ABSTRACT
How do decision-makers choose between alternatives offering outcomes that are not easily quantifiable? Previous literature on decisions under uncertainty focused on alternatives with quantifiable outcomes, for example monetary lotteries. In such scenarios, decision-makers make decisions based on success chance, outcome magnitude, and individual preferences for uncertainty. It is not clear, however, how individuals construct subjective values when outcomes are not directly quantifiable. To explore how decision-makers choose when facing non-quantifiable outcomes, we focus here on medical decisions with qualitative outcomes. Specifically, we ask whether decision-makers exhibit the same attitudes towards two types of uncertainty - risk and ambiguity - across domains with quantitative and qualitative outcomes. To answer this question, we designed an online decision-making task where participants made binary choices between alternatives offering either guaranteed lower outcomes or potentially higher outcomes that are associated with some risk and ambiguity. The outcomes of choices were either different magnitudes of monetary gains or levels of improvement in a medical condition. We recruited 429 online participants and repeated the survey in two waves, which allowed us to compare the between-domain attitude consistency with within-domain consistency, over time. We found that risk and ambiguity attitudes were moderately correlated across domains. Over time, risk attitudes had slightly higher correlations compared to across domains, while in ambiguity over-time correlations were slightly weaker. These findings are consistent with the conceptualization of risk attitude as more trait-like, and ambiguity attitudes as more state-like. We discuss the implications and applicability of our novel modeling approach to broader contexts with non-quantifiable outcomes.
ABSTRACT
The adult mammalian cochlear sensory epithelium houses two major types of cells, mechanosensory hair cells and underlying supporting cells, and lacks regenerative capacity. Recent evidence indicates that a subset of supporting cells can spontaneously regenerate hair cells after ablation only within the first week postparturition. Here in vivo clonal analysis of mouse inner ear cells during development demonstrates clonal relationship between hair and supporting cells in sensory organs. We report the identification in mouse of a previously unknown population of multipotent stem/progenitor cells that are capable of not only contributing to the hair and supporting cells but also to other cell types, including glia, in cochlea undergoing development, maturation and repair in response to damage. These multipotent progenitors originate from Eya1-expressing otic progenitors. Our findings also provide evidence for detectable regenerative potential in the postnatal cochlea beyond 1 week of age.
Subject(s)
Hair Cells, Auditory/cytology , Hearing/physiology , Labyrinth Supporting Cells/cytology , Multipotent Stem Cells/cytology , Neuroglia/cytology , Animals , Animals, Newborn , Basic Helix-Loop-Helix Transcription Factors/genetics , Basic Helix-Loop-Helix Transcription Factors/metabolism , Biomarkers/metabolism , Cell Differentiation , Embryo, Mammalian , Female , Gene Expression , Genes, Reporter , Green Fluorescent Proteins/genetics , Green Fluorescent Proteins/metabolism , Hair Cells, Auditory/metabolism , Intracellular Signaling Peptides and Proteins/genetics , Intracellular Signaling Peptides and Proteins/metabolism , Labyrinth Supporting Cells/metabolism , Luminescent Proteins/genetics , Luminescent Proteins/metabolism , Male , Mice , Multipotent Stem Cells/metabolism , Myosin VIIa , Myosins/genetics , Myosins/metabolism , Neuroglia/metabolism , Nuclear Proteins/genetics , Nuclear Proteins/metabolism , Protein Tyrosine Phosphatases/genetics , Protein Tyrosine Phosphatases/metabolism , Red Fluorescent ProteinABSTRACT
EYA1 is known to be overexpressed in human breast cancer, in which the Myc protein is also accumulated in association with decreased phospho-T58 (pT58) levels. We have recently reported that EYA1 functions as a unique protein phosphatase to dephosphorylate Myc at pT58 to regulate Myc levels. However, it remains unclear whether EYA1-mediated Myc dephosphorylation on T58 is a critical function in regulating Myc protein stability in breast cancer. Furthermore, EYA1's substrate specificity has remained elusive. In this study, we have investigated these questions, and here, we report that depletion of EYA1 using short hairpin RNA (shRNA) in breast cancer cells destabilizes the Myc protein and increases pT58 levels, leading to an increase in the doubling time and impairment of cell cycle progression. In correlation with EYA1-mediated stabilization of cMyc and reduced levels of pT58, EYA1 greatly reduced cMyc-FBW7 binding and cMyc ubiquitination, thus providing novel insight into how EYA1 acts to regulate the FBW7-mediated Myc degradation machinery. We found that the conserved C-terminal haloacid dehalogenase domain of EYA1, which has been reported to have only tyrosine phosphatase activity, has dual phosphatase activities, and both the N- and C-terminal domains interact with substrates to increase the catalytic activity of EYA1. Enzymatic assay and nuclear magnetic resonance (NMR) analysis demonstrated that EYA1 has a striking conformation preference for phospho-T58 of Myc. Together, our results not only provide novel structural evidence about the conformation specificity of EYA1 in dephosphorylating phosphothreonine in Myc but also reveal an important mechanism contributing to Myc deregulation in human breast cancer.
