2024
Multiscale computational model of aortic remodeling following postnatal disruption of TGFβ signaling
Estrada A, Irons L, Tellides G, Humphrey J. Multiscale computational model of aortic remodeling following postnatal disruption of TGFβ signaling. Journal Of Biomechanics 2024, 169: 112152. PMID: 38763809, PMCID: PMC11141772, DOI: 10.1016/j.jbiomech.2024.112152.Peer-Reviewed Original ResearchAdult aortaTGFB signalingSmooth muscle cellsAortic remodelingCardiac-inducedMouse modelNormal mechanical loadingMuscle cellsPostnatal developmentHemodynamic loadNormal loadAortaMechanical homeostasisMechanical loadingMultiscale computational modelIncreasing loadLoadCell signalingGene productsStructural integrityDNA lesion bypass and the stochastic dynamics of transcription-coupled repair
Nicholson M, Anderson C, Odom D, Aitken S, Taylor M. DNA lesion bypass and the stochastic dynamics of transcription-coupled repair. Proceedings Of The National Academy Of Sciences Of The United States Of America 2024, 121: e2403871121. PMID: 38717857, PMCID: PMC11098089, DOI: 10.1073/pnas.2403871121.Peer-Reviewed Original ResearchConceptsTranscription-coupled repairRNA polymerase IIDistribution of mutationsStalling of RNA polymerase IITranscription-coupled repair (TCRDNA damageGene expressionBarriers to gene expressionSites of DNA damageGenome-wide distributionBarrier to transcriptionDamaged DNA strandMammalian model systemsDNA lesion bypassGene bodiesPolymerase IIRNA polymeraseGenetic integrityGene productsDNA base damageLesion bypassAlkylation damageDNA strandsBypass lesionsMutations
2023
Cheating leads to the evolution of multipartite viruses
Leeks A, Young P, Turner P, Wild G, West S. Cheating leads to the evolution of multipartite viruses. PLOS Biology 2023, 21: e3002092. PMID: 37093882, PMCID: PMC10159356, DOI: 10.1371/journal.pbio.3002092.Peer-Reviewed Original Research
2021
DnaJ and ClpX Are Required for HitRS and HssRS Two-Component System Signaling in Bacillus anthracis
Laut C, Leasure C, Pi H, Carlin S, Chu M, Hillebrand G, Lin H, Yi X, Stauff D, Skaar E. DnaJ and ClpX Are Required for HitRS and HssRS Two-Component System Signaling in Bacillus anthracis. Infection And Immunity 2021, 90: e00560-21. PMID: 34748369, PMCID: PMC8788696, DOI: 10.1128/iai.00560-21.Peer-Reviewed Original ResearchConceptsTwo-component systemGene expressionSubstrate-binding subunitSignal transduction activityTarget gene expressionB. anthracisBacillus anthracisGram-positive bacteriumHost-induced stressesClpXP proteaseProtein chaperonesSignal transductionClpXGene productsTransduction activityDnaJVertebrate hostsHeme levelsHomeostasis regulatorGenetic selectionHigh heme levelsCell envelope disruptionBioterror weaponHssRSAnthracisA transgenic system for targeted ablation of reproductive and maternal-effect genes
Bertho S, Kaufman O, Lee K, Santos-Ledo A, Dellal D, Marlow F. A transgenic system for targeted ablation of reproductive and maternal-effect genes. Development 2021, 148 PMID: 34143203, PMCID: PMC8254866, DOI: 10.1242/dev.198010.Peer-Reviewed Original ResearchConceptsMaternal-effect genesForward genetic screensReverse genetics systemEmbryonic developmentRegulation of embryonic developmentTransgenic systemZygotic functionGenetic systemGenetic screeningGene productsMolecular regulationGenesEarly embryosDevelopmental processesNormal embryogenesisLate functionMolecular pathwaysBucky ballEmbryosMutagenesisSevere multisystem pathology, metabolic acidosis, mitochondrial dysfunction, and early death associated with an X-linked AIFM1 variant
