKinase 1Memory CD8Acute infectionGlucocorticoid kinase 1Tumor immunotherapyCD8Cell differentiationPrecursor phenotypeNuclear translocationPowerful targetSerumRecall capacityEssential regulatorCell metabolismCentral and peripheral nervous system responses to chronic and paced hyperventilation in anxious and healthy subjects
Tolin D, O'Bryan E, Davies C, Diefenbach G, Johannesen J. Central and peripheral nervous system responses to chronic and paced hyperventilation in anxious and healthy subjects. Biological Psychology 2022, 176: 108472. PMID: 36481266, PMCID: PMC9839632, DOI: 10.1016/j.biopsycho.2022.108472.Peer-Reviewed Original ResearchConceptsAnxious patientsCentral nervous system correlatesPeripheral nervous system responsesAlpha-1 powerPeripheral nervous systemFurther treatment developmentNervous system responsesHealthy control participantsHypocapnic patientsNormocapnic patientsChronic hyperventilationRespiratory distressEEG abnormalitiesHealthy subjectsSkin conductance levelNervous systemPatientsControl groupHealthy participantsPoor toleranceTreatment developmentSkin conductance response amplitudeControl participantsBreathing taskMechanistic targetDiverging regulation of Bach2 protein and RNA expression determine cell fate in early B cell response
Hu Q, Xu T, Zhang M, Zhang H, Liu Y, Li H, Chen C, Zheng J, Zhang Z, Li F, Shen N, Zhang W, Melnick A, Huang C. Diverging regulation of Bach2 protein and RNA expression determine cell fate in early B cell response. Cell Reports 2022, 40: 111035. PMID: 35793628, PMCID: PMC9550188, DOI: 10.1016/j.celrep.2022.111035.Peer-Reviewed Original ResearchConceptsBach2 proteinCell fateActivated B cellsMemory B cellsB cellsCell fate choiceDetermines cell fateCell fate outcomesRapamycin complex 1B cell fateEffector cellsGerminal centre B cell fatePivotal transcription factorB cell receptor affinityEarly B cell responsesTranscription factorsDependent translationB cell responsesPrimary humoral responseGC fateMechanistic targetHumoral responseProteinPlasma cellsDifferential dynamicsmTORC1 Inhibition Protects Human Regulatory T Cells From Granzyme-B-Induced Apoptosis
Eskandari SK, Allos H, Al Dulaijan B, Melhem G, Sulkaj I, Alhaddad JB, Saad AJ, Deban C, Chu P, Choi JY, Kollar B, Pomahac B, Riella LV, Berger SP, Sanders JSF, Lieberman J, Li L, Azzi JR. mTORC1 Inhibition Protects Human Regulatory T Cells From Granzyme-B-Induced Apoptosis. Frontiers In Immunology 2022, 13: 899975. PMID: 35757726, PMCID: PMC9229986, DOI: 10.3389/fimmu.2022.899975.Peer-Reviewed Original ResearchConceptsRegulatory T cellsT cellsHuman regulatory T cellsHost THumanized mouse modelPro-apoptotic pathwaysSkin allotransplantationClinical efficacyImmunosuppressive potencyIntracytoplasmic expressionTransplant fieldMouse modelCellular therapyHigh expressionTarget cellsRapamycin complex 1Lysosomal granulesFunctional effectsMechanistic targetPatientsApoptosisC-JunGranzymesDrug targetsS6KComplex regulation of fatty liver disease
Ginsberg HN, Mani A. Complex regulation of fatty liver disease. Science 2022, 376: 247-248. PMID: 35420931, PMCID: PMC9619413, DOI: 10.1126/science.abp8276.Peer-Reviewed Original ResearchmTORC1 inhibitor effects on rapid ketamine-induced reductions in suicidal ideation in patients with treatment-resistant depression
Averill LA, Averill CL, Gueorguieva R, Fouda S, Sherif M, Ahn KH, Ranganathan M, D'Souza DC, Southwick SM, Sanacora G, Duman RS, Krystal JH, Abdallah CG. mTORC1 inhibitor effects on rapid ketamine-induced reductions in suicidal ideation in patients with treatment-resistant depression. Journal Of Affective Disorders 2022, 303: 91-97. PMID: 35101523, DOI: 10.1016/j.jad.2022.01.104.Peer-Reviewed Original ResearchConceptsAntisuicidal effectsAntidepressant effectsSuicidal ideationKetamine-induced reductionTreatment-resistant depressionLimited treatment optionsCross-over trialMajor depressive episodeOral rapamycinPublic health crisisKetamine administrationTreatment optionsDepressive episodeParent studyOverall severityKetamineTwo weeksBeck ScaleRapamycin complex 1Mechanistic targetPatientsSignificant main effectHealth crisisRobust improvementFuture studies
