The treatment of infected cells with Torin1 inhibits the phosphorylation of rapamycin-sensitive and rapamycin-resistant mTOR targets and markedly blocks the production of virus progeny. The blockade of mTOR signaling

with Torin1, but not rapamycin, disrupts the assembly of the eIF4F complex and increases the association of the translational repressor 4EBP1 to the 7-methylguanosine cap-binding complex. Torin1 does not affect HCMV entry and only modestly reduces the accumulation of the immediate-early and early viral proteins that were tested despite the disruption of the eIF4F complex. In contrast, Torin1 significantly decreases the accumulation of viral DNA and the pUL99 viral late protein. Similar

BAY 11-7082 chemical structure mTOR signaling events were observed during murine cytomegalovirus (MCMV) infection, and we utilized murine fibroblasts containing several different mutations to dissect the mechanism by which Torin1 inhibits MCMV replication. This approach demonstrated that mTORC2 and the Akt1 and Akt2 kinases are not required for the Torin1-mediated inhibition of cytomegalovirus replication. The inhibition of MCMV replication by Torin1 was rescued in cells lacking 4EBP1, demonstrating that the inactivation of 4EBP1 by mTORC1 is critical for cytomegalovirus replication. Finally, we show that Torin1 inhibits buy MX69 the replication of representative members of the alpha-, beta-, and gammaherpesvirus families, demonstrating the potential of mTOR kinase inhibitors as broad-spectrum antiviral agents.”
“The estrogen hypothesis of schizophrenia suggests that estrogen is a natural neuroprotector in women and that exogenous estrogen may have antipsychotic potential, but results of clinical studies have been inconsistent. second We have recently shown using the latent inhibition (LI) model of schizophrenia that 17 beta-estradiol exerts antipsychotic activity in ovariectomized (OVX) rats. The present study sought to extend the characterization of the antipsychotic

action of 17 beta-estradiol (10, 50 and 150 mu g/kg) by testing its capacity to reverse amphetamine-and MK-801-induced LI aberrations in gonadally intact female and male rats. No-drug controls of both sexes showed LI, ie, reduced efficacy of a previously non-reinforced stimulus to gain behavioral control when paired with reinforcement, if conditioned with two but not five tone-shock pairings. In both sexes, amphetamine (1 mg/kg) and MK-801 (50 mu g/kg) produced disruption (under weak conditioning) and persistence (under strong conditioning) of LI, modeling positive and negative/cognitive symptoms, respectively. 17 beta-estradiol at 50 and 150 mu g/kg potentiated LI under strong conditioning and reversed amphetamine-induced LI disruption in both males and females, mimicking the action of typical and atypical antipsychotic drugs (APDs) in the LI model.