5 research outputs found

    Phosphoinositide-dependent kinase l (PDK1) haplo-insufficiency inhibits production of alpha/beta (α/β) but not gamma delta (γ/δ) T lymphocytes

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    AbstractIn the present study, we have explored the impact of deleting a single allele of PDK1 in T cell progenitors on α/β and γ/δ T cell development. The data show that deleting a single allele of PDK1 allows differentiation of α/β T cells but prevents their proliferative expansion in the thymus. Accordingly, mice with T cells that are haplo-insufficient for PDK1 have reduced numbers of thymocytes and α/β peripheral T cells. T cell progenitors also give rise to γ/δ T cells but in contrast to the loss of α/β T cells in T-PDK1 null and haplo-insufficient mice, there were increased numbers of γ/δ T cells. The production of α/β T cells is dependent on the proliferative expansion of thymocytes and is determined by a balance between the frequency with which cells enter the proliferative phase of the cell cycle and rates of cell death. Herein, we show that PDK1 haplo-insufficient thymocytes have no defects in their ability to enter the cell cycle but show increased apoptosis. PDK1 thus plays a determining role in the development of α/β T lymphocytes but does not limit γ/δ T cell development

    Mood stabilizers inhibit cytomegalovirus infection

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    Cytomegalovirus (CMV) infection can generate debilitating disease in immunocompromised individuals and neonates. It is also the most common infectious cause of congenital birth defects in infected fetuses. Available anti-CMV drugs are partially effective but are limited by some toxicity, potential viral resistance, and are not recommended for fetal exposure. Valproate, valpromide, and valnoctamide have been used for many years to treat epilepsy and mood disorders. We report for the first time that, in contrast to the virus-enhancing actions of valproate, valpromide and valnoctamide evoke a substantial and specific inhibition of mouse and human CMV in vitro. In vivo, both drugs safely attenuate mouse CMV, improving survival, body weight, and developmental maturation of infected newborns. The compounds act by a novel mechanism that interferes with CMV attachment to the cell. Our work provides a novel potential direction for CMV therapeutics through repositioning of agents already approved for use in psychiatric disorders

    The Intestinal Epithelium: The Interface Between Host and Pathogen

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