2021
TSC2 regulates lysosome biogenesis via a non-canonical RAGC and TFEB-dependent mechanism
Alesi N, Akl EW, Khabibullin D, Liu HJ, Nidhiry AS, Garner ER, Filippakis H, Lam HC, Shi W, Viswanathan SR, Morroni M, Ferguson SM, Henske EP. TSC2 regulates lysosome biogenesis via a non-canonical RAGC and TFEB-dependent mechanism. Nature Communications 2021, 12: 4245. PMID: 34253722, PMCID: PMC8275687, DOI: 10.1038/s41467-021-24499-6.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBasic Helix-Loop-Helix Leucine Zipper Transcription FactorsCarcinoma, Renal CellCell NucleusCell ProliferationFemaleGene Expression RegulationHEK293 CellsHeLa CellsHumansKidney NeoplasmsLysosomesMiceMice, Inbred NODMice, SCIDMonomeric GTP-Binding ProteinsOrganelle BiogenesisPhosphorylationPhosphoserineProtein TransportProto-Oncogene ProteinsTranscription, GeneticTuberous Sclerosis Complex 2 ProteinTumor Suppressor ProteinsConceptsTranscription factor EBTSC2-deficient cellsLysosome biogenesisLysosomal biogenesisDeficient cellsRapamycin complex 1TSC1/2 complexTFEB phosphorylationTuberous sclerosis complexTSC proteinsMaster regulatorBiogenesisMechanistic targetRagCCritical regulatorFolliculinPhosphorylationDependent sitesRegulatorProteinOverexpressionTSC2 mutationsCellsGTPaseMTORC1Nucleotide‐binding domain and leucine‐rich‐repeat‐containing protein X1 deficiency induces nicotinamide adenine dinucleotide decline, mechanistic target of rapamycin activation, and cellular senescence and accelerates aging lung‐like changes
Shin HJ, Kim S, Park H, Shin M, Kang I, Kang M. Nucleotide‐binding domain and leucine‐rich‐repeat‐containing protein X1 deficiency induces nicotinamide adenine dinucleotide decline, mechanistic target of rapamycin activation, and cellular senescence and accelerates aging lung‐like changes. Aging Cell 2021, 20: e13410. PMID: 34087956, PMCID: PMC8282248, DOI: 10.1111/acel.13410.Peer-Reviewed Original ResearchConceptsCellular senescenceActivation of mTORNucleotide-binding domainCellular senescence responseReplicative cellular senescenceNLR family membersOrganismal agingCellular physiologyMitochondrial moleculesSenescence responseCellular locationProtein X1Crucial regulatorMechanistic targetMitochondrial functionMolecular hallmarksNLRX1 functionRapamycin (mTOR) activationMitochondrial dysfunctionSenescenceMTORPharmacological inhibitionNLRX1BiologyAging LungTranscriptomics of bronchoalveolar lavage cells identifies new molecular endotypes of sarcoidosis
Vukmirovic M, Yan X, Gibson KF, Gulati M, Schupp JC, DeIuliis G, Adams TS, Hu B, Mihaljinec A, Woolard TN, Lynn H, Emeagwali N, Herzog EL, Chen ES, Morris A, Leader JK, Zhang Y, Garcia JGN, Maier LA, Collman RG, Drake WP, Becich MJ, Hochheiser H, Wisniewski SR, Benos PV, Moller DR, Prasse A, Koth LL, Kaminski N. Transcriptomics of bronchoalveolar lavage cells identifies new molecular endotypes of sarcoidosis. European Respiratory Journal 2021, 58: 2002950. PMID: 34083402, PMCID: PMC9759791, DOI: 10.1183/13993003.02950-2020.Peer-Reviewed Original ResearchConceptsWeighted gene co-expression network analysisGene co-expression network analysisCo-expression network analysisGene expression programsGene expression patternsDistinct transcriptional programsImmune response pathwaysIon Torrent ProtonMicroarray expression datasetsExpression programsTranscriptional programsPhenotypic traitsGene modulesResponse pathwaysRNA sequencingMolecular endotypesExpression patternsGene expressionHilar lymphadenopathyOrgan involvementGenomic researchMechanistic targetExpression datasetsT helper type 1T cell immune responsesConvergent and Divergent Mechanisms of Epileptogenesis in mTORopathies