Moss T, May M, Flanagan-Steet H, Caylor R, Jiang YH, McDonald M, Friez M, McConkie-Rosell A, Steet R. Severe multisystem pathology, metabolic acidosis, mitochondrial dysfunction, and early death associated with an X-linked AIFM1 variant. Molecular Case Studies 2021, 7: a006081. PMID: 34117073, PMCID: PMC8208043, DOI: 10.1101/mcs.a006081.Peer-Reviewed Original ResearchConceptsMitochondrial flavin adenine dinucleotideCaspase-independent typeRespiratory complex assemblyFunctional studiesApoptosis inducer staurosporineGalactose-containing mediumNicotinamide adenine dinucleotide (phosphate) oxidoreductaseApoptotic stimuliSteady-state levelsComplex assemblyGene productsReactive oxygen speciesMitochondrial deficiencyTissue-specific effectsNuclear condensationFlavin adenine dinucleotideReduced abundanceMitochondrial complexesComplex IPyruvate dehydrogenaseMitochondrial dysfunctionPatient cellsExome sequencingOxygen speciesElevated sensitivity12 Iron Metabolism and Related Disorders
Ginzburg Y, Finberg K. 12 Iron Metabolism and Related Disorders. 2021, 445-499. DOI: 10.1016/b978-0-12-812535-9.00012-1.ChaptersGene productsNumerous fundamental biological processesFundamental biological processesIron metabolismGenetic defectsSystemic iron balanceSystemic iron regulationMolecular geneticsBiological processesIron regulationIron-refractory iron deficiency anemiaIron homeostasisIron availabilityFriedreich's ataxiaIron movementMajor genetic disordersErythroid precursorsGenetic disordersIron regulatory hormone hepcidinSideroblastic anemiaMetabolismGenetic formsMutationsKey roleHormone hepcidin
2020
Genome-wide CRISPR Screens Reveal Host Factors Critical for SARS-CoV-2 Infection
Wei J, Alfajaro MM, DeWeirdt PC, Hanna RE, Lu-Culligan WJ, Cai WL, Strine MS, Zhang SM, Graziano VR, Schmitz CO, Chen JS, Mankowski MC, Filler RB, Ravindra NG, Gasque V, de Miguel FJ, Patil A, Chen H, Oguntuyo KY, Abriola L, Surovtseva YV, Orchard RC, Lee B, Lindenbach BD, Politi K, van Dijk D, Kadoch C, Simon MD, Yan Q, Doench JG, Wilen CB. Genome-wide CRISPR Screens Reveal Host Factors Critical for SARS-CoV-2 Infection. Cell 2020, 184: 76-91.e13. PMID: 33147444, PMCID: PMC7574718, DOI: 10.1016/j.cell.2020.10.028.Peer-Reviewed Original ResearchMeSH KeywordsAngiotensin-Converting Enzyme 2AnimalsCell LineChlorocebus aethiopsClustered Regularly Interspaced Short Palindromic RepeatsCoronavirusCoronavirus InfectionsCOVID-19Gene Knockout TechniquesGene Regulatory NetworksGenome-Wide Association StudyHEK293 CellsHMGB1 ProteinHost-Pathogen InteractionsHumansSARS-CoV-2Vero CellsVirus InternalizationConceptsSARS-CoV-2 infectionSARS-CoV-2Vesicular stomatitis virusGenome-wide CRISPR screenSWI/SNF chromatinSARS-CoV-2 host factorsAcute respiratory syndrome coronavirus 2 infectionSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infectionTherapeutic targetHost factorsCoronavirus disease 2019 (COVID-19) pathogenesisSyndrome coronavirus 2 infectionCRISPR screensHost genesGene productsMiddle East respiratory syndrome CoVCoronavirus 2 infectionGenetic hitsHuman cellsSARS-CoV-2 spikeNovel therapeutic targetPotential therapeutic targetVero E6 cellsSARS-CoV-1Small molecule antagonistsAnalysis of blood-induced Anopheles gambiae midgut proteins and sexual stage Plasmodium falciparum interaction reveals mosquito genes important for malaria transmission
