Browsing by Author "Hanquier, Jocelyne"

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    Evaluating the GCN5b bromodomain as a novel therapeutic target against the parasite Toxoplasma gondii
    (Elsevier, 2020-02-28) Hanquier, Jocelyne; Gimeno, Thomas; Jeffers, Victoria; Sullivan, William J., Jr.; Microbiology and Immunology, School of Medicine
    Toxoplasma gondii is a protozoan parasite of great importance in human and veterinary health. The frontline treatment of antifolates suffers a variety of drawbacks, including toxicity and allergic reactions, underscoring the need to identify novel drug targets for new therapeutics to be developed. We previously showed that the Toxoplasma lysine acetyltransferase (KAT) GCN5b is an essential chromatin remodeling enzyme in the parasite linked to the regulation of gene expression. We have previously established that the KAT domain is a liability that can be targeted in the parasite by compounds like garcinol; here, we investigate the potential of the bromodomain as a targetable element of GCN5b. Bromodomains bind acetylated lysine residues on histones, which helps stabilize the KAT complex at gene promoters. Using an inducible dominant-negative strategy, we found that the GCN5b bromodomain is critical for Toxoplasma viability. We also found that the GCN5-family bromodomain inhibitor, L-Moses, interferes with the ability of the GCN5b bromodomain to associate with acetylated histone residues using an in vitro binding assay. Moreover, L-Moses displays potent activity against Toxoplasma tachyzoites in vitro, which can be overcome if parasites are engineered to over-express GCN5b. Collectively, our data support the GCN5b bromodomain as an attractive target for the development of new therapeutics.
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    Functional connectivity in frontostriatal networks differentiate offspring of parents with substance use disorders from other high-risk youth
    (Elsevier, 2021) Kwon, Elizabeth; Hummer, Tom; Andrews, Katharine D.; Finn, Peter; Aalsma, Matthew; Bailey, Allen; Hanquier, Jocelyne; Wang, Ting; Hulvershorn, Leslie; Psychiatry, School of Medicine
    Background: Family history (FH) of substance use disorders (SUDs) is known to elevate SUD risk in offspring. However, the influence of FH SUDs has been confounded by the effect of externalizing psychopathologies in the addiction risk neuroimaging literature. Thus, the current study aimed to assess the association between parental SUDs and offspring functional connectivity in samples matched for psychopathology and demographics. Methods: Ninety 11-12-year-old participants with externalizing disorders were included in the study (48 FH+, 42 FH-). We conducted independent component analyses (ICA) and seed-based analyses (orbitofrontal cortex; OFC, nucleus accumbens (NAcc), dorsolateral prefrontal cortex) with resting state data. Results: FH+ adolescents showed stronger functional connectivity between the right lateral OFC seed and anterior cingulate cortex compared to FH- adolescents (p < 0.05, corrected). Compared to FH-, FH+ adolescents showed stronger negative functional connectivity between the left lateral OFC seed and right postcentral gyrus and between the left NAcc seed and right middle occipital gyrus (p < 0.05, corrected). Poorer emotion regulation was associated with more negative connectivity between right occipital/left NAcc among FH+ adolescents based on the seed-based analysis. FH- adolescents had stronger negative functional connectivity between ventral attention/salience networks and dorsal attention/visuospatial networks in the ICA. Conclusions: Both analytic methods found group differences in functional connectivity between brain regions associated with executive functioning and regions associated with sensory input (e.g., postcentral gyrus, occipital regions). We speculate that families densely loaded for SUD may confer risk by altered neurocircuitry that is associated with emotion regulation and valuation of external stimuli beyond what would be explained by externalizing psychopathology alone.