Nguyen LH, Bordey A. Convergent and Divergent Mechanisms of Epileptogenesis in mTORopathies. Frontiers In Neuroanatomy 2021, 15: 664695. PMID: 33897381, PMCID: PMC8064518, DOI: 10.3389/fnana.2021.664695.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsPI3K-mTOR pathwayCortical developmentGene variantsPotential therapeutic strategyIntractable epilepsyNeuronal placementTherapeutic strategiesAnimal modelsEpilepsyElectrophysiological phenotypeNeurodevelopmental disordersRapamycin complex 1Mechanistic targetEpileptogenesisIndependent mechanismsMTORopathiesGATOR1 complexPersonalized medicineDivergent mechanismsMosaic patternEverolimusMalformationsHyperactivityPathwayVariants
2020
Ectopic HCN4 expression drives mTOR-dependent epilepsy in mice
Hsieh LS, Wen JH, Nguyen LH, Zhang L, Getz SA, Torres-Reveron J, Wang Y, Spencer DD, Bordey A. Ectopic HCN4 expression drives mTOR-dependent epilepsy in mice. Science Translational Medicine 2020, 12 PMID: 33208499, PMCID: PMC9888000, DOI: 10.1126/scitranslmed.abc1492.Peer-Reviewed Original ResearchConceptsFocal cortical dysplasia type IITuberous sclerosis complexFocal cortical malformationsPyramidal neuronsMouse modelHCN4 expressionCortical pyramidal neuronsOnset of seizuresIntracellular cAMP concentrationSeizure activityCortical malformationsRepetitive firingDiseased neuronsSeizuresAbnormal expressionNeuronsEpilepsyCausative linkSeizure mechanismsCAMP concentrationMechanistic targetHCN4Channel activityPatientsGene therapyA Randomized Controlled Trial Protocol for Engaging Distress Tolerance and Working Memory to Aid Smoking Cessation in Low Socioeconomic Status (SES) Adults
Otto MW, Zvolensky MJ, Rosenfield D, Hoyt DL, Witkiewitz K, McKee SA, Bickel WK, Smits JAJ. A Randomized Controlled Trial Protocol for Engaging Distress Tolerance and Working Memory to Aid Smoking Cessation in Low Socioeconomic Status (SES) Adults. Health Psychology 2020, 39: 815-825. PMID: 32833483, PMCID: PMC8489738, DOI: 10.1037/hea0000858.Peer-Reviewed Original ResearchConceptsDistress toleranceMindfulness interventionLow distress toleranceCessation attemptsLow socioeconomic contextExperimental medicine approachRandomized clinical trial designWorking memoryLow socioeconomic status adultsMemory capacitySmoking lapseTarget of treatmentHeightened stressTreatment refinementNicotine useQuit attemptsControlled Trial ProtocolMechanistic targetStrongest predictorSpecific vulnerabilitiesClinical trial designLow educational attainmentEducational attainmentLapseTherapeutic gainRibosome Biogenesis and its Role in Cell Growth and Proliferation in the Liver
Farley‐Barnes K, Baserga S. Ribosome Biogenesis and its Role in Cell Growth and Proliferation in the Liver. 2020, 174-182. DOI: 10.1002/9781119436812.ch15.ChaptersRibosome biogenesisBiogenesis of ribosomesProduction of ribosomesHuman ribosome biogenesisCell growthTumor suppressor p53Cellular cuesNumerous proteinsNucleolar stressRegulated processTranscription factorsBiogenesisNutrient availabilityKey regulatorMechanistic targetSuppressor p53Rapamycin (mTOR) pathwayRibosomesRegulationProliferationSuch diseasesMYCRegulatorCytoplasmProtein
2019
GATORopathies: The role of amino acid regulatory gene mutations in epilepsy and cortical malformations
Iffland PH, Carson V, Bordey A, Crino PB. GATORopathies: The role of amino acid regulatory gene mutations in epilepsy and cortical malformations. Epilepsia 2019, 60: 2163-2173. PMID: 31625153, PMCID: PMC7155771, DOI: 10.1111/epi.16370.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsCellular amino acid levelsRegulatory gene mutationsActivator RhebAmino acid levelsProtein complexesSingle geneRegulatory proteinsGene mutationsMechanistic targetNPRL3Rapamycin (mTOR) pathwayMTOR activationMTOR pathwayMutationsNPRL2MTOR inhibitionGenesFocal cortical dysplasia type IIaMTORDEPDC5ProteinPivotal rolePathwayRecent studiesNeuronal excitabilitymTOR Hyperactivity Levels Influence the Severity of Epilepsy and Associated Neuropathology in an Experimental Model of Tuberous Sclerosis Complex and Focal Cortical Dysplasia