Cui Y, Niu G, Li VL, Wang X, Li J. Analysis of blood-induced Anopheles gambiae midgut proteins and sexual stage Plasmodium falciparum interaction reveals mosquito genes important for malaria transmission. Scientific Reports 2020, 10: 14316. PMID: 32868841, PMCID: PMC7459308, DOI: 10.1038/s41598-020-71186-5.Peer-Reviewed Original ResearchConceptsMidgut proteinsCandidate genesStage parasitesGene expression profilesMosquito genesUnique genesMalaria transmissionInsect cellsMosquito proteinsSexual stage parasitesGene productsAsexual stage parasitesKnockdown assaysP. falciparum invasionProtein sequencesPlasmodium invasionAnopheles gambiaeSecretory proteinsExpression profilesMosquito midgutParasite invasionGenesCell lysatesMosquito susceptibilityProteinA Screen for Antibiotic Resistance Determinants Reveals a Fitness Cost of the Flagellum in Pseudomonas aeruginosa
Rundell EA, Commodore N, Goodman AL, Kazmierczak BI. A Screen for Antibiotic Resistance Determinants Reveals a Fitness Cost of the Flagellum in Pseudomonas aeruginosa. Journal Of Bacteriology 2020, 202: 10.1128/jb.00682-19. PMID: 31871033, PMCID: PMC7043666, DOI: 10.1128/jb.00682-19.Peer-Reviewed Original ResearchConceptsFlagellar assemblyFitness advantageFitness costsCell envelopeOuter membrane barrier functionOuter membrane biogenesisUnbiased high-throughput approachOuter membrane barrierMembrane barrier functionHigh-throughput approachMembrane biogenesisGram-negative bacteriaFlagellar functionInsertion sequencingOuter membraneGene productsPresence of linezolidPresence of antibioticsAntibiotic resistance determinantsMembrane barrierAntibiotic entryFitnessEfflux pumpsGlycopeptide antibiotic vancomycinGenes
2019
Quantitative Fluorescence In Situ Hybridization (FISH) and Immunofluorescence (IF) of Specific Gene Products in KSHV-Infected Cells.
Vallery TK, Steitz JA. Quantitative Fluorescence In Situ Hybridization (FISH) and Immunofluorescence (IF) of Specific Gene Products in KSHV-Infected Cells. Journal Of Visualized Experiments 2019 PMID: 31524859, PMCID: PMC6750728, DOI: 10.3791/59697.Peer-Reviewed Original ResearchConceptsRNA FISHSarcoma-associated herpesvirusSpecific RNAViral replication compartmentsSpecific gene productsSitu hybridizationKaposi's sarcoma-associated herpesvirusMultiple cell typesReplication compartmentsGene productsViral genesHost cellsCell typesQuantitative fluorescenceNuclear factoriesFishCell morphologyHuman hostMechanistic insightsSpatiotemporal activityUninfected cellsBehavior of biomoleculesRNAProteinCellsALG9 Mutation Carriers Develop Kidney and Liver Cysts
Besse W, Chang AR, Luo JZ, Triffo WJ, Moore BS, Gulati A, Hartzel DN, Mane S, Center R, Torres VE, Somlo S, Mirshahi T. ALG9 Mutation Carriers Develop Kidney and Liver Cysts. Journal Of The American Society Of Nephrology 2019, 30: 2091-2102. PMID: 31395617, PMCID: PMC6830805, DOI: 10.1681/asn.2019030298.Peer-Reviewed Original ResearchConceptsProteins polycystin-1Autosomal dominant polycystic kidney diseaseDisease genesRare loss-of-function variantsN-glycan precursorsNovel disease genesLoss-of-function variantsEndoplasmic reticulum lumenLoss-of-function mutationsMonogenic kidney diseaseWhole-exome sequencingGenotype-phenotype correlationProtein biogenesisProtein maturationReticulum lumenPolycystin-1Endoplasmic reticulumGene productsPopulation-based cohortCell-based assaysPhenotypic characterizationPolycystic phenotypeMutation carrier stateDefective glycosylationDominant polycystic kidney diseaseMapping human microbiome drug metabolism by gut bacteria and their genes
