20 research outputs found

    Identifying the Irritability Dimension of ODD: Application of a Modified Bifactor Model Across Five Large Community Samples of Children

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    The importance of irritability, as measured among the symptoms of oppositional defiant disorder (ODD), has dramatically come to the fore in recent years. New diagnostic categories rely on the distinct clinical utility of irritability, and models of psychopathology suggest it plays a key role in explaining developmental pathways within and between disorders into adulthood. However, only a few studies have tested multidimensional models of ODD, and the results have been conflicting. Further, consensus has not been reached regarding which symptoms best identify irritability. The present analyses use 5 large community data sets with 5 different measures of parent-reported ODD, comprising 16,280 youth in total, to help resolve these questions. Across the samples, ages ranged from 5 to 18, and included both boys and girls. Confirmatory factor analyses demonstrated that a modified bifactor model showed the best fit in each data set. The structure of the model included 2 correlated specific factors (irritability and oppositional behavior) in addition to a general ODD factor. In 4 models, the best fit was obtained using the items “being touchy,” “angry,” and “often losing temper” as indicators of irritability. Given the structure of the models and the generally high correlation between the specific dimensions, the results suggest that irritability may not be sufficiently distinct from oppositional behavior to support an entirely independent diagnosis. Rather, irritability may be better understood as a dimension of psychopathology that can be distinguished within ODD, and which may be related to particular forms of psychopathology apart from ODD

    ADP-Ribosylation Factor (ARF) Interaction Is Not Sufficient for Yeast GGA Protein Function or Localization

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    Golgi-localized Îł-ear homology domain, ADP-ribosylation factor (ARF)-binding proteins (GGAs) facilitate distinct steps of post-Golgi traffic. Human and yeast GGA proteins are only ∌25% identical, but all GGA proteins have four similar domains based on function and sequence homology. GGA proteins are most conserved in the region that interacts with ARF proteins. To analyze the role of ARF in GGA protein localization and function, we performed mutational analyses of both human and yeast GGAs. To our surprise, yeast and human GGAs differ in their requirement for ARF interaction. We describe a point mutation in both yeast and mammalian GGA proteins that eliminates binding to ARFs. In mammalian cells, this mutation disrupts the localization of human GGA proteins. Yeast Gga function was studied using an assay for carboxypeptidase Y missorting and synthetic temperature-sensitive lethality between GGAs and VPS27. Based on these assays, we conclude that non-Arf-binding yeast Gga mutants can function normally in membrane trafficking. Using green fluorescent protein-tagged Gga1p, we show that Arf interaction is not required for Gga localization to the Golgi. Truncation analysis of Gga1p and Gga2p suggests that the N-terminal VHS domain and C-terminal hinge and ear domains play significant roles in yeast Gga protein localization and function. Together, our data suggest that yeast Gga proteins function to assemble a protein complex at the late Golgi to initiate proper sorting and transport of specific cargo. Whereas mammalian GGAs must interact with ARF to localize to and function at the Golgi, interaction between yeast Ggas and Arf plays a minor role in Gga localization and function

    Role of Adaptor Complex AP-3 in Targeting Wild-Type and Mutated CD63 to Lysosomes

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    CD63 is a lysosomal membrane protein that belongs to the tetraspanin family. Its carboxyterminal cytoplasmic tail sequence contains the lysosomal targeting motif GYEVM. Strong, tyrosine-dependent interaction of the wild-type carboxyterminal tail of CD63 with the AP-3 adaptor subunit ÎŒ3 was observed using a yeast two-hybrid system. The strength of interaction of mutated tail sequences with ÎŒ3 correlated with the degree of lysosomal localization of similarly mutated human CD63 molecules in stably transfected normal rat kidney cells. Mutated CD63 containing the cytosolic tail sequence GYEVI, which interacted strongly with ÎŒ3 but not at all with ÎŒ2 in the yeast two-hybrid system, localized to lysosomes in transfected normal rat kidney and NIH-3T3 cells. In contrast, it localized to the cell surface in transfected cells of pearl and mocha mice, which have genetic defects in genes encoding subunits of AP-3, but to lysosomes in functionally rescued mocha cells expressing the ÎŽ subunit of AP-3. Thus, AP-3 is absolutely required for the delivery of this mutated CD63 to lysosomes. Using this AP-3–dependent mutant of CD63, we have shown that AP-3 functions in membrane traffic from the trans-Golgi network to lysosomes via an intracellular route that appears to bypass early endosomes
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