Executive functioning involves the complex cognitive abilities to plan and execute multi-step tasks and process new information and is thought to be impaired

in chronic HIV infection as a result of widespread synaptodendritic injury to frontal-striato-thalamo-cortical brain circuits [17]. Such repair of this synaptodendritic injury may not occur immediately after controlling HIV viraemia with cART, and may explain the observation we have made in our study that executive function improvements occurred later than improvements in the other cognitive domains assessed. Cysique and colleagues have recently described changes in NC function over a 1-year period in 37 HIV-infected Selumetinib molecular weight subjects commencing cART, and, similar to our study findings, they observed peak improvements in NC function to occur after 24–36 weeks of therapy [15] with prolonged improvements observed over a 1-year period. However, allocation of cART within this cohort was based on clinician choice, restricting the interpretation of such observations to discern differences between different cART regimens. Also, not all subjects were naïve to cART and all subjects had documented

NC function impairment at baseline. Unlike our study, these selleckchem factors limited the relevance of these observations to HIV-infected neuro-asymptomatic subjects, who represent the majority of HIV-infected subjects commencing cART for the first time. While we have attributed improvements in NC function to the effects of commencing cART, we cannot fully account for confounding factors which may also have resulted in improvements in NC function over the study period. A control arm

within our study allocating subjects not to receive antiretroviral therapy would have strengthened our observations if no improvements ID-8 in NC function were observed in subjects allocated to this arm. However, such an approach would not be ethical or feasible as individuals selected to enter the study clinically required to commence antiretroviral therapy. Furthermore, cognitive function is likely to decline over time, rather than improve, and this decline has been reported to be greater in HIV-infected subjects [18], strengthening the argument that the improvements in NC function observed are secondary to commencing cART. Lastly, a learning effect may account for improvements in NC performance. However, all subjects undertook a practice NC test during the study screening period prior to the study baseline test used in our analysis in order to minimize effects of learning on the study results [10], and such effects would not explain the differences in improvements we observed between the study treatment arms.

The bacterium uses the pLcr plasmid-encoded type III secretion system to deliver virulence factors into host cells. Delivery requires ATP hydrolysis by the YscN ATPase

encoded by the yscN gene also on pLcr. A yscN mutant was constructed in the fully virulent CO92 strain containing a nonpolar, in-frame internal deletion within the gene. We demonstrate that CO92 with a yscN mutation was not able to secrete the LcrV protein (V-Antigen) and attenuated in a subcutaneous model of plague demonstrating that the YscN ATPase was essential for virulence. However, if the yscN mutant was complemented with a functional yscN gene in trans, virulence was restored. To evaluate the mutant as a live vaccine, Swiss–Webster mice were vaccinated twice with the ΔyscN mutant at varying doses and were protected against PCI-32765 mouse bubonic plague in a dose-dependent manner. Antibodies to F1 capsule but not to LcrV were detected in sera from the vaccinated mice. These preliminary results suggest a proof-of-concept for an attenuated, genetically engineered, live vaccine effective against bubonic plague. Yersinia pestis is a zoonotic bacterial agent responsible for bubonic and selleck chemical pneumonic plague, diseases which are transmitted through fleabites and aerosols, respectively (Perry & Fetherston,

1997). The bacterium uses a sophisticated virulence factor delivery system, the type III secretion system (T3SS), that is composed of the Ysc injectisome which secretes proteins referred to as Yops (Yersinia outer proteins) into host cells. The proteins for the T3SS are encoded by genes on the pCD1/pLcr plasmid (Cornelis et al., 1989; Straley, 1991). One of the Yops, LcrV, has various roles. It is surface-exposed prior to interacting with host cells, required for translocation of the effector Yops, and has some role

in Yop regulation (Nilles et al., 1998; Sarker et al., 1998a, b; Pettersson et al., 1999). Also, LcrV is highly antigenic and able to provide protection against plague challenges in animal models of disease (Une & Brubaker, 1984; Motin et al., 1994; Roggenkamp et al., 1997). While the delivery of some Rebamipide Yops may require chaperones for secretion, other Yops do not. Yop delivery also requires cell-to-cell contact (Rosqvist et al., 1994), but the identity of the human receptor for Y. pestis is not known. A Y. pestis T3SS-specific ATPase, designated YscN and also encoded on pCD1/pLcr, removes chaperones from the Yops before translocation into mammalian hosts (Payne & Straley, 1998, 1999). The process requires ATP hydrolysis, but the details of transport are unknown (Akeda & Galan, 2005). It has been hypothesized that the energy for the translocation may be generated by a proton gradient (Paul et al., 2008); however, this hypothesis remains controversial (Galan, 2008). The YscN protein is the only ATPase required for chaperone removal and possibly for the translocation through the pore.