Subject(s)
Breast Neoplasms/metabolism , Cell Cycle Proteins/metabolism , F-Box Proteins/metabolism , Intracellular Signaling Peptides and Proteins/chemistry , Intracellular Signaling Peptides and Proteins/metabolism , Nuclear Proteins/chemistry , Nuclear Proteins/metabolism , Protein Tyrosine Phosphatases/chemistry , Protein Tyrosine Phosphatases/metabolism , Proto-Oncogene Proteins c-myc/metabolism , Ubiquitin-Protein Ligases/metabolism , Cell Cycle , Cell Line, Tumor , F-Box-WD Repeat-Containing Protein 7 , Female , Gene Expression Regulation, Neoplastic , Humans , Models, Molecular , Phosphorylation , Protein Binding , Protein Conformation , Protein Stability , Proto-Oncogene Proteins c-myc/chemistry , Threonine/metabolismABSTRACT
Mouse N-ethyl-N-nitrosourea (ENU) mutagenesis has generated many useful animal models for human diseases. Here we describe the identification of a novel ENU-induced mouse mutant strain Turner (Tur) that displays circling and headtossing behavior and progressive hearing loss. Tur/Tur homozygous animals lack Preyer and righting reflexes and display severe headtossing and reaching response defect. We mapped the Tur mutation to a critical region of 11 cM on chromosome 9 that includes myosin VI. Direct sequence analysis revealed a c.820A>T substitution in exon 8 of the Myo6 gene that changes amino acid Asn200 to Ile (p.N200I) in the motor domain. Analysis of inner ear hair cells by immunohistochemistry, scanning electron microscopy and histology revealed degeneration of hair cells in the inner ear and structural malformation of the stereocilia in the cochlea of Turner homozygous mutant mice. Our data indicate that this novel mouse strain provides a useful model for future studies on the function of myosin VI in mammalian auditory and non-auditory systems and in human syndromes.
Subject(s)
Deafness/genetics , Deafness/physiopathology , Mutation/genetics , Myosin Heavy Chains/genetics , Vestibule, Labyrinth/physiopathology , Animals , Auditory Threshold , Base Sequence , Behavior, Animal , Chromosomes, Mammalian/genetics , Epithelium/pathology , Epithelium/ultrastructure , Ethylnitrosourea , Evoked Potentials, Auditory, Brain Stem , Genes, Dominant , Hair Cells, Auditory/pathology , Hair Cells, Auditory/ultrastructure , Male , Mice, Inbred C57BL , Mice, Mutant Strains , Penetrance , Vestibule, Labyrinth/ultrastructureABSTRACT
Tumor-associated macrophages (TAMs) represent an important cellular subset within the glioblastoma (WHO grade IV) microenvironment and are a potential therapeutic target. TAMs display a continuum of different polarization states between antitumorigenic M1 and protumorigenic M2 phenotypes, with a lower M1/M2 ratio correlating with worse prognosis. Here, we investigated the effect of macrophage polarization on anti-CD47 antibody-mediated phagocytosis of human glioblastoma cells in vitro, as well as the effect of anti-CD47 on the distribution of M1 versus M2 macrophages within human glioblastoma cells grown in mouse xenografts. Bone marrow-derived mouse macrophages and peripheral blood-derived human macrophages were polarized in vitro toward M1 or M2 phenotypes and verified by flow cytometry. Primary human glioblastoma cell lines were offered as targets to mouse and human M1 or M2 polarized macrophages in vitro. The addition of an anti-CD47 monoclonal antibody led to enhanced tumor-cell phagocytosis by mouse and human M1 and M2 macrophages. In both cases, the anti-CD47-induced phagocytosis by M1 was more prominent than that for M2. Dissected tumors from human glioblastoma xenografted within NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ mice and treated with anti-CD47 showed a significant increase of M1 macrophages within the tumor. These data show that anti-CD47 treatment leads to enhanced tumor cell phagocytosis by both M1 and M2 macrophage subtypes with a higher phagocytosis rate by M1 macrophages. Furthermore, these data demonstrate that anti-CD47 treatment alone can shift the phenotype of macrophages toward the M1 subtype in vivo.
Subject(s)
Antibodies/pharmacology , CD47 Antigen/metabolism , Glioblastoma/drug therapy , Glioblastoma/pathology , Macrophages/drug effects , Macrophages/pathology , Phagocytosis/drug effects , Animals , Cell Differentiation/drug effects , Cell Line, Tumor , Glioblastoma/metabolism , Humans , Macrophages/metabolism , Mice , Mice, Inbred NOD , PhenotypeABSTRACT
Self-renewal and proliferation of nephron progenitor cells and the decision to initiate nephrogenesis are crucial events directing kidney development. Despite recent advancements in defining lineage and regulators for the progenitors, fundamental questions about mechanisms driving expansion of the progenitors remain unanswered. Here we show that Eya1 interacts with Six2 and Myc to control self-renewing cell activity. Cell fate tracing reveals a developmental restriction of the Eya1(+) population within the intermediate mesoderm to nephron-forming cell fates and a common origin shared between caudal mesonephric and metanephric nephrons. Conditional inactivation of Eya1 leads to loss of Six2 expression and premature epithelialization of the progenitors. Six2 mediates translocation of Eya1 to the nucleus, where Eya1 uses its threonine phosphatase activity to control Myc phosphorylation/dephosphorylation and function in the progenitor cells. Our results reveal a functional link between Eya1, Six2, and Myc in driving the expansion and maintenance of the multipotent progenitors during nephrogenesis.