Zimmermann M, Zimmermann-Kogadeeva M, Wegmann R, Goodman AL. Mapping human microbiome drug metabolism by gut bacteria and their genes. Nature 2019, 570: 462-467. PMID: 31158845, PMCID: PMC6597290, DOI: 10.1038/s41586-019-1291-3.Peer-Reviewed Original ResearchConceptsHuman gut bacteriaGut bacteriaHigh-throughput genetic analysisMicrobial gene productsDiverse cladeGene contentGenomic contentGene productsGenetic analysisMolecular mechanismsDrug metabolismBacteriaMultiple disease indicationsMetabolic activityDrug-metabolizing activityGut microbiomeMicrobiomeMetabolismDrug developmentMedical therapyTreatment delayMass spectrometryCladeDisease indicationsAdverse effects
2018
Isoform-Level Interpretation of High-Throughput Proteomics Data Enabled by Deep Integration with RNA-seq
Carlyle B, Kitchen RR, Zhang J, Wilson R, Lam T, Rozowsky JS, Williams KR, Sestan N, Gerstein M, Nairn AC. Isoform-Level Interpretation of High-Throughput Proteomics Data Enabled by Deep Integration with RNA-seq. Journal Of Proteome Research 2018, 17: 3431-3444. PMID: 30125121, PMCID: PMC6392456, DOI: 10.1021/acs.jproteome.8b00310.Peer-Reviewed Original ResearchConceptsRNA-seqProteomic dataGene expressionLiquid chromatography-tandem mass spectrometry proteomicsTandem mass spectrometry proteomicsHigh-throughput proteomic dataTranscriptomic profiling methodsDistinct amino acid sequencesTranscript-level expressionAmino acid sequenceMass spectrometry proteomicsHEK293 cell culturesTranslatome dataMost genesProfound functional implicationsProtein isoformsAlternate isoformsGene productsAcid sequenceCellular controlBiosynthetic stateGeneration of peptidesCell typesFunctional relevanceFunctional implicationsSRSF2 mutations drive oncogenesis by activating a global program of aberrant alternative splicing in hematopoietic cells
Liang Y, Tebaldi T, Rejeski K, Joshi P, Stefani G, Taylor A, Song Y, Vasic R, Maziarz J, Balasubramanian K, Ardasheva A, Ding A, Quattrone A, Halene S. SRSF2 mutations drive oncogenesis by activating a global program of aberrant alternative splicing in hematopoietic cells. Leukemia 2018, 32: 2659-2671. PMID: 29858584, PMCID: PMC6274620, DOI: 10.1038/s41375-018-0152-7.Peer-Reviewed Original ResearchConceptsSplicing factorsRNA processingAlternative splicingGene productsSplicing factor SRSF2Gene regulatory eventsAberrant alternative splicingSplice alterationsRecurrent mutationsSplicing proteinsHITS-CLIPSR familyMRNA splicingSplicing genesHematopoietic differentiationRegulatory eventsImpairs hematopoietic differentiationMolecular explanationWidespread modificationSplicingHematopoietic cellsMutationsBinding eventsOncogenesisProteinDynamics and Function of Nuclear Bodies during Embryogenesis
Escayola D, Neugebauer K. Dynamics and Function of Nuclear Bodies during Embryogenesis. Biochemistry 2018, 57: 2462-2469. PMID: 29473743, DOI: 10.1021/acs.biochem.7b01262.Peer-Reviewed Original ResearchConceptsNuclear bodiesCajal bodiesRNA processingZygotic gene productsRNA-protein complexesEfficient RNA processingFunction of nucleoliNuclear body formationGene elementsVariety of organismsZygotic genomeZygotic transitionGenomic lociNascent RNAModel organismsNuclear stepsTranscriptional activationEarly embryosNuclear proteinsGene productsGene locusMembraneless organellesBody formationExcellent modelCell nuclei
2017
ClbS Is a Cyclopropane Hydrolase That Confers Colibactin Resistance