Nguyen LH, Mahadeo T, Bordey A. mTOR Hyperactivity Levels Influence the Severity of Epilepsy and Associated Neuropathology in an Experimental Model of Tuberous Sclerosis Complex and Focal Cortical Dysplasia. Journal Of Neuroscience 2019, 39: 2762-2773. PMID: 30700531, PMCID: PMC6445990, DOI: 10.1523/jneurosci.2260-18.2019.Peer-Reviewed Original ResearchConceptsFocal cortical dysplasiaTuberous sclerosis complexSeverity of epilepsyRapamycin (mTOR) pathway genesPersonalized medicine strategiesAssociated neuropathologyCortical dysplasiaMouse modelActivity levelsPathogenic variantsEpileptogenic cortical malformationsNeuronal soma sizeMedicine strategiesPatient variantsMechanistic targetSevere epilepsy phenotypePreclinical drug testingHyperactivity levelsDose-dependent mannerMicroglial activationSeizure frequencyRecurrent seizuresCortical malformationsIntractable epilepsyClinical assessment
2018
Metabolic control of regulatory T cell stability and function by TRAF3IP3 at the lysosome
Yu X, Teng XL, Wang F, Zheng Y, Qu G, Zhou Y, Hu Z, Wu Z, Chang Y, Chen L, Li HB, Su B, Lu L, Liu Z, Sun SC, Zou Q. Metabolic control of regulatory T cell stability and function by TRAF3IP3 at the lysosome. Journal Of Experimental Medicine 2018, 215: 2463-2476. PMID: 30115741, PMCID: PMC6122976, DOI: 10.1084/jem.20180397.Peer-Reviewed Original ResearchConceptsCell metabolismPhosphatase catalytic subunitRapamycin complex 1Component raptorRegulatory T Cell StabilityCatalytic subunitMetabolic programsMechanistic targetPivotal regulatorSignaling mechanismTRAF3IP3Metabolic regulatorMetabolic fitnessCell functionRegulatorLysosomesMetabolismT reg cell functionCell stabilityPP2AcComplexes 1RaptorsSubunitsDeletionStrong antitumor T-cell responses
2016
Inhibition of Regulatory-Associated Protein of Mechanistic Target of Rapamycin Prevents Hyperoxia-Induced Lung Injury by Enhancing Autophagy and Reducing Apoptosis in Neonatal Mice
Sureshbabu A, Syed M, Das P, Janér C, Pryhuber G, Rahman A, Andersson S, Homer RJ, Bhandari V. Inhibition of Regulatory-Associated Protein of Mechanistic Target of Rapamycin Prevents Hyperoxia-Induced Lung Injury by Enhancing Autophagy and Reducing Apoptosis in Neonatal Mice. American Journal Of Respiratory Cell And Molecular Biology 2016, 55: 722-735. PMID: 27374190, PMCID: PMC5105179, DOI: 10.1165/rcmb.2015-0349oc.Peer-Reviewed Original ResearchMeSH KeywordsAcute Lung InjuryAdaptor Proteins, Signal TransducingAlveolar Epithelial CellsAnimalsAnimals, NewbornApoptosisAutophagyBronchopulmonary DysplasiaCell LineFemaleHumansHyperoxiaHypertension, PulmonaryHypertrophy, Right VentricularInfant, NewbornLungMiceMicrotubule-Associated ProteinsNaphthyridinesPhenotypeRegulatory-Associated Protein of mTORTime FactorsTumor Suppressor Protein p53ConceptsAcute lung injuryBronchopulmonary dysplasiaLung injuryWild-type miceMechanistic targetRegulatory-Associated ProteinLysosomal-associated membrane protein 1Apoptotic cell deathFetal type II alveolar epithelial cellsMouse lungRole of autophagyHyperoxia-Induced Lung InjuryLight chain 3Activation of autophagyType II alveolar epithelial cellsRespiratory distress syndromeMembrane protein 1Developmental lung diseaseUseful therapeutic targetNeonatal mouse lungAlveolar epithelial cellsPharmacological inhibitorsTreatment of hyperoxiaCell deathAutophagic fluxSwitching on mTORC1 induces neurogenesis but not proliferation in neural stem cells of young mice
Mahoney C, Feliciano DM, Bordey A, Hartman NW. Switching on mTORC1 induces neurogenesis but not proliferation in neural stem cells of young mice. Neuroscience Letters 2016, 614: 112-118. PMID: 26812181, DOI: 10.1016/j.neulet.2015.12.042.Peer-Reviewed Original ResearchConceptsNeural stem cellsSubventricular zoneNeonatal subventricular zoneWeek old miceTuberous sclerosis complexStem cellsNewborn neuroblastsYoung miceOld miceProgressive lossYoung adultsRapamycin complex 1Mechanistic targetRecent evidenceProliferative cellsMiceHyperactive mTORC1Terminal differentiationCellsMTORC1 activationProliferationActivationMTORC1NeurogenesisHyperactivity
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