The D 1 dopamine receptor, G protein ␥ 7 subunit, and adenylylcyclase are selectively expressed in the striatum, suggesting their potential interaction in a common signaling pathway. To evaluate this possibility, a ribozyme strategy was used to suppress the expression of the G protein . Studies suggest that imbalances between these two opposing classes lead to deficiencies in movement and cognitive performance (2, 3). In particular, alterations in the D 1 -like dopamine receptors are implicated in a variety of neurologic and psychiatric disorders, such as Parkinson's disease, Tourette's syndrome, and schizophrenia. Thus, achieving a better understanding of the D 1 -like dopamine receptors and the signaling pathways they activate may suggest more selective therapeutic targets in these diseases.The D 1 and D 5 dopamine receptors stimulate adenylylcyclase activity through their coupling to heterotrimeric G proteins (1, 4 -6). Because the function of these heterotrimeric G proteins was originally ascribed to the ␣ subunit, most research has focused on determining its identity. Of the several ␣ subunits identified to date, reconstitution studies have shown that coupling of D 1 dopamine receptors to adenylylcyclase can be mediated only by the ␣ s and ␣ olf subunits of the G s subclass (4, 5, 7-9). Although sharing 88% amino acid homology, the ␣s and ␣ olf subunits show very divergent expression patterns, ranging from the ubiquitous expression of the ␣ s subunit to the olfactory and neuron-specific expression of the ␣ olf subunit (10). Immunoprecipitation studies (11) have confirmed the interaction between the ␣ s subunit and the D 1 dopamine receptors in cells, whereas in situ hybridization (12, 13) and gene targeting (14) studies have suggested a possible interaction between the ␣ olf subunit and the D 1 dopamine receptor in striatum.By contrast, little effort has focused on determining the identity of the ␥ subunits of the G protein despite mounting evidence for their importance in receptor recognition (15,16). Of particular interest, reconstitution studies (17-21) and reverse genetic approaches (22,23) have shown that the nature of the ␥ subunit is an important determinant of its interaction with receptor. Consistent with such a role, 12 ␥ subunit genes have been identified that show extensive structural diversity (24). Recently, we used a ribozyme approach to begin to elucidate their functions (23,25,26). This approach identified the ␥ 7 subunit as a specific component of the G protein that couples the -adrenergic receptor, but not the prostaglandin E 1 receptor, to stimulation of adenylylcyclase in HEK 293 cells (23). Although expressed in a variety of tissues and cell types (27,28), the ␥ 7 subunit expression is most abundant in medium spiny neurons in striatum (13). This pattern of expression is shared by the D 1 dopamine receptor and adenylylcyclase (4, 12, 29 -31), raising the possibility that all of these components may be involved in the same signaling pathway. In the present study, we used the ribozyme ...
BackgroundMacaque models of simian or simian/human immunodeficiency virus (SIV or SHIV) infection are critical for the evaluation of antiretroviral (ARV)-based HIV treatment and prevention strategies. However, modelling human oral ARV administration is logistically challenging and fraught by limited adherence. Here, we developed a protocol for administering daily oral doses of ARVs to macaques with a high rate of compliance.MethodsParameters of positive reinforcement training (PRT), behavioral responses and optimal drug delivery foods were defined in 7 male rhesus macaques (Macaca mulatta). Animals were trained to sit in a specified cage location prior to receiving ARVs, emtricitabine (FTC) and tenofovir alafenamide (TAF), in a blended food mixture, which was followed immediately with a juice chaser. Consistency of daily oral adherence was evaluated in 4 trained macaques receiving clinically equivalent doses of FTC and TAF (20 and 1.5 mg/kg, respectively) in a short-term (1 month) and an extended (6 month) trial. Adherence was monitored using medication diaries and by quantifying intracellular FTC-triphosphate (FTC-TP) and tenofovir-diphosphate (TFV-DP) concentrations in peripheral mononuclear blood cells (PBMCs).ResultsTrained macaques quickly and consistently took daily oral ARVs for 1 month with an average 99.8% observed adherence. Intracellular concentrations of TFV-DP (median = 845.8 fmol/million cells [range, 620.8–1031.3]) and FTC-TP (median = 367.0 fmol/million cells [range, 289.5–413.5) in PBMCs were consistent with high adherence. Extended treatment with select subjects yielded similar observations for three months (99.5% adherence, 352/356 complete doses taken), although a sudden drop in adherence was observed after splenic biopsy surgery.ConclusionsWe demonstrate that trained macaques reliably adhere to a daily oral ARV regimen, although unexpected adherence issues are possible. Our approach, using clinical doses of oral FTC and TAF daily, further refines macaque models of HIV treatment and prevention by mimicking the human route and timing of ARV administration.
HHS Public Access Author Manuscript Author ManuscriptAuthor Manuscript Author ManuscriptThe Centers for Disease Control and Prevention (CDC) Quarantine Stations distribute select lifesaving drug products that are not commercially available or are in limited supply in the United States for emergency treatment of certain health conditions. Following a retrospective analysis of shipment records, the authors estimated an average of 6.66 hours saved per shipment when drug products were distributed from quarantine stations compared to a hypothetical centralized site from CDC headquarters in Atlanta, GA. This evaluation supports the continued use of a decentralized model which leverages CDC's regional presence and maximizes efficiency in the distribution of lifesaving drugs.
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