Tripathi P, Shine EE, Healy AR, Kim CS, Herzon SB, Bruner SD, Crawford JM. ClbS Is a Cyclopropane Hydrolase That Confers Colibactin Resistance. Journal Of The American Chemical Society 2017, 139: 17719-17722. PMID: 29112397, PMCID: PMC6202678, DOI: 10.1021/jacs.7b09971.Peer-Reviewed Original ResearchConceptsGene productsBiosynthetic gene clusterSpecific mechanistic roleMolecular functionsGene clusterResidue mutantsHost bacteriaCancer formationColorectal cancer formationEscherichia coliCommensal Escherichia coliColibactinMechanistic roleHydrolase activityPrecolibactinsX-ray structureMolecular-level viewShare similaritiesElectrophilic CyclopropanesBacterial viabilityBacteriaHydrolaseGenotoxic effectsMutantsBiosynthesisStructure and Functional Analysis of ClbQ, an Unusual Intermediate-Releasing Thioesterase from the Colibactin Biosynthetic Pathway
Guntaka NS, Healy AR, Crawford JM, Herzon SB, Bruner SD. Structure and Functional Analysis of ClbQ, an Unusual Intermediate-Releasing Thioesterase from the Colibactin Biosynthetic Pathway. ACS Chemical Biology 2017, 12: 2598-2608. PMID: 28846367, PMCID: PMC5830302, DOI: 10.1021/acschembio.7b00479.Peer-Reviewed Original ResearchConceptsColibactin gene clusterÅ crystal structurePolyketide secondary metabolitesAcyl-thioester substratesColibactin biosynthesisGene clusterBiosynthetic pathwayAtypical roleGene productsBiochemical characterizationFunctional analysisSecondary metabolitesGreater catalytic efficiencyCancer formationColorectal cancer formationHuman gutSpecific functionsNovel insightsCarrier proteinThioesteraseGenetic deletionClbQColibactinCatalytic efficiencyPathwayIsolated polycystic liver disease genes define effectors of polycystin-1 function
Besse W, Dong K, Choi J, Punia S, Fedeles SV, Choi M, Gallagher AR, Huang EB, Gulati A, Knight J, Mane S, Tahvanainen E, Tahvanainen P, Sanna-Cherchi S, Lifton RP, Watnick T, Pei YP, Torres VE, Somlo S. Isolated polycystic liver disease genes define effectors of polycystin-1 function. Journal Of Clinical Investigation 2017, 127: 3558-3558. PMID: 28862642, PMCID: PMC5669574, DOI: 10.1172/jci96729.Peer-Reviewed Original ResearchPolycystin-1 functionPolycystin-1Protein biogenesis pathwaysGenome-wide basisPolycystic liver diseaseLoss-of-function mutationsWhole-exome sequencingHeterozygous loss-of-function mutationsBiogenesis pathwayLoss of functionAdditional genesDisease genesGene productsCell line modelsCandidate genesExome sequencingEndoplasmic reticulumCausative genesFunction mutationsGenesAutosomal dominant polycystic kidney diseaseDominant polycystic kidney diseaseSec63Defective maturationKidney cystsLanosterol Modulates TLR4-Mediated Innate Immune Responses in Macrophages
Araldi E, Fernández-Fuertes M, Canfrán-Duque A, Tang W, Cline GW, Madrigal-Matute J, Pober JS, Lasunción MA, Wu D, Fernández-Hernando C, Suárez Y. Lanosterol Modulates TLR4-Mediated Innate Immune Responses in Macrophages. Cell Reports 2017, 19: 2743-2755. PMID: 28658622, PMCID: PMC5553565, DOI: 10.1016/j.celrep.2017.05.093.Peer-Reviewed Original ResearchConceptsToll-like receptor 4Activator of transcriptionCholesterol biosynthetic pathwayTranscriptional repressionBiosynthetic pathwayLanosterol accumulationGene productsSterol intermediatesSignal transducerGene expressionSelective regulatorSTAT2 activationInnate immune responseType I interferonConditional disruptionCritical functionsMembrane fluidityROS productionMacrophage immunityListeria monocytogenes infectionResistance of miceMouse macrophagesInnate immunityI interferonCYP51A1
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