The presence of the casein kinase II phosphorylation sites of Vpu enhances the CD4+ T cell loss caused by the simian–human immunodeficiency virus SHIVKU-lbMC33 in pig-tailed macaques

AbstractThe simian–human immunodeficiency virus (SHIV)/ macaque model for human immunodeficiency virus type 1 has become a useful tool to assess the role of Vpu in lentivirus pathogenesis. In this report, we have mutated the two phosphorylated serine residues of the HIV-1 Vpu to glycine residues and have reconstructed a SHIV expressing this nonphosphorylated Vpu (SHIVS52,56G). Expression studies revealed that this protein was localized to the same intracellular compartment as wild-type Vpu. To determine if this virus was pathogenic, four pig-tailed macaques were inoculated with SHIVS52,56G and virus burdens and circulating CD4+ T cells monitored up to 1 year. Our results indicate that SHIVS52,56G caused rapid loss in the circulating CD4+ T cells within 3 weeks of inoculation in one macaque (CC8X), while the other three macaques developed no or gradual numbers of CD4+ T cells and a wasting syndrome. Histological examination of tissues revealed that macaque CC8X had lesions in lymphoid tissues (spleen, lymph nodes, and thymus) that were typical for macaques inoculated with pathogenic parental SHIVKU-1bMC33 and had no lesions within the CNS. To rule out that macaque CC8X had selected for a virus in which there was reversion of the glycine residues at positions 52 and 56 to serine residues and/or compensating mutations occurred in other genes associated with CD4 down-regulation, sequence analysis was performed on amplified vpu sequences isolated from PBMC and from several lymphoid tissues at necropsy. Sequence analysis revealed a reversion of the glycine residues back to serine residues in this macaque. The other macaques maintained low virus burdens, with one macaque (P003) developing a wasting syndrome between months 9 and 11. Histological examination of tissues from this macaque revealed a thymus with severe atrophy that was similar to that of a previously reported macaque inoculated with a SHIV lacking vpu (Virology 293, 2002, 252). Sequence analysis revealed no reversion of the glycine residues in the vpu sequences isolated from this macaque. These results contrast with those from four macaques inoculated with the parental pathogenic SHIVKU-1bMC33, all of which developed severe CD4+ T cell loss within 1 month after inoculation. Taken together, these results indicate that casein kinase II phosphorylation sites of Vpu contributes to the pathogenicity of the SHIVKU-1bMC33 and suggest that the SHIVKU-1bMC33/pig-tailed macaque model will be useful in analyzing amino acids/domains of Vpu that contribute to the pathogenesis of HIV-1

Protected area visitor data collection and management: Emerging issues and gaps in current Australian practices

Protected area agencies are charged with the preservation, conservation and management of areas including wilderness, national parks and forests. These agencies are faced with increasing visitor numbers and decreasing budgets at a time where activities like tourism have to be managed alongside their traditional roles as natural resource managers. This paper reports on the outcomes of the first stage of a research project that seeks to guide a nationally consistent approach to visitor use data collection for protected area agencies. First, the paper provides a background literature review of approaches to visitor use data collection for protected area agencies. Second, the paper outlines the participatory action research approach used in the study where thirteen protected area agencies are collaborators in the research process. This approach ensures that the protected areas agencies data needs are central to the research outcomes and recognises the pragmatic organisational cultural issues associated with visitor data collection, management and use. The research process incorporates organisational networking at all levels from head office, regions, branches and individual parks involving management information systems, interviews, focus groups, presentations, briefings and follow-up contact. Third, the paper then presents the emergent themes that examine the issues and gaps in current visitor data collection, management and use systems. The paper concludes with discussion of the challenges to developing a national system of visitor data collection and use

Hijacking cortical motor output with repetitive microstimulation

High-frequency repetitive microstimulation has been widely used as a method of investigating the properties of cortical motor output. Despite its widespread use, few studies have investigated how activity evoked by high-frequency stimulation may interact with the existing activity of cortical cells resulting from natural synaptic inputs. A reasonable assumption might be that the stimulus-evoked activity sums with the existing natural activity. However, another possibility is that the stimulus-evoked firing of cortical neurons might block and replace the natural activity. We refer to this latter possibility as “neural hijacking.” Evidence from analysis of EMG activity evoked by repetitive microstimulation (200 Hz, 500 ms) of primary motor cortex in two rhesus monkeys during performance of a reach-to-grasp task strongly supports the neural hijacking hypothesis

Methods for chronic recording of EMG activity from large numbers of hindlimb muscles in awake rhesus macaques

Studies of the neural control of movement often rely on the ability to record EMG activity during natural behavioral tasks over long periods of time. Increasing the number of recorded muscles and the time over which recordings are made allows more rigorous answers to many questions related to the descending control of motor output. Chronic recording of EMG activity from multiple hindlimb muscles has been reported in the cat but few studies have been done in non-human primates. This paper describes two chronic EMG implant methods that are minimally invasive, relatively non-traumatic and capable of recording from large numbers of hindlimb muscles simultaneously for periods of many months to years

Cortical output to fast and slow muscles of the ankle in the rhesus macaque.

The cortical control of fast and slow muscles of the ankle has been the subject of numerous reports yielding conflicting results. Although it is generally agreed that cortical stimulation yields short latency facilitation of fast muscles, the effects on the slow muscle, soleus, remain controversial. Some studies have shown predominant facilitation of soleus from the cortex while others have provided evidence of differential control in which soleus is predominantly inhibited from the cortex. The objective of this study was to investigate the cortical control of fast and slow muscles of the ankle using stimulus triggered averaging of EMG activity, which is a sensitive method of detecting output effects on muscle activity. This method also has relatively high spatial resolution and can be applied in awake, behaving subjects. Two rhesus macaques were trained to perform a hindlimb push-pull task. Stimulus triggered averages of EMG activity (15, 30 and 60 A at 15 Hz) were computed for four muscles of the ankle (tibialis anterior, medial gastrocnemius, lateral gastrocnemius and soleus) as the monkeys performed the task. Poststimulus facilitation was observed in both the fast muscles (tibialis anterior, medial and lateral gastrocnemius) as well as the slow muscle (soleus) and was as common and as strong in soleus as in the fast muscles. However, while poststimulus suppression was observed in all muscles, it was more common in the slow muscle compared to the fast muscles and was as common as facilitation at low stimulus intensities. Overall, our results demonstrate that cortical facilitation of soleus has an organization that is very similar to that of the fast ankle muscles. However, cortical inhibition is organized differently allowing for more prominent suppression of soleus motoneurons

An Experimental Investigation of Rating-Market Regulation

We introduce a simple game-theoretical model that captures the main aspects of the repeated interaction between an issuer and a credit rating agency. The scenario is characterized by up-front payments of issuer-fees and regulatory sanctions for false rating. We chose parameters such that in the Bayesian Nash equilibrium the credit rating agency should always provide truthful ratings. Knowing this, the issuer should never request a rating. Conducting laboratory experiments, we find that issuers frequently request ratings, which in turn is reciprocated with a high proportion of untruthful “good” ratings, even though the credit rating agency faces (low or high) financial penalties for being untruthful. Our results are different from the game-theoretical prediction but they are in keeping with a “cooperative solution”, similar to the “deterrence theory” in Reinard Selten’s “chain store paradox” (Selten, 1978)